Source: Taylor and Francis Online

Abstract

Macroautophagy (herein referred to as autophagy) is a highly conserved mechanism for the lysosomal degradation of cytoplasmic components. Autophagy is critical for the maintenance of intracellular homeostasis, both in baseline conditions and in the context of adaptive responses to stress.

In line with this notion, defects in the autophagic machinery have been etiologically associated with various human disorders including infectious, inflammatory and neoplastic conditions.

Once tumors are established, however, autophagy sustains the survival of malignant cells, hence representing an appealing target for the design of novel anticancer regimens. Accordingly, inhibitors of autophagy including chloroquine and hydroxychloroquine have been shown to mediate substantial antineoplastic effects in preclinical models, especially when combined with chemo- or radiotherapeutic interventions.

The pharmacological profile of chloroquine and hydroxychloroquine, however, appear to involve mechanisms other than autophagy inhibition.

Here, we discuss the dual role of autophagy in oncogenesis and tumor progression, and summarize the results or design of clinical studies recently completed or initiated to evaluate the therapeutic activity of chloroquine derivatives in cancer patients.

Introduction

The term autophagy (from ancient Greek, αυτο/auto = “self” + φαγos, φαγεĩν/phagein = “to eat”; i.e., self-eating) cumulatively refers to a group of catabolic mechanisms involved in the maintenance of cell and tissue homeostasis in all eukaryotes. Autophagy plays an essential role in multiple physiological processes, including development, differentiation, normal growth and immunity.13 In line with this notion, defects in the executioner and regulatory mechanisms of autophagy have been involved in the etiology of a panel of clinically relevant disorders, including infectious, neurodegenerative and neoplastic diseases.1,46

Mammalian cells are endowed with at least 3 distinct autophagic pathways: macroautophagy, microautophagy, and chaperone-mediated autophagy.7,8 Macroautophagy (herein referred to as autophagy, for the sake of simplicity) is a highly conserved mechanism responsible for lysosomal degradation of cytoplasmic components, including invading pathogens, cytotoxic protein aggregates and damaged organelles.2,8 Autophagy relies on a peculiar double-membraned vesicle commonly known as autophagosome.9 Autophagosomes are generated in the cytoplasm from precursor organelles known as phagophores, which progressively enwrap the material to be degraded and – upon closure – fuse with lysosomes.911 This activates H+ pumps to lower the pH of the lysosomal lumen and hence unleash the catabolic activity of lysosomal hydrolases. The products of the degradation of the autophagic cargo eventually reach the cytosol through lysosomal permeases, hence becoming available for reuse in biosynthetic metabolic circuitries.12 A detailed description of the autophagic machinery and its regulators goes largely beyond the scope of the present Trial Watch and can be found in Refs.8,9,1318

Although autophagosomes were initially believed to take up cytoplasmic material in a relatively non-selective fashion, a growing body of evidence has revealed the existence of highly specialized autophagic pathways that selectively recognize their substrates. As a standalone example, mitophagy has been shown to specifically eliminate superfluous or damaged mitochondria, hence operating as a key quality control mechanism.1921

Beside operating to preserve cellular homeostasis in physiological conditions, autophagy responds to a wide variety of perturbations including nutrient and growth factor deprivation, hypoxia, pathogen invasion, and exposure to cytotoxic agents.2,22 In this setting, autophagy generally orchestrates a cell-wide adaptive response that aims at (1) physically removing the initiating stimulus (when possible), (2) coping with its cytotoxic effects, and (3) re-establishing cellular homeostasis. Thus, autophagy most often constitutes a cytoprotective response allowing cells to adapt to stressful conditions.23,24 However, in a limited number of scenarios, including the development of Caenorhabditis elegans25 and Drosophila melanogaster cells,2628 as well as the exposure of cancer cells to specific stimuli,2932 autophagy appears to mediate (at least in part) cell death. Only in such settings, i.e., when the pharmacological or genetic inhibition of the autophagic machinery delays (rather than accelerates) cell death, the term “autophagic cell death” should be employed to indicate a specific cell death subroutine.24,33,34

Along the lines of the Trial Watch series published on a monthly basis in OncoImmunology,3538 here we summarize the dual role of autophagy in oncogenesis and tumor progression and discuss recent clinical trials investigating the use of chloroquine (CQ), hydroxychloroquine (HCQ) in cancer patients. Importantly, although these agents were initially tested in oncological scenarios owing to their ability to inhibit autophagy, it is now clear that their therapeutic effects involve other mechanisms.3941

Autophagy and cancer

A large body of evidence suggests that the relationship between autophagy and cancer is complex.42,43 On the one hand, autophagy appears to inhibit malignant transformation, reflecting its capability to limit the accumulation of potentially oncogenic entities like depolarized mitochondria (which overproduce potentially genotoxic reactive oxygen species, ROS). On the other hand, autophagy supports the progression and metastatic dissemination of established tumors, increasing the ability of malignant cells to cope with adverse microenvironmental conditions like nutrient deprivation and hypoxia (two common denominators of rapidly growing solid tumors).

Autophagy in oncogenesis

Several distinct genetic manipulations that compromise (at least to some extent) the proficiency of the autophagic machinery have been shown to increase the propensity of laboratory animals to develop neoplastic lesions, be them spontaneous, genetically driven or chemically induced. This applies to the monoallelic loss of Beclin 1 (Becn1), coding for a key subunit of the class III phosphoinositide-3-kinase (PI3K) complex that controls the formation and elongation of autophagosomes;44,45 to the whole-body absence of autophagy related 4C, cysteine peptidase (Atg4c), encoding a protease involved in one of the conjugation systems required for autophagy;46 the whole-body or tissue-specific deletion of Atg5 and Atg7, coding for two of the components involved in the other of such conjugation systems;4750 as well as to the whole-body ablation of sequestosome 1 (SQSTM1), encoding an autophagic adaptor best known as p62.51 Apparently at odds with these data, the ablation of RB1-inducible coiled-coil 1 (Rb1cc1), coding for a component of the autophagic machinery also known as FIP200, has been reported to inhibit the development of mammary carcinomas in mice expressing the polyoma middle T antigen under the control of the mouse mammary tumor virus long-terminal repeat.52 Along similar lines, the monoallelic loss of Becn1 has been shown to limit mammary tumorigenesis driven by partner and localizer of BRCA2 (PALB2).53 However, it remains to be determined whether such effects truly depend on autophagy rather than reflecting indirect alterations of the tumor protein p53 (TP53, best known as p53) system.54,55 FIP200 is indeed known to influence the stability of p53 and the oncogenic effects of the Becn1+/− were lost in a conditionally Trp53-null background.53,56,57

Further demonstrating the oncosuppressive functions of autophagy, the monoallelic deletion of BECN1 has been detected in a large fraction (more than 40%) of human breast, ovarian and prostate carcinomas,1,58,59 while mutations in ATG5 and ATG12 have been documented in a proportion of colorectal neoplasms.60 Along similar lines, the expression levels of ATG5 and BECN1 are altered in various types of cancer,6170 leading some to speculate that the proficiency of the autophagic machinery may predict the propensity of a specific tissue to undergo malignant transformation. However, unambiguous clinical data in support of this hypothesis are missing.

Of note, several bona fide oncosuppressor proteins like phosphatase and tensin homolog (PTEN) and serine/threonine kinase 11 (STK11, best known as LKB1) stimulate autophagy, while multiple oncogenic pathways inhibit it.43 For instance, this applies to the hyperactivation of the PI3K-AKT1 signal transduction cascade,7175 to mutations that render the epidermal growth factor receptor (EGFR) constitutively active,76 as well as to the overexpression of anti-apoptotic Bcl-2 family members like B-cell CLL/lymphoma 2 (BCL2) itself and BCL2-like 1 (BCL2L1, best known as BCL-XL).43,77

The current hypothesis is that the suppression of autophagy would promote oncogenesis by (1) altering bioenergetic metabolism and favoring the establishment of oxidative stress, two strictly interdependent processes resulting from impaired mitochondrial turnover;42,7880 (2) fostering genomic instability, at least in part as a consequence of oxidative stress;8183) (3) impairing oncogene-induced senescence, a mechanism that permanently blocks the proliferation of malignant cells while allowing for their elimination by the immune system;68,8487 and (4) favoring the accumulation of p62-containing protein aggregates, which deliver oncogenic signals upon the activation of the transcription factor nuclear factor, erythroid 2-like 2 (NFE2L2, best known as NRF2).88,89 Finally, autophagy appears to be critically involved in immunogenic cell death, a peculiar type of apoptosis that is associated with the elicitation of an adaptive immune response.37,90,91 Thus, autophagy-deficient malignant cells are less prone than their autophagy-competent counterparts to be recognized and eliminated by the immune system,92 a situation that impacts both oncogenesis and tumor progression (see below). Along similar lines, recent data indicate that the ablation of Atg5 accelerates KRAS-driven oncogenesis while favoring tumor infiltration by immunosuppressive CD4+CD25+FOXP3+ regulatory T cells.48 Defects in the autophagic machinery might therefore promote oncogenesis not only by impairing the capacity of cells to cope with potentially tumorigenic stimuli, but also by compromising oncosuppressive pathways that are mediated by the tumor microenvironment.

Autophagy in tumor progression

It is now clear that established neoplastic lesions benefit from the preservation (or reactivation) of autophagic functions. Even in the absence of therapy, indeed, hematological and (especially so) solid malignancies are exposed to unfavorable microenvironmental conditions, including a limited availability of nutrients and low oxygen concentrations. In line with this notion, cancer cells from poorly vascularized, hypoxic tumor regions contain elevated amounts of autophagosomes, allowing them to deal with limited oxygen supplies.93 Moreover, several cell lines obtained from established cancers not only are characterized by increased levels of autophagy in baseline conditions, but also appear to require an elevated autophagic flux for the maintenance of metabolic functions and proliferation.80,94,95 These observations indicate that cancer cells rely on autophagy (at least to some extent) for coping with the metabolic and oxidative load imposed by the malignant phenotype.

Accumulating evidence corroborates the notion that autophagy promotes the progression of established cancers. First, the downregulation of Atg5 induces extensive central necrosis in Tsc2−/−xenografts, while the heterozygous loss of Becn1 limits the development of macroscopic renal tumors in Tsc2+/− mice.96 Second, the tissue-specific deletion of Atg5 or Atg7 reportedly arrests the progression of benign hepatomas to hepatocellular carcinomas (HCCs),47 of KRASG12D-driven pancreatic lesions to overtly malignant pancreatic ductal adenocarcinomas,50 as well as of KRASG12D– or BRAFV600E-driven pulmonary adenomas to lung adenocarcinomas,48 sometimes diverting it to the formation of relatively benign oncocytomas.49,97 Apparently in contrast with these observations, a tyrosine phosphomimetic variant of BECN1 has been shown to favor the growth, progression and resistance to therapy of non-small cell lung carcinoma (NSCLC) xenografts expressing constitutively active EGFR, an effect that correlated with a decrease in autophagic flux.76 However, it is difficult to determine to which extent this stems from the inhibition of autophagy as opposed to the increased availability of antiapoptotic BCL2-like proteins caused by BECN1 phosphorylation.75,98

The current view is that autophagy facilitates the progression of established neoplasms by (1) favoring their adaptation to adverse microenvironmental conditions, including limited nutrient availability and hypoxia; (2) preserving mitochondrial functions, both as it controls the quality of the mitochondrial network and as it provides metabolic substrates for mitochondrial metabolism; and (3) limiting the accumulation of potentially cytotoxic entities, such as ROS, which is accrued in malignant cells owing to both intracellular and extracellular alterations.

CQ derivatives in Cancer therapy

Preclinical and clinical studies

The notion that neoplastic cells of diverse histological origin require a proficient autophagic machinery to actively proliferate53,80,97,99101 in spite of adverse microenvironmental conditions, be them endogenous102,103 or elicited by therapy,74,104116 has rendered this catabolic pathway an attractive target for the development of novel antineoplastic agents.42,117119 Thus, throughout the past decade, distinct approaches based on the inhibition of autophagy have been conceived and evaluated (in vitro and in vivo) for their ability to (1) mediate therapeutic effects as standalone interventions, or (2) boost the antineoplastic activity of conventional or targeted chemotherapeutics. In these studies, autophagy was disabled either genetically, through the knockout of autophagy-relevant genes or the knockdown of their products,93,106,120126 or pharmacologically, by the administration of (1) lysosomotropic agents including CQ, HCQ, Lys0569 and monensin, all of which inhibit the fusion of autophagosomes with lysosomes and their degradation;74,112,115,120,127132 (2) class III PI3K inhibitors, such as 3-methyladenine, wortmannin, LY294002 and pyrvinium;109,122,126,130,133137 (3) the V-type ATPase inhibitor bafilomycin A1, which inhibits lysosomal acidification and hence the degradation of autophagosomes;121,125,138 (4) spautin-1, which promotes the ubiquitination-dependent degradation of BECN1.139142 All these interventions have been shown to exert anticancer effects or to boost the activity of conventional antineoplastic regimens. However, the antineoplastic effects of CQ and HCQ stem in large part from the modulation of pathways other than autophagy.3941 These lysosomotropic agents are indeed very efficient at inducing lysosomal membrane permeabilization, hence initiating the mitochondrial pathway of apoptosis.39,143 Moreover, CQ has recently been show to target cancer stem cells by inhibiting Janus kinase 2 (JAK2) signaling.144 The precise reasons why neoplastic cells appear to be more sensitive to CQ and HCQ than their non-transformed counterparts, however, remain to be elucidated.

The therapeutic potential of CQ, which has been widely employed (and is currently approved by the US Food and Drug Administration, FDA) for the prophylactic treatment of malaria (source http://www.fda.gov), has been investigated in a double-blinded clinical trial involving 30 patients with glioblastoma multiforme (NCT00224978).127 In this setting (a Phase III clinical trial), eligible patients with surgically confirmed glioblastoma were randomized to receive conventional chemotherapy and radiotherapy plus placebo or 150 mg/d CQ per os. Of note, although the study was insufficiently powered to detect a statistical difference in the survival rate of the study arms, CQ-receiving patients exhibited an improved mid-term survival as compared with their control counterparts.127 CQ has also been evaluated for its ability to boost the therapeutic activity of whole-brain radiation therapy (WBRT) in 20 patients bearing intracranial metastases of various histological derivation (NCT01894633).145 In the context of this single-cohort Phase II clinical study, CQ therapy (250 mg/day per os) was initiated 1 we before WBRT, and the primary endpoint was radiologic response. Five months after WBRT, 16 patients were evaluable, of which: 2 manifested a complete response, 13 a partial response and 1 disease stabilization. No treatment-related Grade 3/4 toxicities were recorded, and mean overall survival was 8.9 mo.145 As such a high intracranial disease control warrants further investigation, this clinical paradigm remains under investigation (see below).

The safety and antineoplastic activity of HCQ, a CQ derivative approved by the US FDA as an antimalarial drug as well as for the management of (chronic, discoid or systemic) lupus erythematosus and acute or chronic rheumatoid arthritis (source http://www.fda.gov), has recently been evaluated in 20 patients with metastatic pancreatic cancer that failed to respond to conventional treatments (NCT01273805).146 In this setting (a Phase II clinical trial), patients received 400 (n = 10) or 600 (n = 10) mg HCQ twice daily as a single therapeutic agent. Although this regimen was well tolerated (only 2 patients developed treatment-related Grade 3/4 side effects), only 2 individuals (10%) did not exhibit disease progression 2 mo after the initiation of HCQ.146 HCQ has also been investigated as a means to boost the therapeutic profile of erlotinib (an FDA-approved chemical inhibitor of EGFR)147150 in 27 subjects with advanced NSCLC (NCT01026844).114 In this 2-arms Phase I study, 8 patients were treated with HCQ only, while 19 received HCQ plus erlotinib. Only one patient experienced a partial response to erlotinib plus HCQ, but no dose-limiting toxicities related to HCQ were documented, and the authors recommended the use of 1000 mg/day HCQ in combination with 150 mg/day erlotinib for a subsequent Phase II study.114

Altogether, these preclinical and clinical observations suggest that CQ and HCQ may not mediate significant therapeutic benefits as standalone interventions but may exacerbate the effects of conventional anticancer agents.

Ongoing clinical trials

When this Trial Watch was being redacted (May 2014), official sources listed 39 ongoing clinical trials launched after 2007, January 1st to investigate the safety and therapeutic potential of CQ derivatives, either as a standalone therapeutic interventions or as part of combinatorial chemotherapeutic regimens, in cancer patients (http://www.clinicaltrials.gov/) (Table 1). Of these trials, 8 involve CQ and 31 HCQ. Of note, the latter is generally preferred to the former owing to its tolerability and toxicity profile.151,152

The safety and antineoplastic activity of CQ derivatives as standalone chemotherapeutic interventions are being assessed (1) in subjects with breast ductal carcinoma in situ, who receive CQ per os for 1 mo prior to surgical tumor excision (NCT01023477); (2) in prostate cancer patients, who are treated with HCQ upon raise in the circulating levels of prostate-specific antigen (PSA) (NCT00726596); and (3) in individuals with primary renal cell carcinoma (RCC), who receive HCQ orally for 14 d before surgery (NCT01144169).

In a vast majority of ongoing clinical trials, CQ derivatives are given in combination with conventional chemo-, radio- or immunotherapeutic regimens. In particular, the safety and efficacy of CQ are being tested: (1) in subjects with advanced or metastatic breast carcinoma resistant to anthracycline-based chemotherapy,37,90,91 who receive CQ in combination with microtubular poisons of the taxane or epothilone family153155 (NCT01446016); (2) in patients with Stage IV small cell lung carcinoma, who are treated with CQ in combination with conventional radiotherapy156,157 (NCT01575782) and/or DNA-damaging chemotherapeutic regimens including standard-dose cisplatin-etoposide158161 (NCT0969306); (3) in subjects with multiple myeloma, receiving CQ in combination with cyclophosphamide, an immunogenic alkylating agent,162,163 and bortezomib (NCT01438177); (4) in pancreatic cancer patients, who receive CQ in combination with the immunostimulatory chemotherapeutic gemcitabine164,165 (NCT01777477); (5) in patients with advanced solid tumors, receiving CQ together with gemcitabine and carboplatin (a cisplatin-derived DNA-damaging agent)166 (NCT02071537); and (6) in subjects bearing brain metastases from various neoplasms, who receive a short course of CQ in combination with WBRT (NCT01727531).

Moreover, HCQ is being investigated as means to improve the therapeutic profile of (1) neoadjuvant gemcitabine and/or paclitaxel protein-bound particles (Abraxane®), in individuals affected by advanced pancreatic carcinoma (NCT01506973; NCT01128296; NCT01978184); (2) the alkylating agent temozolomide,167169 in patients with metastatic or unresectable solid tumors (NCT00714181); (3) radiation therapy, in patients with high grade glioma (NCT01602588) or bearing bone metastases of diverse histological derivation (NCT01417403); (4) temozomolide and radiation therapy, in individuals with newly diagnosed glioblastoma multiforme (NCT00486603); (5) capecitabine (an antimetabolite currently employed for the treatment of several neoplasms)170 plus radiation therapy, in patients with resectable pancreatic cancer (NCT01494155); (6) capecitabine, oxaliplatin (an FDA-approved cisplatin derivative),171,172 and bevacizumab (a monoclonal antibody specific for vascular endothelial growth factor, VEGF),38,173175 in subjects with metastatic colorectal carcinoma (NCT01006369); (7) paclitaxel (an FDA-approved microtubular poison of the taxane family), carboplatin and bevacizumab, in NSCLC patients (NCT00933803; NCT01649947), (8) an oxaliplatin-based chemotherapeutic regimen combined with bevacizumab, in individuals affected by colorectal carcinoma (NCT01206530); (9) transarterial chemoembolization (TACE),176,177 in patients with unresectable HCC (NCT02013778); (10) the AKT1 inhibitor MK2206,178 in patients affected by advanced solid malignancies (NCT01480154); (11) rapamycin and/or vorinostat, in subjects with refractory soft tissue sarcomas (NCT01842594) or other solid tumors (NCT01023737; NCT01266057); (12) temsirolimus (an FDA-approved rapamycin derivative that also exerts antineoplastic effects by inhibiting mechanistic target of rapamycin, MTOR),179 in patients with metastatic solid tumors that failed to respond to conventional therapeutic regimens (NCT00909831); (13) everolimus (yet another rapamycin-like molecule licensed by the US FDA), in individuals with advanced RCC (NCT01510119); (14) sirolimus, cyclophosphamide and dexamethasone, in patients with relapsed or refractory multiple myeloma (NCT01689987); (15) erlotinib or gefitinib (a chemical inhibitor of EGFR currently licensed by the US FDA),148,180 in NSCLC patients (NCT00809237; NCT00977470); (16) imatinib (an FDA-approved inhibitor or BCR-ABL, KIT and platelet-derived growth factor receptor β),181,182 in individuals with chronic myeloid leukemia (NCT01227135); (17) sorafenib or sunitinib (two multi-kinase inhibitor nowadays approved by the US FDA for the treatment of various solid tumors),183188 in patients with refractory and/or relapsed solid tumors (NCT00813423; NCT01634893); (18) bortezomib, in subjects with refractory and/or relapsed multiple myeloma (NCT00568880); (19) vemurafenib (an FDA-approved inhibitor of mutant BRAF),189 in melanoma patients (NCT01897116); (20) ABT-263 (an experimental inhibitor of anti-apoptotic Bcl-2 family members)143,190,191 and abiraterone (an FDA-approved antiandrogen),192 in individuals with metastatic castration-resistant prostate cancer (NCT01828476); and (21) interleukin-2 (an immunostimulatory cytokine currently approved by the US FDA and other regulatory agencies for the treatment of metastatic forms of melanoma and RCC),193,194 in patients with metastatic RCC (NCT01550367).

Concluding remarks

Accumulating evidence suggests that inhibiting autophagy may constitute an efficient means to improve the therapeutic profile of chemo-, radio- and immunotherapeutic anticancer regimens.

However, autophagy not only sustains the survival of established neoplasm exposed to therapy, but also plays a key role in the maintenance of intracellular homeostasis in healthy tissues (de facto operating as an oncosuppressive mechanism),42,43 and is required for the elicitation of innate and adaptive immune responses.195 

This implies that the whole-body inhibition of autophagy may, at least theoretically, favor the insurgence of treatment-related neoplasms as well as of other disorders (e.g., infectious diseases, neurodegenerative conditions) and promote some degree of immunosuppression.

Moreover, the wide majority of autophagy inhibitors that have been investigated so far in clinical trials, in particular CQ and HCQ, influence lysosomal (and possibly non-lysosomal) processes other than autophagy.3941 

Indeed, the therapeutic activity of HQ and HCQ appears to stem mainly from the modulation of autophagy-unrelated mechanisms. Finally, autophagy seems to promote, rather than antagonize, the therapeutic activity of specific antineoplastic agents.76,196200 

Hence, the co-administration of autophagy inhibitors may decrease, rather than increase, the cytostatic/cytotoxic potential of a fraction of chemicals currently employed in anticancer therapy. Taken together, these notions suggest that modulating autophagy may constitute a powerful means to achieve superior antineoplastic effects, yet should be implemented with caution.

Future studies will have to elucidate whether and how autophagy can be modulated in a tissue- or cell-restricted manner that is compatible with clinical applications, as well as if biomarkers that predict the propensity of specific cancer patient subsets to autophagy regulators exist.

These discoveries as well as the identification of compounds that regulate autophagy in a highly specific manner will surely widen the clinical utility of this therapeutic paradigm.

Abbreviations:
BCL2B-cell CLL/lymphoma 2
BECN1Beclin 1
CQchloroquine
EGFRepidermal growth factor receptor
FDAFood and Drug Administration
HCChepatocellular carcinoma
HCQhydroxychloroquine
NSCLCnon-small-cell lung carcinoma
PI3Kphosphoinositide-3-kinase
RCCrenal cell carcinoma
ROSreactive oxygen species
WBRTwhole-brain radiation therapy

10.4161/mco.29911

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Authors are supported by the European Commission (ArtForce); Agence National de la Recherche (ANR); “Associazione Italiana per la Ricerca sul Cancro (AIRC);”. Ligue Nationale contre le Cancer; Fondation pour la Recherche Médicale (FRM); Institut National du Cancer (INCa); Association pour la Recherche sur le Cancer (ARC), LabEx Immuno-Oncologie; Fondation de France; Fondation Bettencourt-Schueller; AXA Chair for Longevity Research; Cancéropôle Ile-de-France, Paris Alliance of Cancer Research Institutes (PACRI) and Cancer Research for Personalized Medicine (CARPEM).

  • Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med 2013; 368:651 – 62; http://dx.doi.org/10.1056/NEJMra1205406; PMID: 23406030  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011; 147:728 – 41; http://dx.doi.org/10.1016/j.cell.2011.10.026; PMID: 22078875  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451:1069 – 75; http://dx.doi.org/10.1038/nature06639; PMID: 18305538  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132:27 – 42; http://dx.doi.org/10.1016/j.cell.2007.12.018; PMID: 18191218  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med 2013; 19:983 – 97; http://dx.doi.org/10.1038/nm.3232; PMID: 23921753  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell 2011; 146:682 – 95; http://dx.doi.org/10.1016/j.cell.2011.07.030; PMID: 21884931  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mijaljica D, Prescott M, Devenish RJ. Microautophagy in mammalian cells: revisiting a 40-year-old conundrum. Autophagy 2011; 7:673 – 82; http://dx.doi.org/10.4161/auto.7.7.14733; PMID: 21646866  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010; 22:124 – 31; http://dx.doi.org/10.1016/j.ceb.2009.11.014; PMID: 20034776  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol 2013; 14:759 – 74; http://dx.doi.org/10.1038/nrm3696; PMID: 24201109  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, Oomori H, Noda T, Haraguchi T, Hiraoka Y, et al. Autophagosomes form at ER-mitochondria contact sites. Nature 2013; 495:389 – 93; http://dx.doi.org/10.1038/nature11910; PMID: 23455425  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 2009; 11:1433 – 7; http://dx.doi.org/10.1038/ncb1991; PMID: 19898463  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kuma A, Mizushima N. Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin Cell Dev Biol 2010; 21:683 – 90; http://dx.doi.org/10.1016/j.semcdb.2010.03.002; PMID: 20223289  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mariño G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014; 15:81 – 94; http://dx.doi.org/10.1038/nrm3735; PMID: 24401948  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kraft C, Martens S. Mechanisms and regulation of autophagosome formation. Curr Opin Cell Biol 2012; 24:496 – 501; http://dx.doi.org/10.1016/j.ceb.2012.05.001; PMID: 22664348  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Codogno P, Mehrpour M, Proikas-Cezanne T. Canonical and non-canonical autophagy: variations on a common theme of self-eating?. Nat Rev Mol Cell Biol 2012; 13:7 – 12; PMID: 22166994  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 2011; 27:107 – 32; http://dx.doi.org/10.1146/annurev-cellbio-092910-154005; PMID: 21801009  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010; 90:1383 – 435; http://dx.doi.org/10.1152/physrev.00030.2009; PMID: 20959619  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43:67 – 93; http://dx.doi.org/10.1146/annurev-genet-102808-114910; PMID: 19653858  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Green DR, Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell 2014; 157:65 – 75; http://dx.doi.org/10.1016/j.cell.2014.02.049; PMID: 24679527  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol 2011; 12:9 – 14; http://dx.doi.org/10.1038/nrm3028; PMID: 21179058  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 2011; 333:1109 – 12; http://dx.doi.org/10.1126/science.1201940; PMID: 21868666  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010; 40:280 – 93; http://dx.doi.org/10.1016/j.molcel.2010.09.023; PMID: 20965422  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Boya P, González-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Métivier D, Meley D, Souquere S, Yoshimori T, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 2005; 25:1025 – 40; http://dx.doi.org/10.1128/MCB.25.3.1025-1040.2005; PMID: 15657430  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012; 19:107 – 20; http://dx.doi.org/10.1038/cdd.2011.96; PMID: 21760595  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Erdélyi P, Borsos E, Takács-Vellai K, Kovács T, Kovács AL, Sigmond T, Hargitai B, Pásztor L, Sengupta T, Dengg M, et al. Shared developmental roles and transcriptional control of autophagy and apoptosis in Caenorhabditis elegans. J Cell Sci 2011; 124:1510 – 8; http://dx.doi.org/10.1242/jcs.080192; PMID: 21502138  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Berry DL, Baehrecke EH. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 2007; 131:1137 – 48; http://dx.doi.org/10.1016/j.cell.2007.10.048; PMID: 18083103  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Denton D, Shravage B, Simin R, Mills K, Berry DL, Baehrecke EH, Kumar S. Autophagy, not apoptosis, is essential for midgut cell death in Drosophila. Curr Biol 2009; 19:1741 – 6; http://dx.doi.org/10.1016/j.cub.2009.08.042; PMID: 19818615  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Nezis IP, Shravage BV, Sagona AP, Lamark T, Bjørkøy G, Johansen T, Rusten TE, Brech A, Baehrecke EH, Stenmark H. Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis. J Cell Biol 2010; 190:523 – 31; http://dx.doi.org/10.1083/jcb.201002035; PMID: 20713604  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Grandér D, Kharaziha P, Laane E, Pokrovskaja K, Panaretakis T. Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies. Autophagy 2009; 5:1198 – 200; http://dx.doi.org/10.4161/auto.5.8.10122; PMID: 19855186  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Laane E, Tamm KP, Buentke E, Ito K, Kharaziha P, Oscarsson J, Corcoran M, Björklund AC, Hultenby K, Lundin J, et al. Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy. Cell Death Differ 2009; 16:1018 – 29; http://dx.doi.org/10.1038/cdd.2009.46; PMID: 19390558  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Lamy L, Ngo VN, Emre NC, Shaffer AL 3rd, Yang Y, Tian E, Nair V, Kruhlak MJ, Zingone A, Landgren O, et al. Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell 2013; 23:435 – 49; http://dx.doi.org/10.1016/j.ccr.2013.02.017; PMID: 23541952  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Liu Y, Shoji-Kawata S, Sumpter RM Jr., Wei Y, Ginet V, Zhang L, Posner B, Tran KA, Green DR, Xavier RJ, et al. Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc Natl Acad Sci U S A 2013; 110:20364 – 71; http://dx.doi.org/10.1073/pnas.1319661110; PMID: 24277826  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Denton D, Nicolson S, Kumar S. Cell death by autophagy: facts and apparent artefacts. Cell Death Differ 2012; 19:87 – 95; http://dx.doi.org/10.1038/cdd.2011.146; PMID: 22052193  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kroemer G, Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 2008; 9:1004 – 10; http://dx.doi.org/10.1038/nrm2529; PMID: 18971948  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Aranda F, Vacchelli E, Eggermont A, Galon J, Fridman WH, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Immunostimulatory monoclonal antibodies in cancer therapy. Oncoimmunology 2014; 3:e27297; http://dx.doi.org/10.4161/onci.27297; PMID: 24701370  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Aranda F, Vacchelli E, Eggermont A, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Peptide vaccines in cancer therapy. Oncoimmunology 2013; 2:e26621; http://dx.doi.org/10.4161/onci.26621; PMID: 24498550  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Vacchelli E, Aranda F, Eggermont A, Galon J, Sautès-Fridman C, Cremer I, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 2014; 3:e27878; http://dx.doi.org/10.4161/onci.27878; PMID: 24800173  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Vacchelli E, Aranda F, Eggermont A, Galon J, Sautès-Fridman C, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy. Oncoimmunology 2014; 3:e27048; http://dx.doi.org/10.4161/onci.27048; PMID: 24605265  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Boya P, Gonzalez-Polo RA, Poncet D, Andreau K, Vieira HL, Roumier T, Perfettini JL, Kroemer G. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 2003; 22:3927 – 36; http://dx.doi.org/10.1038/sj.onc.1206622; PMID: 12813466  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Maycotte P, Aryal S, Cummings CT, Thorburn J, Morgan MJ, Thorburn A. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy 2012; 8:200 – 12; http://dx.doi.org/10.4161/auto.8.2.18554; PMID: 22252008  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 2012; 11:709 – 30; http://dx.doi.org/10.1038/nrd3802; PMID: 22935804  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012; 12:401 – 10; http://dx.doi.org/10.1038/nrc3262; PMID: 22534666  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Morselli E, Galluzzi L, Kepp O, Mariño G, Michaud M, Vitale I, Maiuri MC, Kroemer G. Oncosuppressive functions of autophagy. Antioxid Redox Signal 2011; 14:2251 – 69; http://dx.doi.org/10.1089/ars.2010.3478; PMID: 20712403  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112:1809 – 20; http://dx.doi.org/10.1172/JCI20039; PMID: 14638851  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 2003; 100:15077 – 82; http://dx.doi.org/10.1073/pnas.2436255100; PMID: 14657337  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mariño G, Salvador-Montoliu N, Fueyo A, Knecht E, Mizushima N, López-Otín C. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J Biol Chem 2007; 282:18573 – 83; http://dx.doi.org/10.1074/jbc.M701194200; PMID: 17442669  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K, Mizushima N. Autophagy-deficient mice develop multiple liver tumors. Genes Dev 2011; 25:795 – 800; http://dx.doi.org/10.1101/gad.2016211; PMID: 21498569  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Rao S, Tortola L, Perlot T, Wirnsberger G, Novatchkova M, Nitsch R, Sykacek P, Frank L, Schramek D, Komnenovic V, et al. A dual role for autophagy in a murine model of lung cancer. Nat Commun 2014; 5:3056; http://dx.doi.org/10.1038/ncomms4056; PMID: 24445999  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, Chen G, Price S, Lu W, Teng X, et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev 2013; 27:1447 – 61; http://dx.doi.org/10.1101/gad.219642.113; PMID: 23824538  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Rosenfeldt MT, O’Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 2013; 504:296 – 300; http://dx.doi.org/10.1038/nature12865; PMID: 24305049  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, Moscat J. The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell 2008; 13:343 – 54; http://dx.doi.org/10.1016/j.ccr.2008.02.001; PMID: 18394557  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Wei H, Wei S, Gan B, Peng X, Zou W, Guan JL. Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev 2011; 25:1510 – 27; http://dx.doi.org/10.1101/gad.2051011; PMID: 21764854  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Huo Y, Cai H, Teplova I, Bowman-Colin C, Chen G, Price S, Barnard N, Ganesan S, Karantza V, White E, et al. Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer. Cancer Discov 2013; 3:894 – 907; http://dx.doi.org/10.1158/2159-8290.CD-13-0011; PMID: 23650262  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ganley IG, Lam H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 2009; 284:12297 – 305; http://dx.doi.org/10.1074/jbc.M900573200; PMID: 19258318  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009; 20:1992 – 2003; http://dx.doi.org/10.1091/mbc.E08-12-1249; PMID: 19225151  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Morselli E, Shen S, Ruckenstuhl C, Bauer MA, Mariño G, Galluzzi L, Criollo A, Michaud M, Maiuri MC, Chano T, et al. p53 inhibits autophagy by interacting with the human ortholog of yeast Atg17, RB1CC1/FIP200. Cell Cycle 2011; 10:2763 – 9; http://dx.doi.org/10.4161/cc.10.16.16868; PMID: 21775823  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Melkoumian ZK, Peng X, Gan B, Wu X, Guan JL. Mechanism of cell cycle regulation by FIP200 in human breast cancer cells. Cancer Res 2005; 65:6676 – 84; http://dx.doi.org/10.1158/0008-5472.CAN-04-4142; PMID: 16061648  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC, Levine B. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999; 59:59 – 65; http://dx.doi.org/10.1006/geno.1999.5851; PMID: 10395800  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402:672 – 6; http://dx.doi.org/10.1038/45257; PMID: 10604474  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Kim SS, Ahn CH, Yoo NJ, Lee SH. Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability. J Pathol 2009; 217:702 – 6; http://dx.doi.org/10.1002/path.2509; PMID: 19197948  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Li BX, Li CY, Peng RQ, Wu XJ, Wang HY, Wan DS, Zhu XF, Zhang XS. The expression of beclin 1 is associated with favorable prognosis in stage IIIB colon cancers. Autophagy 2009; 5:303 – 6; http://dx.doi.org/10.4161/auto.5.3.7491; PMID: 19066461  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Chen Y, Lu Y, Lu C, Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1alpha expression. Pathol Oncol Res 2009; 15:487 – 93; http://dx.doi.org/10.1007/s12253-008-9143-8; PMID: 19130303  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kim HS, Lee SH, Do SI, Lim SJ, Park YK, Kim YW. Clinicopathologic correlation of beclin-1 expression in pancreatic ductal adenocarcinoma. Pathol Res Pract 2011; 207:247 – 52; http://dx.doi.org/10.1016/j.prp.2011.02.007; PMID: 21420796  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Jiang ZF, Shao LJ, Wang WM, Yan XB, Liu RY. Decreased expression of Beclin-1 and LC3 in human lung cancer. Mol Biol Rep 2012; 39:259 – 67; http://dx.doi.org/10.1007/s11033-011-0734-1; PMID: 21556768  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ding ZB, Shi YH, Zhou J, Qiu SJ, Xu Y, Dai Z, Shi GM, Wang XY, Ke AW, Wu B, et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res 2008; 68:9167 – 75; http://dx.doi.org/10.1158/0008-5472.CAN-08-1573; PMID: 19010888  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Pirtoli L, Cevenini G, Tini P, Vannini M, Oliveri G, Marsili S, Mourmouras V, Rubino G, Miracco C. The prognostic role of Beclin 1 protein expression in high-grade gliomas. Autophagy 2009; 5:930 – 6; http://dx.doi.org/10.4161/auto.5.7.9227; PMID: 19556884  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Huang JJ, Zhu YJ, Lin TY, Jiang WQ, Huang HQ, Li ZM. Beclin 1 expression predicts favorable clinical outcome in patients with diffuse large B-cell lymphoma treated with R-CHOP. Hum Pathol 2011; 42:1459 – 66; http://dx.doi.org/10.1016/j.humpath.2010.12.014; PMID: 21450329  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Liu H, He Z, von Rütte T, Yousefi S, Hunger RE, Simon HU. Down-regulation of autophagy-related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma. Sci Transl Med 2013; 5:ra123; http://dx.doi.org/10.1126/scitranslmed.3005864; PMID: 24027027  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L, Wu XY, Xu J, Long ZJ, Zhao Y, et al. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 2010; 6:395 – 404; http://dx.doi.org/10.4161/auto.6.3.11303; PMID: 20150769  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Kim MS, Song SY, Lee JY, Yoo NJ, Lee SH. Expressional and mutational analyses of ATG5 gene in prostate cancers. APMIS 2011; 119:802 – 7; http://dx.doi.org/10.1111/j.1600-0463.2011.02812.x; PMID: 21995634  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Degtyarev M, De Mazière A, Orr C, Lin J, Lee BB, Tien JY, Prior WW, van Dijk S, Wu H, Gray DC, et al. Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 2008; 183:101 – 16; http://dx.doi.org/10.1083/jcb.200801099; PMID: 18838554  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, Haas-Kogan D, James CD, Oakes SA, Debnath J, et al. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 2010; 3:ra81; http://dx.doi.org/10.1126/scisignal.2001017; PMID: 21062993  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Lamoureux F, Thomas C, Crafter C, Kumano M, Zhang F, Davies BR, Gleave ME, Zoubeidi A. Blocked autophagy using lysosomotropic agents sensitizes resistant prostate tumor cells to the novel Akt inhibitor AZD5363. Clin Cancer Res 2013; 19:833 – 44; http://dx.doi.org/10.1158/1078-0432.CCR-12-3114; PMID: 23258740  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Firat E, Weyerbrock A, Gaedicke S, Grosu AL, Niedermann G. Chloroquine or chloroquine-PI3K/Akt pathway inhibitor combinations strongly promote γ-irradiation-induced cell death in primary stem-like glioma cells. PLoS One 2012; 7:e47357; http://dx.doi.org/10.1371/journal.pone.0047357; PMID: 23091617  [Crossref][PubMed][Google Scholar]
  • Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27:5497 – 510; http://dx.doi.org/10.1038/onc.2008.245; PMID: 18794884  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G, Kinch L, Koduru P, Christudass CS, Veltri RW, et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 2013; 154:1269 – 84; http://dx.doi.org/10.1016/j.cell.2013.08.015; PMID: 24034250  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, Kroemer G. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ 2009; 16:87 – 93; http://dx.doi.org/10.1038/cdd.2008.131; PMID: 18806760  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discov 2013; 12:829 – 46; http://dx.doi.org/10.1038/nrd4145; PMID: 24113830  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007; 21:1621 – 35; http://dx.doi.org/10.1101/gad.1565707; PMID: 17606641  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell’antonio G, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev 2011; 25:717 – 29; http://dx.doi.org/10.1101/gad.2016111; PMID: 21406549  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S, White E. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007; 21:1367 – 81; http://dx.doi.org/10.1101/gad.1545107; PMID: 17510285  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Xie R, Wang F, McKeehan WL, Liu L. Autophagy enhanced by microtubule- and mitochondrion-associated MAP1S suppresses genome instability and hepatocarcinogenesis. Cancer Res 2011; 71:7537 – 46; http://dx.doi.org/10.1158/0008-5472.CAN-11-2170; PMID: 22037873  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Rello-Varona S, Lissa D, Shen S, Niso-Santano M, Senovilla L, Mariño G, Vitale I, Jemaá M, Harper F, Pierron G, et al. Autophagic removal of micronuclei. Cell Cycle 2012; 11:170 – 6; http://dx.doi.org/10.4161/cc.11.1.18564; PMID: 22185757  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Iannello A, Thompson TW, Ardolino M, Lowe SW, Raulet DH. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med 2013; 210:2057 – 69; http://dx.doi.org/10.1084/jem.20130783; PMID: 24043758  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445:656 – 60; http://dx.doi.org/10.1038/nature05529; PMID: 17251933  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Iannello A, Raulet DH. Immunosurveillance of senescent cancer cells by natural killer cells. Oncoimmunology 2014; 3:e27616; http://dx.doi.org/10.4161/onci.27616; PMID: 24800169  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, Tavaré S, Arakawa S, Shimizu S, Watt FM, et al. Autophagy mediates the mitotic senescence transition. Genes Dev 2009; 23:798 – 803; http://dx.doi.org/10.1101/gad.519709; PMID: 19279323  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Øvervatn A, McMahon M, Hayes JD, Johansen T. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 2010; 285:22576 – 91; http://dx.doi.org/10.1074/jbc.M110.118976; PMID: 20452972  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O, Watanabe S, Ando J, Iwadate M, Yamamoto M, et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol 2011; 193:275 – 84; http://dx.doi.org/10.1083/jcb.201102031; PMID: 21482715  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Vacchelli E, Senovilla L, Eggermont A, Fridman WH, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 2013; 2:e23510; http://dx.doi.org/10.4161/onci.23510; PMID: 23687621  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31:51 – 72; http://dx.doi.org/10.1146/annurev-immunol-032712-100008; PMID: 23157435  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, Shen S, Kepp O, Scoazec M, Mignot G, et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011; 334:1573 – 7; http://dx.doi.org/10.1126/science.1208347; PMID: 22174255  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gélinas C, Fan Y, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10:51 – 64; http://dx.doi.org/10.1016/j.ccr.2006.06.001; PMID: 16843265  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 2011; 25:460 – 70; http://dx.doi.org/10.1101/gad.2016311; PMID: 21317241  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Wang Y, Wang XD, Lapi E, Sullivan A, Jia W, He YW, Ratnayaka I, Zhong S, Goldin RD, Goemans CG, et al. Autophagic activity dictates the cellular response to oncogenic RAS. Proc Natl Acad Sci U S A 2012; 109:13325 – 30; http://dx.doi.org/10.1073/pnas.1120193109; PMID: 22847423  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ, et al. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 2011; 108:12455 – 60; http://dx.doi.org/10.1073/pnas.1104361108; PMID: 21746920  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Chen S, Guan JL. Tumor-promoting and -suppressive roles of autophagy in the same mouse model of BrafV600E-driven lung cancer. Cancer Discov 2013; 3:1225 – 7; http://dx.doi.org/10.1158/2159-8290.CD-13-0664; PMID: 24203955  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Chen N, Karantza-Wadsworth V. Role and regulation of autophagy in cancer. Biochim Biophys Acta 2009; 1793:1516 – 23; http://dx.doi.org/10.1016/j.bbamcr.2008.12.013; PMID: 19167434  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mancias JD, Kimmelman AC. Targeting autophagy addiction in cancer. Oncotarget 2011; 2:1302 – 6; PMID: 22185891  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Guo JY, Xia B, White E. Autophagy-mediated tumor promotion. Cell 2013; 155:1216 – 9; http://dx.doi.org/10.1016/j.cell.2013.11.019; PMID: 24315093  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 2014; 124:1406 – 17; http://dx.doi.org/10.1172/JCI70454; PMID: 24569374  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, Mazure NM. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 2009; 29:2570 – 81; http://dx.doi.org/10.1128/MCB.00166-09; PMID: 19273585  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Wilkinson S, O’Prey J, Fricker M, Ryan KM. Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity. Genes Dev 2009; 23:1283 – 8; http://dx.doi.org/10.1101/gad.521709; PMID: 19487569  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Zhuang W, Qin Z, Liang Z. The role of autophagy in sensitizing malignant glioma cells to radiation therapy. Acta Biochim Biophys Sin (Shanghai) 2009; 41:341 – 51; http://dx.doi.org/10.1093/abbs/gmp028; PMID: 19430698  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Lomonaco SL, Finniss S, Xiang C, Decarvalho A, Umansky F, Kalkanis SN, Mikkelsen T, Brodie C. The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells. Int J Cancer 2009; 125:717 – 22; http://dx.doi.org/10.1002/ijc.24402; PMID: 19431142  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Sun WL, Chen J, Wang YP, Zheng H. Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development. Autophagy 2011; 7:1035 – 44; http://dx.doi.org/10.4161/auto.7.9.16521; PMID: 21646864  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Mukubou H, Tsujimura T, Sasaki R, Ku Y. The role of autophagy in the treatment of pancreatic cancer with gemcitabine and ionizing radiation. Int J Oncol 2010; 37:821 – 8; PMID: 20811703  [PubMed][Web of Science ®][Google Scholar]
  • Li J, Hou N, Faried A, Tsutsumi S, Kuwano H. Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model. Eur J Cancer 2010; 46:1900 – 9; http://dx.doi.org/10.1016/j.ejca.2010.02.021; PMID: 20231086  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Liu D, Yang Y, Liu Q, Wang J. Inhibition of autophagy by 3-MA potentiates cisplatin-induced apoptosis in esophageal squamous cell carcinoma cells. Med Oncol 2011; 28:105 – 11; http://dx.doi.org/10.1007/s12032-009-9397-3; PMID: 20041317  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ding ZB, Hui B, Shi YH, Zhou J, Peng YF, Gu CY, Yang H, Shi GM, Ke AW, Wang XY, et al. Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. Clin Cancer Res 2011; 17:6229 – 38; http://dx.doi.org/10.1158/1078-0432.CCR-11-0816; PMID: 21825039  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Josset E, Burckel H, Noël G, Bischoff P. The mTOR inhibitor RAD001 potentiates autophagic cell death induced by temozolomide in a glioblastoma cell line. Anticancer Res 2013; 33:1845 – 51; PMID: 23645729  [PubMed][Web of Science ®][Google Scholar]
  • Selvakumaran M, Amaravadi RK, Vasilevskaya IA, O’Dwyer PJ. Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy. Clin Cancer Res 2013; 19:2995 – 3007; http://dx.doi.org/10.1158/1078-0432.CCR-12-1542; PMID: 23461901  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Han W, Pan H, Chen Y, Sun J, Wang Y, Li J, Ge W, Feng L, Lin X, Wang X, et al. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One 2011; 6:e18691; http://dx.doi.org/10.1371/journal.pone.0018691; PMID: 21655094  [Crossref][PubMed][Google Scholar]
  • Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P, Temel JS, Heist RS, Shaw AT, McCarthy PO, et al. A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. J Thorac Oncol 2012; 7:1602 – 8; http://dx.doi.org/10.1097/JTO.0b013e318262de4a; PMID: 22878749  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Carew JS, Medina EC, Esquivel JA 2nd, Mahalingam D, Swords R, Kelly K, Zhang H, Huang P, Mita AC, Mita MM, et al. Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J Cell Mol Med 2010; 14:2448 – 59; http://dx.doi.org/10.1111/j.1582-4934.2009.00832.x; PMID: 19583815  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Xie X, White EP, Mehnert JM. Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma. PLoS One 2013; 8:e55096; http://dx.doi.org/10.1371/journal.pone.0055096; PMID: 23383069  [Crossref][PubMed][Google Scholar]
  • Maycotte P, Thorburn A. Autophagy and cancer therapy. Cancer Biol Ther 2011; 11:127 – 37; http://dx.doi.org/10.4161/cbt.11.2.14627; PMID: 21178393  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Janku F, McConkey DJ, Hong DS, Kurzrock R. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 2011; 8:528 – 39; http://dx.doi.org/10.1038/nrclinonc.2011.71; PMID: 21587219  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Lorin S, Hamaï A, Mehrpour M, Codogno P. Autophagy regulation and its role in cancer. Semin Cancer Biol 2013; 23:361 – 79; http://dx.doi.org/10.1016/j.semcancer.2013.06.007; PMID: 23811268  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Katayama M, Kawaguchi T, Berger MS, Pieper RO. DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ 2007; 14:548 – 58; http://dx.doi.org/10.1038/sj.cdd.4402030; PMID: 16946731  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117:326 – 36; http://dx.doi.org/10.1172/JCI28833; PMID: 17235397  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A. Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 2007; 14:500 – 10; http://dx.doi.org/10.1038/sj.cdd.4402039; PMID: 16990848  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Qadir MA, Kwok B, Dragowska WH, To KH, Le D, Bally MB, Gorski SM. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res Treat 2008; 112:389 – 403; http://dx.doi.org/10.1007/s10549-007-9873-4; PMID: 18172760  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res 2010; 70:7699 – 709; http://dx.doi.org/10.1158/0008-5472.CAN-10-1626; PMID: 20876807  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Zou Z, Yuan Z, Zhang Q, Long Z, Chen J, Tang Z, Zhu Y, Chen S, Xu J, Yan M, et al. Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells. Autophagy 2012; 8:1798 – 810; http://dx.doi.org/10.4161/auto.22110; PMID: 23026799  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Pan X, Zhang X, Sun H, Zhang J, Yan M, Zhang H. Autophagy inhibition promotes 5-fluorouraci-induced apoptosis by stimulating ROS formation in human non-small cell lung cancer A549 cells. PLoS One 2013; 8:e56679; http://dx.doi.org/10.1371/journal.pone.0056679; PMID: 23441212  [Crossref][PubMed][Google Scholar]
  • Sotelo J, Briceño E, López-González MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2006; 144:337 – 43; http://dx.doi.org/10.7326/0003-4819-144-5-200603070-00008; PMID: 16520474  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Sasaki K, Tsuno NH, Sunami E, Tsurita G, Kawai K, Okaji Y, Nishikawa T, Shuno Y, Hongo K, Hiyoshi M, et al. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer 2010; 10:370; http://dx.doi.org/10.1186/1471-2407-10-370; PMID: 20630104  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • McAfee Q, Zhang Z, Samanta A, Levi SM, Ma XH, Piao S, Lynch JP, Uehara T, Sepulveda AR, Davis LE, et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci U S A 2012; 109:8253 – 8; http://dx.doi.org/10.1073/pnas.1118193109; PMID: 22566612  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • O’Donovan TR, O’Sullivan GC, McKenna SL. Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics. Autophagy 2011; 7:509 – 24; http://dx.doi.org/10.4161/auto.7.5.15066; PMID: 21325880  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW, Wang XY, Dai Z, Peng YF, Gu CY, et al. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy 2011; 7:1159 – 72; http://dx.doi.org/10.4161/auto.7.10.16818; PMID: 21691147  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Xu CX, Zhao L, Yue P, Fang G, Tao H, Owonikoko TK, Ramalingam SS, Khuri FR, Sun SY. Augmentation of NVP-BEZ235’s anticancer activity against human lung cancer cells by blockage of autophagy. Cancer Biol Ther 2011; 12:549 – 55; http://dx.doi.org/10.4161/cbt.12.6.16397; PMID: 21738008  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Li J, Hou N, Faried A, Tsutsumi S, Takeuchi T, Kuwano H. Inhibition of autophagy by 3-MA enhances the effect of 5-FU-induced apoptosis in colon cancer cells. Ann Surg Oncol 2009; 16:761 – 71; http://dx.doi.org/10.1245/s10434-008-0260-0; PMID: 19116755  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Leng S, Hao Y, Du D, Xie S, Hong L, Gu H, Zhu X, Zhang J, Fan D, Kung HF. Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy. Int J Cancer 2013; 133:2781 – 90; PMID: 23737395  [PubMed][Web of Science ®][Google Scholar]
  • Chen YS, Song HX, Lu Y, Li X, Chen T, Zhang Y, Xue JX, Liu H, Kan B, Yang G, et al. Autophagy inhibition contributes to radiation sensitization of esophageal squamous carcinoma cells. Dis Esophagus 2011; 24:437 – 43; http://dx.doi.org/10.1111/j.1442-2050.2010.01156.x; PMID: 21166739  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Liu F, Liu D, Yang Y, Zhao S. Effect of autophagy inhibition on chemotherapy-induced apoptosis in A549 lung cancer cells. Oncol Lett 2013; 5:1261 – 5; PMID: 23599776  [PubMed][Web of Science ®][Google Scholar]
  • Deng L, Lei Y, Liu R, Li J, Yuan K, Li Y, Chen Y, Liu Y, Lu Y, Edwards CK 3rd, et al. Pyrvinium targets autophagy addiction to promote cancer cell death. Cell Death Dis 2013; 4:e614; http://dx.doi.org/10.1038/cddis.2013.142; PMID: 23640456  [Crossref][PubMed][Google Scholar]
  • Cerniglia GJ, Karar J, Tyagi S, Christofidou-Solomidou M, Rengan R, Koumenis C, Maity A. Inhibition of autophagy as a strategy to augment radiosensitization by the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Mol Pharmacol 2012; 82:1230 – 40; http://dx.doi.org/10.1124/mol.112.080408; PMID: 22989521  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Shao S, Li S, Qin Y, Wang X, Yang Y, Bai H, Zhou L, Zhao C, Wang C. Spautin-1, a novel autophagy inhibitor, enhances imatinib-induced apoptosis in chronic myeloid leukemia. Int J Oncol 2014; 44:1661 – 8; PMID: 24585095  [PubMed][Web of Science ®][Google Scholar]
  • Vakifahmetoglu-Norberg H, Kim M, Xia HG, Iwanicki MP, Ofengeim D, Coloff JL, Pan L, Ince TA, Kroemer G, Brugge JS, et al. Chaperone-mediated autophagy degrades mutant p53. Genes Dev 2013; 27:1718 – 30; http://dx.doi.org/10.1101/gad.220897.113; PMID: 23913924  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mateo R, Nagamine CM, Spagnolo J, Méndez E, Rahe M, Gale M Jr., Yuan J, Kirkegaard K. Inhibition of cellular autophagy deranges dengue virion maturation. J Virol 2013; 87:1312 – 21; http://dx.doi.org/10.1128/JVI.02177-12; PMID: 23175363  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L, Cai Y, Norberg HV, Zhang T, Furuya T, et al. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 2011; 147:223 – 34; http://dx.doi.org/10.1016/j.cell.2011.08.037; PMID: 21962518  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Galluzzi L, Kepp O, Kroemer G. Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol 2012; 13:780 – 8; http://dx.doi.org/10.1038/nrm3479; PMID: 23175281  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Choi DS, Blanco E, Kim YS, Rodriguez AA, Zhao H, Huang TH, Chen CL, Jin G, Landis MD, Burey LA, et al. Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells 2014; Forthcoming http://dx.doi.org/10.1002/stem.1746; PMID: 24809620  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Eldredge HB, Denittis A, Duhadaway JB, Chernick M, Metz R, Prendergast GC. Concurrent Whole Brain Radiotherapy and Short-Course Chloroquine in Patients with Brain Metastases: A Pilot Trial. J Radiat Oncol 2013; 2. [Google Scholar]
  • Wolpin BM, Rubinson DA, Wang X, Chan JA, Cleary JM, Enzinger PC, Fuchs CS, McCleary NJ, Meyerhardt JA, Ng K, et al. Phase II and Pharmacodynamic Study of Autophagy Inhibition Using Hydroxychloroquine in Patients With Metastatic Pancreatic Adenocarcinoma. Oncologist 2014; 19:637 – 8; http://dx.doi.org/10.1634/theoncologist.2014-0086; PMID: 24821822  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Boehrer S, Adès L, Braun T, Galluzzi L, Grosjean J, Fabre C, Le Roux G, Gardin C, Martin A, de Botton S, et al. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. Blood 2008; 111:2170 – 80; http://dx.doi.org/10.1182/blood-2007-07-100362; PMID: 17925489  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008; 358:1160 – 74; http://dx.doi.org/10.1056/NEJMra0707704; PMID: 18337605  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000; 19:6550 – 65; http://dx.doi.org/10.1038/sj.onc.1204082; PMID: 11426640  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, et al, National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353:123 – 32; http://dx.doi.org/10.1056/NEJMoa050753; PMID: 16014882  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010; 69:20 – 8; http://dx.doi.org/10.1136/ard.2008.101766; PMID: 19103632  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Gunja N, Roberts D, McCoubrie D, Lamberth P, Jan A, Simes DC, Hackett P, Buckley NA. Survival after massive hydroxychloroquine overdose. Anaesth Intensive Care 2009; 37:130 – 3; PMID: 19157361  [PubMed][Web of Science ®][Google Scholar]
  • Hoffmann J, Vitale I, Buchmann B, Galluzzi L, Schwede W, Senovilla L, Skuballa W, Vivet S, Lichtner RB, Vicencio JM, et al. Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone. Cancer Res 2008; 68:5301 – 8; http://dx.doi.org/10.1158/0008-5472.CAN-08-0237; PMID: 18593931  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Doménech E, Malumbres M. Mitosis-targeting therapies: a troubleshooting guide. Curr Opin Pharmacol 2013; 13:519 – 28; http://dx.doi.org/10.1016/j.coph.2013.03.011; PMID: 23583638  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004; 4:253 – 65; http://dx.doi.org/10.1038/nrc1317; PMID: 15057285  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Galluzzi L, Kepp O, Kroemer G. Immunogenic cell death in radiation therapy. Oncoimmunology 2013; 2:e26536; http://dx.doi.org/10.4161/onci.26536; PMID: 24404424  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Vacchelli E, Vitale I, Tartour E, Eggermont A, Sautès-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Anticancer radioimmunotherapy. Oncoimmunology 2013; 2:e25595; http://dx.doi.org/10.4161/onci.25595; PMID: 24319634  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M, Kroemer G. Molecular mechanisms of cisplatin resistance. Oncogene 2012; 31:1869 – 83; http://dx.doi.org/10.1038/onc.2011.384; PMID: 21892204  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A, Castedo M, Kroemer G. Systems biology of cisplatin resistance: past, present and future. Cell Death Dis 2014; 5:e1257; http://dx.doi.org/10.1038/cddis.2013.428; PMID: 24874729  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Basu B, Yap TA, Molife LR, de Bono JS. Targeting the DNA damage response in oncology: past, present and future perspectives. Curr Opin Oncol 2012; 24:316 – 24; http://dx.doi.org/10.1097/CCO.0b013e32835280c6; PMID: 22476188  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature 2012; 481:287 – 94; http://dx.doi.org/10.1038/nature10760; PMID: 22258607  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Walter S, Weinschenk T, Reinhardt C, Singh-Jasuja H. Single-dose cyclophosphamide synergizes with immune responses to the renal cell cancer vaccine IMA901. Oncoimmunology 2013; 2:e22246; http://dx.doi.org/10.4161/onci.22246; PMID: 23482454  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Malvicini M, Alaniz L, Bayo J, Garcia M, Piccioni F, Fiore E, Atorrasagasti C, Aquino JB, Matar P, Mazzolini G. Single low-dose cyclophosphamide combined with interleukin-12 gene therapy is superior to a metronomic schedule in inducing immunity against colorectal carcinoma in mice. Oncoimmunology 2012; 1:1038 – 47; http://dx.doi.org/10.4161/onci.20684; PMID: 23170252  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 2013; 39:74 – 88; http://dx.doi.org/10.1016/j.immuni.2013.06.014; PMID: 23890065  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 2012; 11:215 – 33; http://dx.doi.org/10.1038/nrd3626; PMID: 22301798  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell 2010; 40:179 – 204; http://dx.doi.org/10.1016/j.molcel.2010.09.019; PMID: 20965415  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Danson SJ, Middleton MR. Temozolomide: a novel oral alkylating agent. Expert Rev Anticancer Ther 2001; 1:13 – 9; http://dx.doi.org/10.1586/14737140.1.1.13; PMID: 12113120  [Taylor & Francis Online][Google Scholar]
  • Margison GP, Santibáñez Koref MF, Povey AC. Mechanisms of carcinogenicity/chemotherapy by O6-methylguanine. Mutagenesis 2002; 17:483 – 7; http://dx.doi.org/10.1093/mutage/17.6.483; PMID: 12435845  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Michels J, Vitale I, Galluzzi L, Adam J, Olaussen KA, Kepp O, Senovilla L, Talhaoui I, Guegan J, Enot DP, et al. Cisplatin resistance associated with PARP hyperactivation. Cancer Res 2013; 73:2271 – 80; http://dx.doi.org/10.1158/0008-5472.CAN-12-3000; PMID: 23554447  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Walko CM, Lindley C. Capecitabine: a review. Clin Ther 2005; 27:23 – 44; http://dx.doi.org/10.1016/j.clinthera.2005.01.005; PMID: 15763604  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Culy CR, Clemett D, Wiseman LR. Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 2000; 60:895 – 924; http://dx.doi.org/10.2165/00003495-200060040-00005; PMID: 11085200  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Raymond E, Faivre S, Chaney S, Woynarowski J, Cvitkovic E. Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther 2002; 1:227 – 35; PMID: 12467217  [PubMed][Web of Science ®][Google Scholar]
  • Vacchelli E, Eggermont A, Galon J, Sautès-Fridman C, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Monoclonal antibodies in cancer therapy. Oncoimmunology 2013; 2:e22789; http://dx.doi.org/10.4161/onci.22789; PMID: 23482847  [Taylor & Francis Online][Google Scholar]
  • Muhsin M, Graham J, Kirkpatrick P. Bevacizumab. Nat Rev Drug Discov 2004; 3:995 – 6; http://dx.doi.org/10.1038/nrd1601; PMID: 15645606  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3:391 – 400; http://dx.doi.org/10.1038/nrd1381; PMID: 15136787  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Giunchedi P, Maestri M, Gavini E, Dionigi P, Rassu G. Transarterial chemoembolization of hepatocellular carcinoma. Agents and drugs: an overview. Part 1. Expert Opin Drug Deliv 2013; 10:679 – 90; http://dx.doi.org/10.1517/17425247.2013.770733; PMID: 23406440  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Kerr SH, Kerr DJ. Novel treatments for hepatocellular cancer. Cancer Lett 2009; 286:114 – 20; http://dx.doi.org/10.1016/j.canlet.2009.07.001; PMID: 19664880  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Pal SK, Reckamp K, Yu H, Figlin RA. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 2010; 19:1355 – 66; http://dx.doi.org/10.1517/13543784.2010.520701; PMID: 20846000  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5:671 – 88; http://dx.doi.org/10.1038/nrd2062; PMID: 16883305  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • de La Motte Rouge T, Galluzzi L, Olaussen KA, Zermati Y, Tasdemir E, Robert T, Ripoche H, Lazar V, Dessen P, Harper F, et al. A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib. Cancer Res 2007; 67:6253 – 62; http://dx.doi.org/10.1158/0008-5472.CAN-07-0538; PMID: 17616683  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 2002; 1:493 – 502; http://dx.doi.org/10.1038/nrd839; PMID: 12120256  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Ostman A, Heldin CH. PDGF receptors as targets in tumor treatment. Adv Cancer Res 2007; 97:247 – 74; http://dx.doi.org/10.1016/S0065-230X(06)97011-0; PMID: 17419949  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kharaziha P, De Raeve H, Fristedt C, Li Q, Gruber A, Johnsson P, Kokaraki G, Panzar M, Laane E, Osterborg A, et al. Sorafenib has potent antitumor activity against multiple myeloma in vitro, ex vivo, and in vivo in the 5T33MM mouse model. Cancer Res 2012; 72:5348 – 62; http://dx.doi.org/10.1158/0008-5472.CAN-12-0658; PMID: 22952216  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kharaziha P, Rodriguez P, Li Q, Rundqvist H, Björklund AC, Augsten M, Ullén A, Egevad L, Wiklund P, Nilsson S, et al. Targeting of distinct signaling cascades and cancer-associated fibroblasts define the efficacy of Sorafenib against prostate cancer cells. Cell Death Dis 2012; 3:e262; http://dx.doi.org/10.1038/cddis.2012.1; PMID: 22278289  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Abrams TJ, Murray LJ, Pesenti E, Holway VW, Colombo T, Lee LB, Cherrington JM, Pryer NK. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with “standard of care” therapeutic agents for the treatment of breast cancer. Mol Cancer Ther 2003; 2:1011 – 21; PMID: 14578466  [PubMed][Web of Science ®][Google Scholar]
  • Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D, Bortolon E, Ichetovkin M, Chen C, McNabola A, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 2007; 59:561 – 74; http://dx.doi.org/10.1007/s00280-006-0393-4; PMID: 17160391  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003; 101:3597 – 605; http://dx.doi.org/10.1182/blood-2002-07-2307; PMID: 12531805  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64:7099 – 109; http://dx.doi.org/10.1158/0008-5472.CAN-04-1443; PMID: 15466206  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 2008; 105:3041 – 6; http://dx.doi.org/10.1073/pnas.0711741105; PMID: 18287029  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008; 68:3421 – 8; http://dx.doi.org/10.1158/0008-5472.CAN-07-5836; PMID: 18451170  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10:389 – 99; http://dx.doi.org/10.1016/j.ccr.2006.08.027; PMID: 17097561  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Reid AH, Attard G, Barrie E, de Bono JS. CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol 2008; 5:610 – 20; http://dx.doi.org/10.1038/ncpuro1237; PMID: 18985049  [Crossref][PubMed][Google Scholar]
  • Vacchelli E, Eggermont A, Fridman WH, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Immunostimulatory cytokines. Oncoimmunology 2013; 2:e24850; http://dx.doi.org/10.4161/onci.24850; PMID: 24073369  [Taylor & Francis Online][Web of Science ®][Google Scholar]
  • Vacchelli E, Aranda F, Obrist F, Eggermont A, Galon J, Cremer I, et al. Trial Watch: Immunostimulatory cytokines in cancer therapy. OncoImmunology 2014; 3:e29030; http://dx.doi.org/10.4161/onci.29030  [Taylor & Francis Online][Google Scholar]
  • Ma Y, Galluzzi L, Zitvogel L, Kroemer G. Autophagy and cellular immune responses. Immunity 2013; 39:211 – 27; http://dx.doi.org/10.1016/j.immuni.2013.07.017; PMID: 23973220  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Bareford MD, Park MA, Yacoub A, Hamed HA, Tang Y, Cruickshanks N, Eulitt P, Hubbard N, Tye G, Burow ME, et al. Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Cancer Res 2011; 71:4955 – 67; http://dx.doi.org/10.1158/0008-5472.CAN-11-0898; PMID: 21622715  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Elgendy M, Sheridan C, Brumatti G, Martin SJ. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol Cell 2011; 42:23 – 35; http://dx.doi.org/10.1016/j.molcel.2011.02.009; PMID: 21353614  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Gump JM, Staskiewicz L, Morgan MJ, Bamberg A, Riches DW, Thorburn A. Autophagy variation within a cell population determines cell fate through selective degradation of Fap-1. Nat Cell Biol 2014; 16:47 – 54; http://dx.doi.org/10.1038/ncb2886; PMID: 24316673  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Kohli L, Kaza N, Coric T, Byer SJ, Brossier NM, Klocke BJ, Bjornsti MA, Carroll SL, Roth KA. 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Cancer Res 2013; 73:4395 – 405; http://dx.doi.org/10.1158/0008-5472.CAN-12-3765; PMID: 23722551  [Crossref][PubMed][Web of Science ®][Google Scholar]
  • Voss V, Senft C, Lang V, Ronellenfitsch MW, Steinbach JP, Seifert V, Kögel D. The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Mol Cancer Res 2010; 8:1002 – 16; http://dx.doi.org/10.1158/1541-7786.MCR-09-0562; PMID: 20587533  [Crossref][PubMed][Web of Science ®][Google Scholar]

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