Targeting autophagy with small molecules for cancer therapy

Abstract

Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine, etc.) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5’-monophosphate-activated protein kinase (e.g., sulforaphane). The study results suggest that many potential “druggable” targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.

Keywords

Autophagy / cancer / ATG / ULK inhibitor / Vps34 inhibitor / mammalian target of rapamycin inhibitors / lysosome fusion inhibitors

References

[1] Morel E,Botti J,Hamaï A.Autophagy: a druggable process..Annu Rev Pharmacol Toxicol2017;57:375-98

[2] Saha S,Patil S.Autophagy in health and disease: a comprehensive review..Biomed Pharmacother2018;104:485-95

[3] Masui A,Kameyama H,Takasu A.Autophagy as a survival mechanism for squamous cell carcinoma cells in endonuclease g-mediated apoptosis..PLoS One2016;11:1-19 PMCID:PMC5033396

[4] Towers CG.Therapeutic targeting of autophagy..EBioMedicine2016;14:15-23 PMCID:PMC5161418

[5] Li W,Mao Z.Chaperone-mediated autophagy: machinery, regulation and biological consequences..Cell Mol Life Sci2011;68:749-63

[6] Li WW,Bao JK.Microautophagy: lesser-known self-eating..Cell Mol Life Sci2012;69:1125-36

[7] Yoshii SR.Monitoring and measuring autophagy..Int J Mol Sci2017;18:1-13 PMCID:PMC5618514

[8] Nascimbeni AC,Dupont N,Vaccaro MI.ER-plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI3P synthesis..EMBO J2017;36:2018-33 PMCID:PMC5509996

[9] Nakamura S.New insights into autophagosome-lysosome fusion..J Cell Sci2017;130:1209-16

[10] Klionsky DJ,Deretic V.Autophagosomes, phagosomes, autolysosomes, phagolysosomes, autophagolysosomes... wait, I’m confused..Autophagy2014;10:549-51 PMCID:PMC4091142

[11] Fang Y,Zhang Q.Signaling pathways and mechanisms of hypoxia-induced autophagy in the animal cells..Cell Biol Int2015;39:891-8

[12] Thorburn A.Autophagy and disease..J Biol Chem2018;293:5425-30 PMCID:PMC5900754

[13] Eskelinen EL.Autophagy: a lysosomal degradation pathway with a central role in health and disease..Biochim Biophys Acta - Mol Cell Res2009;1793:664-73

[14] Dikic I.Mechanism and medical implications of mammalian autophagy..Nat Rev Mol Cell Biol2018;19:349-64

[15] Amaravadi R,White E.Recent insights into the function of autophagy in cancer..Genes Dev2016;30:1913-30 PMCID:PMC5066235

[16] Zachari M.The mammalian ULK1 complex and autophagy initiation..Essays Biochem2017;61:585-96 PMCID:PMC5869855

[17] Tanida I.Autophagy basics..Microbiol Immunol2011;55:1-11

[18] Dunlop EA,Acosta-Jaquez HA,Tee AR.ULK1 inhibits mTORC1 signaling, promotes multisite raptor phosphorylation and hinders substrate binding..Autophagy2011;7:737-47 PMCID:PMC3149699

[19] Roach PJ.AMPK -> ULK1 -> autophagy..Mol Cell Biol2011;31:3082-4 PMCID:PMC3147606

[20] Lin S-Y,Liu Q,Li X.GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy..Science2012;336:477-81

[21] Pyo JO,Jung YK.Molecules and their functions in autophagy..Exp Mol Med2012;44:73-80 PMCID:PMC3296815

[22] Mercer TJ,Tooze SA.A molecular perspective of mammalian autophagosome biogenesis..J Biol Chem2018;293:5386-95 PMCID:PMC5900756

[23] Kang R,Lotze MT.The beclin 1 network regulates autophagy and apoptosis..Cell Death Differ2011;18:571-80 PMCID:PMC3131912

[24] Kim JH,Lee JK,Roh KH.Insights into autophagosome maturation revealed by the structures of ATG5 with its interacting partners..Autophagy2015;11:75-87 PMCID:PMC4502675

[25] Sakoh-Nakatogawa M,Asai E,Ishii J.Atg12-Atg5 conjugate enhances E2 activity of Atg3 by rearranging its catalytic site..Nat Struct Mol Biol2013;20:433-9

[26] Lao Y.Autophagy in cancer chemoprevention: identifcation of novel autophagy modulators with anticancer potential..Compr Toxicol Second Ed2016;1379:151-63

[27] Manni D. Oxidation-dependent regulation of the selective autophagy receptor SQSTM1/p62. Available from: https://theses.ncl.ac.uk/dspace/handle/10443/3675 [Last accessed on 3 Apr 2019]

[28] Weidberg H,Shpilka T,Shinder V.LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis..EMBO J2010;29:1792-802 PMCID:PMC2885923

[29] Fader CM,Furlán M.Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in K562 cells..Traffic2008;9:230-50

[30] Lee JA,Ahmad ST,Gao FB.Escrt-III dysfunction causes autophagosome accumulation and neurodegeneration..Curr Biol2007;17:1561-7

[31] Li C,Warren LK.Skeletal muscle from aged American Quarter Horses shows impairments in mitochondrial biogenesis and expression of autophagy markers..Exp Gerontol2018;102:19-27

[32] Mawatwal S,Ghosh A,Mishra A.Calcimycin mediates mycobacterial killing by inducing intracellular calcium-regulated autophagy in a P2RX7 dependent manner..Biochim Biophys Acta - Gen Subj2017;1861:3190-200

[33] Settembre C,Rubinsztein DC.Lysosomal storage diseases as disorders of autophagy..Autophagy2008;4:113-4

[34] Cai Y,Yang L,Periyasamy P.Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders..Autophagy2016;12:225-44 PMCID:PMC4835965

[35] Singh SS,Chia AYQ,Deng S.Dual role of autophagy in hallmarks of cancer..Oncogene2018;37:1142-58

[36] Comel A,Capaci V.The cytoplasmic side of p53’s oncosuppressive activities..FEBS Lett2014;588:2600-9

[37] Choi AM,Levine B.Autophagy in human health and disease..N Engl J Med2013;368:651-62

[38] Takahashi Y,Matsushita N,Sun M.Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis..Nat Cell Biol2007;9:1142-51 PMCID:PMC2254521

[39] Coppola D,Eschrich SA,Yeatman T.Down-regulation of bax-interacting factor-1 in colorectal adenocarcinoma..Cancer2008;113:2665-70 PMCID:PMC2614910

[40] He S,Yang Y,Zhang X.Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers..Nat Commun2015;6:7839 PMCID:PMC4526116

[41] Perera RM,Nicolay BN,Fitamant J.Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism..Nature2015;524:361-5 PMCID:PMC5086585

[42] Fulda S.Autophagy in cancer therapy..Front Oncol2017;7:128 PMCID:PMC5475391

[43] Thorburn A.Autophagy and its effects: making sense of double-edged swords..PLoS Biol2014;12:e1001967 PMCID:PMC4196727

[44] Yun CW.The roles of autophagy in cancer..Int J Mol Sci2018;19:3466 PMCID:PMC6274804

[45] Koustas E,Karamouzis MV.The role of autophagy in the treatment of BRAF mutant colorectal carcinomas differs based on microsatellite instability status..PLoS One2018;13:e0207227 PMCID:PMC6241137

[46] Boutouja F,Mastalski T,Platta HW.Regulation of the tumor-suppressor beclin 1 by distinct ubiquitination cascades..Int J Mol Sci2017;18:E2541 PMCID:PMC5751144

[47] Miracco C,Oliveri G,Pacenti L.Protein and mRNA expression of autophagy gene beclin 1 in human brain tumours..Int J Oncol2007;30:429-36

[48] Yang ZJ,Huang S.The role of autophagy in cancer: therapeutic implications..Mol Cancer Ther2011;10:1533-41 PMCID:PMC3170456

[49] Kang MR,Oh JE,Song SY.Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATGI2 in gastric and colorectal cancers with microsatellite instability..J Pathol2009;217:702-6

[50] Lipinski MM,Ng A,Py BF.A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions..Dev Cell2010;18:1041-52 PMCID:PMC2935848

[51] Tang F,Yang Z,Gong J.SBI0206965, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways..Oncol Rep2017;37:3449-58

[52] Bellot G,Gounon P,Roux D.Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains..Mol Cell Biol2009;29:2570-81 PMCID:PMC2682037

[53] Karnoub AE.Ras oncogenes: split personalities..Nat Rev Mol Cell Biol2008;9:517-31 PMCID:PMC3915522

[54] Ahn JH.Autophagy-dependent survival of mutant B-Raf melanoma cells selected for resistance to apoptosis induced by inhibitors against oncogenic B-Raf..Biomol Ther2013;21:114-20 PMCID:PMC3762312

[55] Russo M.Autophagy inducers in cancer..Biochem Pharmacol2018;153:51-61

[56] He S,Jiang X,Feng F.Design of small molecule autophagy modulators: a promising druggable strategy..J Med Chem2018;61:4656-87

[57] Kwitkowski VE,Ibrahim A,Justice R.FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma..Oncologist2010;15:428-35 PMCID:PMC3227966

[58] Koschmann C,Kasaian K,Zamler D.Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event..NPJ Precis Oncol2017;1:32 PMCID:PMC5871904

[59] Klionsky DJ,Deretic V.Autophagosomes, phagosomes, autolysosomes, phagolysosomes, autophagolysosomes… wait, I’m confused..Autophagy2014;10:549-51 PMCID:PMC4091142

[60] Wymann MP,Zvelebil MJ,Vanhaesebroeck B.Wortmannin inactivates phosphoinositide 3-Kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction..Mol Cell Biol1996;16:1722-33 PMCID:PMC231159

[61] McNamara CR.Small-molecule inhibitors of the PI3K signaling network..Future Med Chem2011;3:549-65 PMCID:PMC3132554

[62] Gharbi SI,Shuttleworth SJ,Saghir N.Exploring the specificity of the PI3K family inhibitor LY294002..Biochem J2007;404:15-21 PMCID:PMC1868829

[63] Harding JJ,Tan DSW,Rodon J.Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor..Invest New Drugs2019;37:271-81 PMCID:PMC6440935

[64] Knight SD,Burgess JL,Darcy MG.Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin..ACS Med Chem Lett2010;1:39-43 PMCID:PMC4007793

[65] Basu D,Bauer B,Patel JR.The dual PI3K/mToR inhibitor omipalisib/GSK2126458 inhibits clonogenic growth in oncogenically-transformed cells from neurocutaneous melanocytosis..Cancer Genomics and Proteomics2018;15:239-48 PMCID:PMC6070711

[66] Liu Q,Kirubakaran S,Hur W.Characterization of torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR..Cancer Res2013;73:2574-86 PMCID:PMC3760004

[67] Nelson EE.The development of the ventral prefrontal cortex and social flexibility..Dev Cogn Neurosci2011;1:233-45 PMCID:PMC3143481

[68] Chresta CM,Hickson I,Cosulich S.AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity..Cancer Res2010;70:288-98

[69] Wang L,Wang S.Autophagy inhibition sensitizes WYE-354-induced anti-colon cancer activity in vitro and in vivo..Tumor Biol2016;37:11743-52

[70] Park S,Bardet V,Gallay N.PI-103, a dual inhibitor of class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML..Leukemia2008;22:1698-706

[71] Mallon R,Lucas J,Dehnhardt C.Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor..Clin Cancer Res2011;17:3193-203

[72] Powles T,Oudard S,Ralph C.Randomized open-label phase II trial of apitolisib (GDC-0980), a novel inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma..J Clin Oncol2016;34:1660-8 PMCID:PMC5569691

[73] Simioni C,Martelli AM,Alameen AA.The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells..Oncotarget2015;6:17147-60 PMCID:PMC4627298

[74] Li H,Zhang Z,Kong X.Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP-BEZ235 in renal cell carcinoma cells..Cell Biochem Funct2013;31:427-33

[75] Lazarus MB,Shokat KM.Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors..ACS Chem Biol2015;10:257-61 PMCID:PMC4301081

[76] Martin KR,Solitro AR,Scott M.A potent and selective ULK1 inhibitor suppresses autophagy and sensitizes cancer cells to nutrient stress..iScience2018;8:74-84 PMCID:PMC6172447

[77] Limpert AS,Bakas NA,Brun SN.Autophagy in cancer: regulation by small molecules..Trends Pharmacol Sci2018;39:53-63

[78] Lazarus MB.Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1..Bioorganic Med Chem2015;23:5483-8 PMCID:PMC4864979

[79] Matsunaga K,Saitoh T,Ktistakis NT.Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L..J Cell Biol2010;190:511-21 PMCID:PMC2928018

[80] Honda A,Cornella-Taracido I,Knapp MS.Potent, selective, and orally bioavailable inhibitors of VPS34 provide chemical tools to modulate autophagy in vivo..ACS Med Chem Lett2016;7:72-6 PMCID:PMC4716600

[81] Dowdle WE,Nagel J,Liu S.Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo..Nat Cell Biol2014;16:1069-79

[82] Pasquier B,Filoche-Rommé B,Fassy F.Discovery of (2 S)-8-[(3 R)-3-methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2 H -pyrimido[1,2- a ]pyrimidin-6-one: a novel potent and selective inhibitor of Vps34 for the treatment of solid tumors..J Med Chem2015;58:376-400

[83] Manic G,Kroemer G,Galluzzi L.Chloroquine and hydroxychloroquine for cancer therapy..Mol Cell Oncol2014;1:e29911 PMCID:PMC4905171

[84] Shi TT,Yan LJ.Research progress of hydroxychloroquine and autophagy inhibitors on cancer..Cancer Chemother Pharmacol2017;79:287-94

[85] Mauthe M,Rocchi C,Luhr M.Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion..Autophagy2018;14:1435-55 PMCID:PMC6103682

[86] Chude CI.Targeting autophagy in cancer: update on clinical trials and novel inhibitors..Int J Mol Sci2017;18:E1279 PMCID:PMC5486101

[87] Xu R,Xu C.The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers: a systematic review and meta-analysis..Medicine (Baltimore)2018;97:e12912 PMCID:PMC6257684

[88] Amaravadi RK.Lys05: a new lysosomal autophagy inhibitor..Autophagy2012;8:1383-4 PMCID:PMC3442884

[89] McAfee Q,Samanta A,Ma XH.Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency..Proc Natl Acad Sci2012;109:8253-8 PMCID:PMC3361415

[90] Kasi PD,Skalicka-Woźniak K,Daglia M.Molecular targets of curcumin for cancer therapy: an updated review..Tumor Biol2016;37:13017-28

[91] Zhu Y.Curcumin induces autophagy, apoptosis, and cell cycle arrest in human pancreatic cancer cells..Evidence-Based Complement Altern Med2017;2017:5787218 PMCID:PMC5610853

[92] Xiao K,Guan C,Wang G.Curcumin induces autophagy via activating the AMPK signaling pathway in lung adenocarcinoma cells..J Pharmacol Sci2013;123:102-9

[93] Kobori M,Sakurai M,Tsushida T.Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice..Mol Nutr Food Res2016;60:300-12 PMCID:PMC5063128

[94] Lou M,Ji PG,Liu JH.Quercetin nanoparticles induced autophagy and apoptosis through AKT/ERK/Caspase-3 signaling pathway in human neuroglioma cells: In vitro and in vivo..Biomed Pharmacother2016;84:1-9

[95] Liu Y,Yang ZY,Gong C.Quercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer..Apoptosis2017;22:544-57

[96] Hwang JJ,Mendelson D,Deeken JF.Phase I dose finding studies of obatoclax (GX15-070), a small molecule Pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma..Clin Cancer Res2010;16:4038-45 PMCID:PMC3703245

[97] Basit F,Fulda S.Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes..Cell Death Differ2013;20:1161-73 PMCID:PMC3741498

[98] Yang Y,Zhang Y,Song Y.Induction of autophagy by spermidine is neuroprotective via inhibition of caspase 3-mediated Beclin 1 cleavage..Cell Death Dis2017;8:e2738 PMCID:PMC5477584

[99] Sacitharan PK,Gharios GB.Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300..Exp Mol Med2018;50:123 PMCID:PMC6145946

[100] Welsh PA,Prakashagowda C,Feith D.Spermine synthase overexpression in vivo does not increase susceptibility to DMBA/TPA skin carcinogenesis or Min-Apc intestinal tumorigenesis..Cancer Biol Ther2012;13:358-68 PMCID:PMC3341213

[101] Matsui TA,Sakabe T,Horie N.Sulforaphane induces cell cycle arrest and apoptosis in murine osteosarcoma cells in vitro and inhibits tumor growth in vivo..Oncol Rep2007;18:1263-8

[102] Xiao D,Antosiewicz J,Bommareddy A.Cellular responses to cancer chemopreventive agent D,L-sulforaphane in human prostate cancer cells are initiated by mitochondrial reactive oxygen species..Pharm Res2009;26:1729-38 PMCID:PMC2744077

[103] Liu H,Ball SS,Bowater RP.Sulforaphane promotes ER stress, autophagy, and cell death: implications for cataract surgery..J Mol Med2017;95:553-64 PMCID:PMC5403866

[104] Wiczk A,Konopa G.Sulforaphane, a cruciferous vegetable-derived isothiocyanate, inhibits protein synthesis in human prostate cancer cells..Biochim Biophys Acta - Mol Cell Res2012;1823:1295-305

[105] Cohen MH,Pazdur R.Food and drug administration drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme..Clin Cancer Res2005;11:6767-71

[106] Würstle S,Ringel F,Lämmer F.Temozolomide induces autophagy in primary and established glioblastoma cells in an EGFR independent manner..Oncol Lett2017;14:322-8 PMCID:PMC5494811

[107] Dai C,Liu X,Yang Y.Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice..Endocrinology2013;154:1247-59

[108] Chen B,Li B,Zhou J.The role of epithelial-mesenchymal transition and IGF-1R expression in prediction of gefitinib activity as the second-line treatment for advanced nonsmall-cell lung cancer..Cancer Invest2013;31:454-60

[109] Zhao ZQ,Li J.Gefitinib induces lung cancer cell autophagy and apoptosis via blockade of the PI3K/AKT/mTOR pathway..Oncol Lett2016;12:63-8 PMCID:PMC4906680

[110] Sugita S,Yamashiro Y,Che XF.EGFR-independent autophagy induction with gefitinib and enhancement of its cytotoxic effect by targeting autophagy with clarithromycin in non-small cell lung cancer cells..Biochem Biophys Res Commun2015;461:28-34

[111] Dowling RJO,Stambolic V.Understanding the benefit of metformin use in cancer treatment..BMC Med2011;9:33 PMCID:PMC3224599

[112] Feng Y,Tang Q,Zheng X.Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling..Cell Death Dis2014;5:1-12 PMCID:PMC3944271

[113] Wang Y,Yan Z,Mi J.Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways..J Exp Clin Cancer Res2018;37:1-12 PMCID:PMC5859411

[114] Field-smith A,Davies FE.Bortezomib (velcadetrade mark) in the treatment of multiple myeloma..Ther Clin Risk Manag2006;2:271-9 PMCID:PMC1936263

[115] Kao C,Tsai CL,Huang WP.Bortezomib enhances cancer cell death by blocking the autophagic flux through stimulating ERK phosphorylation..Cell Death Dis2014;5:e1510 PMCID:PMC4260726

[116] Yang X,Howell SH.Activation of autophagy by unfolded proteins during endoplasmic reticulum stress..Plant J2016;85:83-95

[117] Akbarzadeh L,Sabetkasaei M.Comparison of anticancer effects of carbamazepine and valproic acid..Iran Red Crescent Med J2016;18:e37230 PMCID:PMC5291934

[118] Kania E,O’Prey J,Litwiniuk A.Verapamil treatment induces cytoprotective autophagy by modulating cellular metabolism..FEBS J2017;284:1370-87

[119] Shimizu T,Yoshida T,Goto N.Morphometrical study of physical growth in infant cynomolgus monkeys using multivariate analysis..Jikken Dobutsu1988;37:145-51

[120] Tan Q,Wang M,Wouters BG.Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity..Cancer Chemother Pharmacol2017;79:959-69

[121] Tan Q,Saggar JK,Wang M.Effect of pantoprazole to enhance activity of docetaxel against human tumour xenografts by inhibiting autophagy..Br J Cancer2015;112:832-40 PMCID:PMC4453951

[122] Cao Y,Tang D,Ding X.The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses article..Cell Death Dis2018;9:604 PMCID:PMC5964200

[123] Lu Y,Liu SS,Zou Y.Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells..J Transl Med2016;14:270 PMCID:PMC5029099