Sự phân lập tự thể và kháng thuốc hóa trị: một mục tiêu điều trị hứa hẹn cho việc điều trị ung thư

Cell Death and Disease - Tập 4 Số 10 - Trang e838-e838
Xinbing Sui1, Rou-fen Chen2, Zheng Wang1, Zhenzhen Huang2, Na Kong1, M Zhang2, Weidong Han1, Fang Lou1, Jing‐Jing Yang1, Qi Zhang3, Xian Wang4, Chao He2, Hongming Pan4
1Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
2Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
3Department of Gastrointestinal Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, China
4Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China

Tóm tắt

Tóm tắt

Việc kích thích chết tế bào và ngăn chặn sự sống sót của tế bào là những nguyên tắc chính trong liệu pháp ung thư. Kháng thuốc chống hóa trị là một vấn đề lớn trong ngành ung thư học, điều này hạn chế hiệu quả của các loại thuốc chống ung thư. Nhiều yếu tố góp phần vào kháng thuốc, bao gồm các yếu tố từ cơ thể, những biến đổi di truyền hoặc biểu sinh cụ thể trong các tế bào ung thư, v.v. Mặc dù đã có nhiều nghiên cứu xác định rõ các cơ chế mà qua đó các tế bào ung thư trở nên kháng thuốc trong môi trường vi mô, cách vượt qua kháng thuốc này để cải thiện hiệu quả chống ung thư vẫn chưa được xác định rõ. Sự phân lập tự thể, một cơ chế tái chế tế bào sinh lý quan trọng, hiện đang nổi lên như một tác nhân quan trọng trong phản ứng với căng thẳng chuyển hóa và trị liệu, nhằm cố gắng duy trì/phục hồi cân bằng chuyển hóa thông qua sự phân hủy catabolic của các protein thừa hoặc không cần thiết và các bào quan hỏng hoặc đã già. Gần đây, một số nghiên cứu đã chỉ ra rằng sự phân lập tự thể tạo thành một mục tiêu tiềm năng cho liệu pháp ung thư và việc kích thích sự phân lập tự thể trong phản ứng với các liệu pháp có thể được xem như có vai trò thúc đẩy chết tế bào hoặc sinh tồn, điều này góp phần vào hiệu quả chống ung thư của các loại thuốc này cũng như kháng thuốc. Do đó, việc hiểu rõ chức năng mới của sự phân lập tự thể có thể cho phép chúng ta phát triển một chiến lược điều trị đầy hứa hẹn nhằm tăng cường hiệu quả của hóa trị liệu và cải thiện kết quả lâm sàng trong việc điều trị bệnh nhân ung thư.

Từ khóa


Tài liệu tham khảo

Ringborg U, Platz A . Chemotherapy resistance mechanisms. Acta Oncol 1996; 35: 76–80.

Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM . Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006; 5: 219–234.

Yang Z, Klionsky DJ . Eaten alive: a history of macroautophagy. Nat Cell Biol 2010; 12: 814–822.

Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 2012; 8: 445–544.

Sui X, Jin L, Huang X, Geng S, He C, Hu X . p53 signaling and autophagy in cancer: a revolutionary strategy could be developed for cancer treatment. Autophagy 2011; 7: 565–571.

Yang Z, Klionsky DJ . An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 2009; 335: 1–32.

Kondo Y, Kanzawa T, Sawaya R, Kondo S . The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 2005; 5: 726–734.

Maycotte P, Thorburn A . Autophagy and cancer therapy. Cancer Biol Ther 2011; 11: 127–137.

Janku F, McConkey DJ, Hong DS, Kurzrock R . Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 2011; 8: 528–539.

Glick D, Barth S, Macleod KF . Autophagy: cellular and molecular mechanisms. J Pathol 2010; 221: 3–12.

Cecconi F, Levine B . The role of autophagy in mammalian development: cell makeover rather than cell death. Dev Cell 2008; 15: 344–357.

Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012; 142: 1504–1515.

Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 2010; 465: 942–946.

He C, Klionsky DJ . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67–93.

Yang Z, Klionsky DJ . Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010; 22: 124–131.

Tsuchihara K, Fujii S, Esumi H . Autophagy and cancer: dynamism of the metabolism of tumor cells and tissues. Cancer Lett 2009; 278: 130–138.

Hardie DG . AMPK and Raptor: matching cell growth to energy supply. Mol Cell 2008; 30: 263–265.

Mahoney E, Lucas DM, Gupta SV, Wagner AJ, Herman SE, Smith LL et al. ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol. Blood 2012; 120: 1262–1273.

Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H et al. ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 2007; 14: 230–239.

Park KJ, Lee SH, Lee CH, Jang JY, Chung J, Kwon MH et al. Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death. Biochem Biophys Res Commun 2009; 382: 726–729.

Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL . Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 2008; 10: 935–945.

Ciuffreda L, Di Sanza C, Incani UC, Milella M . The mTOR pathway: a new target in cancer therapy. Curr Cancer Drug Targets 2010; 10: 484–495.

Botrugno OA, Robert T, Vanoli F, Foiani M, Minucci S . Molecular pathways: old drugs define new pathways: non-histone acetylation at the crossroads of the DNA damage response and autophagy. Clin Cancer Res 2012; 18: 2436–2442.

Shubassi G, Robert T, Vanoli F, Minucci S, Foiani M . Acetylation: a novel link between double-strand break repair and autophagy. Cancer Res 2012; 72: 1332–1335.

Zhao Y, Chen H, Shang Z, Jiao B, Yuan B, Sun W et al. SD118-xanthocillin X (1), a novel marine agent extracted from Penicillium commune, induces autophagy through the inhibition of the MEK/ERK pathway. Mar Drugs 2012; 10: 1345–1359.

Hu YL, Jahangiri A, Delay M, Aghi MK . Tumor cell autophagy as an adaptive response mediating resistance to treatments such as antiangiogenic therapy. Cancer Res 2012; 72: 4294–4299.

Zou Z, Yuan Z, Zhang Q, Long Z, Chen J, Tang Z et al. Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells. Autophagy 2012; 8: 1798–1810.

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.

Carew JS, Nawrocki ST, Kahue CN, Zhang H, Yang C, Chung L et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 2007; 110: 313–322.

Sotelo J, Briceno E, Lopez-Gonzalez MA . Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2006; 144: 337–343.

Poole B, Ohkuma S . Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages. J Cell Biol 1981; 90: 665–669.

Nilsson JR . Does chloroquine, an antimalarial drug, affect autophagy in Tetrahymena pyriformis? J Protozool 1992; 39: 9–16.

Gunja N, Roberts D, McCoubrie D, Lamberth P, Jan A, Simes DC et al. Survival after massive hydroxychloroquine overdose. Anaesth Intensive Care 2009; 37: 130–133.

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: 1035–1044.

Schoenlein PV, Periyasamy-Thandavan S, Samaddar JS, Jackson WH, Barrett JT . Autophagy facilitates the progression of ERalpha-positive breast cancer cells to antiestrogen resistance. Autophagy 2009; 5: 400–403.

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: 200–212.

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: 1900–1909.

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: 7699–7709.

Paillas S, Causse A, Marzi L, de Medina P, Poirot M, Denis V et al. MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy. Autophagy 2012; 8: 1098–1112.

de la Cruz-Morcillo MA, Valero ML, Callejas-Valera JL, Arias-González L, Melgar-Rojas P, Galán-Moya EM et al. P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance. Oncogene 2012; 31: 1073–1085.

Sasaki K, Tsuno NH, Sunami E, Tsurita G, Kawai K, Okaji Y et al. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer 2010; 10: 370.

Sasaki K, Tsuno NH, Sunami E, Kawai K, Hongo K, Hiyoshi M et al. Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study. Anticancer Drugs 2012; 23: 675–682.

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: 105–111.

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: 509–524.

Chen YS, Song HX, Lu Y, Li X, Chen T, Zhang Y et al. Autophagy inhibition contributes to radiation sensitization of esophageal squamous carcinoma cells. Dis Esophagus 2011; 24: 437–443.

Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res 2012; 72: 1773–1783.

Rosenfeld MRGS, Brem S, Mikkelson T, Wang D, Piao S, Davis L et al. Pharmacokinetic analysis and pharmacodynamic evidence of autophagy inhibition in patients with newly diagnosed glioblastoma treated on a phase I trial of hydroxychloroquine in combination with adjuvant temozolomide and radiation (ABTC 0603). J Clin Oncol 2010; 28: 3086.

Ding ZB, Hui B, Shi YH, Zhou J, Peng YF, Gu CY et al. Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. Clin Cancer Res 2011; 17: 6229–6238.

Guo XL, Li D, Sun K, Wang J, Liu Y, Song JR et al. Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma. J Mol Med (Berl) 2013; 91: 473–483.

Shi YH, Ding ZB, Zhou J, Hui B, Shi GM, Ke AW et al. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis. Autophagy 2011; 7: 1159–1172.

Liu L, Yang M, Kang R, Wang Z, Zhao Y, Yu Y X et al. DAMP-mediated autophagy contributes to drug resistance. Autophagy 2011; 7: 112–114.

Zhao M, Yang M, Yang L, Yu Y, Xie M, Zhu S et al. HMGB1 regulates autophagy through increasing transcriptional activities of JNK and ERK in human myeloid leukemia cells. BMB Rep 2011; 44: 601–606.

Lagneaux L, Delforge A, Carlier S, Massy M, Bernier M, Bron D . Early induction of apoptosis in B-chronic lymphocytic leukaemia cells by hydroxychloroquine: activation of caspase-3 and no protection by survival factors. Br J Haematol 2001; 112: 344–352.

Rosich L, Xargay-Torrent S, López-Guerra M, Campo E, Colomer D, Roué G . Counteracting autophagy overcomes resistance to everolimus in mantle cell lymphoma. Clin Cancer Res 2012; 18: 5278–5289.

Han W, Pan H, Chen Y, Sun J, Wang Y, Li J et al. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One 2011; 6: e18691.

Wang Y, Peng RQ, Li DD, Ding Y, Wu XQ, Zeng YX et al. Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells. Chin J Cancer 2011; 30: 690–700.

Xu CX, Zhao L, Yue P, Fang G, Tao H, Owonikoko TK et al. Augmentation of NVP-BEZ235’s anticancer activity against human lung cancer cells by blockage of autophagy. Cancer Biol Ther 2011; 12: 549–555.

Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P et al. A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. J Thorac Oncol 2012; 7: 1602–1608.

Kang R, Tang D, Schapiro NE, Livesey KM, Farkas A, Loughran P et al. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ 2010; 17: 666–676.

Mirzoeva OK, Hann B, Hom YK, Debnath J, Aftab D, Shokat K et al. Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma. J Mol Med (Berl) 2011; 89: 877–889.

Kaini RR, Sillerud LO, Zhaorigetu S, Hu CA . Autophagy regulates lipolysis and cell survival through lipid droplet degradation in androgen-sensitive prostate cancer cells. Prostate 2012; 72: 1412–1422.

Li H, Jin X, Zhang Z, Xing Y, Kong X . Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP-BEZ235 in renal cell carcinoma cells. Cell Biochem Funct 2013; 31: 427–433.

Kumano M, Furukawa J, Shiota M, Zardan A, Zhang F, Beraldi E et al. Cotargeting stress-activated Hsp27 and autophagy as a combinatorial strategy to amplify endoplasmic reticular stress in prostate cancer. Mol Cancer Ther 2012; 11: 1661–1671.

Shin SW, Kim SY, Park JW . Autophagy inhibition enhances ursolic acid-induced apoptosis in PC3 cells. Biochim Biophys Acta 2012; 1823: 451–457.

Saleem A, Dvorzhinski D, Santanam U, Mathew R, Bray K, Stein M et al. Effect of dual inhibition of apoptosis and autophagy in prostate cancer. Prostate 2012; 72: 1374–1381.

Liang X, De Vera ME, Buchser WJ, Romo de Vivar Chavez A, Loughran P, Beer Stolz D et al. Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. Cancer Res 2012; 72: 2791–2801.

Gibson SB . Autophagy in clear cell ovarian cancer, a potential marker for hypoxia and poor prognosis? J Pathol 2012; 228: 434–436.

Zhang Y, Cheng Y, Ren X, Zhang L, Yap KL, Wu H et al. NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response. Oncogene 2012; 31: 1055–1064.

Zhang N, Qi Y, Wadham C, Wang L, Warren A, Di W et al. FTY720 induces necrotic cell death and autophagy in ovarian cancer cells: a protective role of autophagy. Autophagy 2010; 6: 1157–1167.

Zhao S, Ma CM, Liu CX, Wei W, Sun Y, Yan H et al. Autophagy inhibition enhances isobavachalcone-induced cell death in multiple myeloma cells. Int J Mol Med 2012; 30: 939–944.

Shingu T, Fujiwara K, Bögler O, Akiyama Y, Moritake K, Shinojima N et al. Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int J Cancer 2009; 124: 1060–1071.

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: 1261–1265.

Cao X, Liu B, Cao W, Zhang W, Zhang F, Zhao H et al. Autophagy inhibition enhances apigenin-induced apoptosis in human breast cancer cells. Chin J Cancer Res 2013; 25: 212–222.

Gao P, Bauvy C, Souquère S, Tonelli G, Liu L, Zhu Y et al. The Bcl-2 homology domain 3 mimetic gossypol induces both Beclin 1-dependent and Beclin 1-independent cytoprotective autophagy in cancer cells. J Biol Chem 2010; 285: 25570–25581.

Harhaji-Trajkovic L, Vilimanovich U, Kravic-Stevovic T, Bumbasirevic V, Trajkovic V . AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells. J Cell Mol Med 2009; 13: 3644–3654.

Ren Y, Huang F, Liu Y, Yang Y, Jiang Q, Xu C . Autophagy inhibition through PI3K/Akt increases apoptosis by sodium selenite in NB4 cells. BMB Rep 2009; 42: 599–604.

Filomeni G, Desideri E, Cardaci S, Graziani I, Piccirillo S, Rotilio G et al. Carcinoma cells activate AMP-activated protein kinase-dependent autophagy as survival response to kaempferol-mediated energetic impairment. Autophagy 2010; 6: 202–216.

Deng L, Lei Y, Liu R, Li J, Yuan K, Li Y et al. Pyrvinium targets autophagy addiction to promote cancer cell death. Cell Death Dis 2013; 4: e614.

Henson ES, Gibson SB . Surviving cell death through epidermal growth factor (EGF) signal transduction pathway: implications for cancer therapy. Cell Signal 2006; 18: 2089–2097.

Kohli L, Kaza N, Lavalley NJ, Turner KL, Byer S, Carroll SL et al. The pan erbB inhibitor PD168393 enhances lysosomal dysfunction-induced apoptotic death in malignant peripheral nerve sheath tumor cells. Neuro Oncol 2012; 14: 266–277.

Ghadimi MP, Lopez G, Torres KE, Belousov R, Young ED, Liu J et al. Targeting the PI3K/mTOR axis, alone and in combination with autophagy blockade, for the treatment of malignant peripheral nerve sheath tumors. Mol Cancer Ther 2012; 11: 1758–1769.

Chiarini F, Grimaldi C, Ricci F, Tazzari PL, Evangelisti C, Ognibene A et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res 2010; 70: 8097–8107.

Lin JF, Tsai TF, Liao PC, Lin YH, Lin YC, Chen HE et al. Benzyl isothiocyanate induces protective autophagy in human prostate cancer cells via inhibition of mTOR signaling. Carcinogenesis 2013; 34: 406–414.

Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117: 326–336.

Stanton MJ, Dutta S, Zhang H, Polavaram NS, Leontovich AA, Hönscheid P et al. Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance. Cancer Res 2013; 73: 160–171.

Weidhaas JB, Babar I, Nallur SM, Trang P, Roush S, Boehm M et al. MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res 2007; 67: 11111–11116.

Chen G, Zhu W, Shi D, Lv L, Zhang C, Liu P et al. MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. Oncol Rep 2010; 23: 997–1003.

Yu Y, Cao L, Yang L, Kang R, Lotze M, Tang D . microRNA 30A promotes autophagy in response to cancer therapy. Autophagy 2012; 8: 853–855.

Yu Y, Yang L, Zhao M, Zhu S, Kang R, Vernon P et al. Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells. Leukemia 2012; 26: 1752–1760.

Zou Z, Wu L, Ding H, Wang Y, Zhang Y, Chen X et al. MicroRNA-30a sensitizes tumor cells to cis-platinum via suppressing beclin 1-mediated autophagy. J Biol Chem 2012; 287: 4148–4156.

Xu N, Zhang J, Shen C, Luo Y, Xia L, Xue F et al. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. Biochem Biophys Res Commun 2012; 423: 826–831.

Huang Y, Chuang AY, Ratovitski EA . Phospho-ΔNp63α/miR-885-3p axis in tumor cell life and cell death upon cisplatin exposure. Cell Cycle 2011; 10: 3938–3947.

Enzenmüller S, Gonzalez P, Debatin KM, Fulda S . Chloroquine overcomes resistance of lung carcinoma cells to the dual PI3K/mTOR inhibitor PI103 by lysosome-mediated apoptosis. Anticancer Drugs 2013; 24: 14–19.

Seitz C, Hugle M, Cristofanon S, Tchoghandjian A, Fulda S . The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int J Cancer 2013; 132: 2682–2693.

Boya P, Gonzalez-Polo RA, Poncet D, Andreau K, Vieira HL, Roumier T et al. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 2003; 22: 3927–3936.

Xiong HY, Guo XL, Bu XX, Zhang SS, Ma NN, Song JR et al. Autophagic cell death induced by 5-FU in Bax or PUMA deficient human colon cancer cell. Cancer Lett 2010; 288: 68–74.

Lee YJ, Won AJ, Lee J, Jung JH, Yoon S, Lee BM et al. Molecular mechanism of SAHA on regulation of autophagic cell death in tamoxifen-resistant MCF-7 breast cancer cells. Int J Med Sci 2012; 9: 881–893.

Li JR, Cheng CL, Yang CR, Ou YC, Wu MJ, Ko JL . Dual inhibitor of phosphoinositide 3-kinase/mammalian target of rapamycin NVP-BEZ235 effectively inhibits cisplatin-resistant urothelial cancer cell growth through autophagic flux. Toxicol Lett 2013; 220: 267–276.

Cloonan SM, Williams DC . The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt's lymphoma. Int J Cancer 2011; 128: 1712–1723.

Leng S, Hao Y, Du D, Xie S, Hong L, Gu H et al. Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy. Int J Cancer 2013 e-pub ahead of print 16 July 2013; doi:10.1002/ijc.28301.

Ren SX, Shen J, Cheng AS, Lu L, Chan RL, Li ZJ et al. FK-16 derived from the anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells. PLoS One 2013; 8: e63641.

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: 1845–1851.

Guo WJ, Zhang YM, Zhang L, Huang B, Tao FF, Chen W et al. Novel monofunctional platinum (II) complex Mono-Pt induces apoptosis-independent autophagic cell death in human ovarian carcinoma cells, distinct from cisplatin. Autophagy 2013; 9: 996–1008.

Tai WT, Shiau CW, Chen HL, Liu CY, Lin CS, Cheng AL et al. Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells. Cell Death Dis 2013; 4: e485.

Salazar M, Carracedo A, Salanueva IJ, Hernández-Tiedra S, Lorente M, Egia A et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 2009; 119: 1359–1372.

Donadelli M, Dando I, Zaniboni T, Costanzo C, Dalla Pozza E, Scupoli MT et al. Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis 2011; 2: e152.

Dando I, Donadelli M, Costanzo C, Dalla Pozza E, D'Alessandro A, Zolla L et al. Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis 2013; 4: e664.

Vara D, Salazar M, Olea-Herrero N, Guzmán M, Velasco G, Díaz-Laviada I . Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 2011; 18: 1099–1111.

Torres S, Lorente M, Rodríguez-Fornés F, Hernández-Tiedra S, Salazar M, García-Taboada E et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 2011; 10: 90–103.

Yun SM, Jung JH, Jeong SJ, Sohn EJ, Kim B, Kim SH et al. Tanshinone IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 leukemia cells. Phytother Res 2013 e-pub ahead of print 27 June 2013; doi:10.1002/ptr.5015.

Kohli L, Kaza N, Coric T, Byer SJ, Brossier NM, Klocke BJ et al. 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Cancer Res 2013; 73: 4395–4405.

Cai Y, Wan Z, Sun T, Shi Y, Sun Y, Huang P et al. Diarylquinoline compounds induce autophagy-associated cell death by inhibiting the Akt pathway and increasing reactive oxygen species in human nasopharyngeal carcinoma cells. Oncol Rep 2013; 29: 983–992.

Chang HW, Lee YS, Nam HY, Han MW, Kim HJ, Moon SY et al. Knockdown of β-catenin controls both apoptotic and autophagic cell death through LKB1/AMPK signaling in head and neck squamous cell carcinoma cell lines. Cell Signal 2013; 25: 839–847.

Franzetti E, Huang ZJ, Shi YX, Xie K, Deng XJ, Li JP et al. Autophagy precedes apoptosis during the remodeling of silkworm larval midgut. Apoptosis 2012; 17: 305–324.

Zhang N, Chen Y, Jiang R, Li E, Chen X, Xi Z et al. PARP and RIP 1 are required for autophagy induced by 11'-deoxyverticillin A, which precedes caspase-dependent apoptosis. Autophagy 2011; 7: 598–612.

Abe A, Yamada H, Moriya S, Miyazawa K . The β-carboline alkaloid harmol induces cell death via autophagy but not apoptosis in human non-small cell lung cancer A549 cells. Biol Pharm Bull 2011; 34: 1264–1272.

Yahiro K, Satoh M, Nakano M, Hisatsune J, Isomoto H, Sap J et al. Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA. J Biol Chem 2012; 287: 31104–31115.

Francisco R, Pérez-Perarnau A, Cortés C, Gil J, Tauler A, Ambrosio S . Histone deacetylase inhibition induces apoptosis and autophagy in human neuroblastoma cells. Cancer Lett 2012; 318: 42–52.

Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011; 17: 654–666.

Choi KS . Autophagy and cancer. Exp Mol Med 2012; 44: 109–120.

Buchser WJ, Laskow TC, Pavlik PJ, Lin HM, Lotze MT . Cell-mediated autophagy promotes cancer cell survival. Cancer Res 2012; 72: 2970–2979.