Small-Molecule Regulators of Autophagy as Potential Anti-cancer Therapy

Chapter

Abstract

Autophagy is an evolutionary conserved lysosomal pathway functioned in the turnover of cellular macromolecules and organelles. It is known that autophagy can have a cytoprotective effect in tumor cells under therapeutic treatment. Autophagy inhibitors thus may be used as auxiliary drugs to augment the anti-tumor activity of cancer therapies. On the other hand, autophagy is a cytotoxic event that can kill tumor cells. Autophagy inducers that increase the level of autophagy thus may be developed as a new class of anti-cancer therapy. This chapter will describe the known pathway of autophagy and its relationship to cancer. The focus of this chapter is to give a summary of the known small-molecule regulators of autophagy, including inhibitors and inducers, discovered as potential therapies for cancer treatment.

Keywords

Autophagy Cell death Autophagy inhibitor Autophagy inducer Anti-cancer treatment 

References

  1. Akin, D., Wang, S. K., Habibzadegah-Tari, P., Law, B., Ostrov, D., Li, M., et al. (2014). A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy, 10(11), 2021–2035.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Albert, J. M., Kim, K. W., Cao, C., & Lu, B. (2006). Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Molecular Cancer Therapeutics, 5(5), 1183–1189.PubMedCrossRefGoogle Scholar
  3. Arnold, A. A., Aboukameel, A., Chen, J., Yang, D., Wang, S., Al-Katib, A., et al. (2008). Preclinical studies of Apogossypolone: A new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model. Molecular Cancer, 7, 20.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Azad, M. B., Chen, Y., Henson, E. S., Cizeau, J., McMillan-Ward, E., Israels, S. J., et al. (2008). Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy, 4(2), 195–204.PubMedCrossRefGoogle Scholar
  5. Baek, K. H., Park, J., & Shin, I. (2012). Autophagy-regulating small molecules and their therapeutic applications. Chemical Society Reviews, 41(8), 3245–3263.PubMedCrossRefGoogle Scholar
  6. Balic, A., Sorensen, M. D., Trabulo, S. M., Sainz, B., Jr., Cioffi, M., Vieira, C. R., et al. (2014). Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling. Molecular Cancer Therapeutics, 13(7), 1758–1771.PubMedCrossRefGoogle Scholar
  7. Bases, R. E., & Mendez, F. (1997). Topoisomerase inhibition by lucanthone, an adjuvant in radiation therapy. International Journal of Radiation Oncology, Biology, and Physics, 37(5), 1133–1137.CrossRefGoogle Scholar
  8. Blommaart, E. F., Krause, U., Schellens, J. P., Vreeling-Sindelarova, H., & Meijer, A. J. (1997). The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. European Journal of Biochemistry, 243(1–2), 240–246.PubMedCrossRefGoogle Scholar
  9. Bonapace, L., Bornhauser, B. C., Schmitz, M., Cario, G., Ziegler, U., Niggli, F. K., et al. (2010). Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. Journal of Clinical Investigation, 120(4), 1310–1323.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Cao, C., Subhawong, T., Albert, J. M., Kim, K. W., Geng, L., Sekhar, K. R., et al. (2006). Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Research, 66(20), 10040–10047.PubMedCrossRefGoogle Scholar
  11. Carew, J. S., Espitia, C. M., Esquivel, J. A., 2nd, Mahalingam, D., Kelly, K. R., Reddy, G., et al. (2011). Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. Journal of Biological Chemistry, 286(8), 6602–6613.PubMedCrossRefGoogle Scholar
  12. Cerny, J., Feng, Y., Yu, A., Miyake, K., Borgonovo, B., Klumperman, J., et al. (2004). The small chemical vacuolin-1 inhibits Ca(2+)-dependent lysosomal exocytosis but not cell resealing. EMBO Reports, 5(9), 883–888.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Chen, Y. J., Chi, C. W., Su, W. C., & Huang, H. L. (2014). Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma. Oncotarget, 5(13), 4845–4854.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Chen, J., Mei, Q., Xu, Y. C., Du, J., Wei, Y., & Xu, Z. M. (2006). Effects of matrine injection on T-lymphocyte subsets of patients with malignant tumor after gamma knife radiosurgery. Zhong Xi Yi Jie He Xue Bao, 4(1), 78–79.PubMedCrossRefGoogle Scholar
  15. Chen, S., Zhu, X., Qiao, H., Ye, M., Lai, X., Yu, S., et al. (2015). Protective autophagy promotes the resistance of HER2-positive breast cancer cells to lapatinib. Tumour Biology. DIALOG. Retrieved September 14, 2015, from http://link.springer.com/article/10.1007%2Fs13277-015-3800-9
  16. Clarke, P. G. (1990). Developmental cell death: Morphological diversity and multiple mechanisms. Anatomy and Embryology, 181(3), 195–213.PubMedCrossRefGoogle Scholar
  17. Deng, L., Lei, Y., Liu, R., Li, J., Yuan, K., Li, Y., et al. (2013). Pyrvinium targets autophagy addiction to promote cancer cell death. Cell Death & Disease, 4, e614.CrossRefGoogle Scholar
  18. Donadelli, M., Dando, I., Zaniboni, T., Costanzo, C., Dalla Pozza, E., Scupoli, M. T., et al. (2011). Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death & Disease, 2, e152.CrossRefGoogle Scholar
  19. Fleming, A., Noda, T., Yoshimori, T., & Rubinsztein, D. C. (2011). Chemical modulators of autophagy as biological probes and potential therapeutics. Nature Chemical Biology, 7(1), 9–17.PubMedCrossRefGoogle Scholar
  20. Frisch, S. M., & Screaton, R. A. (2001). Anoikis mechanisms. Current Opinion in Cell Biology, 13(5), 555–562.PubMedCrossRefGoogle Scholar
  21. Fu, J., Shao, C. J., Chen, F. R., Ng, H. K., & Chen, Z. P. (2010). Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines. Neuro-Oncology, 12(4), 328–340.PubMedCrossRefGoogle Scholar
  22. Fukuda, T., Oda, K., Wada-Hiraike, O., Sone, K., Inaba, K., Ikeda, Y., et al. (2015). The anti-malarial chloroquine suppresses proliferation and overcomes cisplatin resistance of endometrial cancer cells via autophagy inhibition. Gynecologic Oncology, 137(3), 538–545.PubMedCrossRefGoogle Scholar
  23. Fulda, S., & Kogel, D. (2015). Cell death by autophagy: Emerging molecular mechanisms and implications for cancer therapy. Oncogene, 34(40), 5105–5113.PubMedCrossRefGoogle Scholar
  24. Fung, C., Lock, R., Gao, S., Salas, E., & Debnath, J. (2008). Induction of autophagy during extracellular matrix detachment promotes cell survival. Molecular Biology of the Cell, 19(3), 797–806.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Gewirtz, D. A. (2014). The four faces of autophagy: Implications for cancer therapy. Cancer Research, 74(3), 647–651.PubMedCrossRefGoogle Scholar
  26. Goussetis, D. J., Altman, J. K., Glaser, H., McNeer, J. L., Tallman, M. S., & Platanias, L. C. (2010). Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide. Journal of Biological Chemistry, 285(39), 29989–29997.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Green, D. R., & Levine, B. (2014). To be or not to be? How selective autophagy and cell death govern cell fate. Cell, 157(1), 65–75.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Hamer, H. M., Jonkers, D., Venema, K., Vanhoutvin, S., Troost, F. J., & Brummer, R. J. (2008). Review article: The role of butyrate on colonic function. Alimentary Pharmacology and Therapeutics, 27(2), 104–119.PubMedCrossRefGoogle Scholar
  29. Harada, M., Sakisaka, S., Yoshitake, M., Kin, M., Ohishi, M., Shakado, S., et al. (1996). Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPases, inhibits the receptor-mediated endocytosis of asialoglycoproteins in isolated rat hepatocytes. Journal of Hepatology, 24(5), 594–603.PubMedCrossRefGoogle Scholar
  30. He, J. H., Liao, X. L., Wang, W., Li, D. D., Chen, W. D., Deng, R., et al. (2014). Apogossypolone, a small-molecule inhibitor of Bcl-2, induces radiosensitization of nasopharyngeal carcinoma cells by stimulating autophagy. International Journal of Oncology, 45(3), 1099–1108.PubMedGoogle Scholar
  31. Heidari, N., Hicks, M. A., & Harada, H. (2010). GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy. Cell Death & Disease, 1, e76.CrossRefGoogle Scholar
  32. Homewood, C. A., Warhurst, D. C., Peters, W., & Baggaley, V. C. (1972). Lysosomes, pH and the anti-malarial action of chloroquine. Nature, 235(5332), 50–52.PubMedCrossRefGoogle Scholar
  33. Hoyer-Hansen, M., Bastholm, L., Szyniarowski, P., Campanella, M., Szabadkai, G., Farkas, T., et al. (2007). Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Molecular Cell, 25(2), 193–205.PubMedCrossRefGoogle Scholar
  34. Hoyer-Hansen, M., & Jaattela, M. (2007). Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death and Differentiation, 14(9), 1576–1582.PubMedCrossRefGoogle Scholar
  35. Jangamreddy, J. R., Panigrahi, S., & Los, M. J. (2015). Monitoring of autophagy is complicated—Salinomycin as an example. Biochimica et Biophysica Acta, 1853(3), 604–610.PubMedCrossRefGoogle Scholar
  36. Jazirehi, A. R. (2010). Regulation of apoptosis-associated genes by histone deacetylase inhibitors: Implications in cancer therapy. Anti-Cancer Drugs, 21(9), 805–813.PubMedCrossRefGoogle Scholar
  37. Jung, C. H., Jun, C. B., Ro, S. H., Kim, Y. M., Otto, N. M., Cao, J., et al. (2009). ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Molecular Biology of the Cell, 20(7), 1992–2003.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Kim, Y. C., & Guan, K. L. (2015). mTOR: A pharmacologic target for autophagy regulation. Journal of Clinical Investigation, 125(1), 25–32.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Kim, J., Kim, Y. C., Fang, C., Russell, R. C., Kim, J. H., Fan, W., et al. (2013a). Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell, 152(1–2), 290–303.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Kim, Y., Kim, Y. S., Kim, D. E., Lee, J. S., Song, J. H., Kim, H. G., et al. (2013b). BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production. Autophagy, 9(12), 2126–2139.PubMedCrossRefGoogle Scholar
  41. Kimura, T., Takabatake, Y., Takahashi, A., & Isaka, Y. (2013). Chloroquine in cancer therapy: A double-edged sword of autophagy. Cancer Research, 73(1), 3–7.PubMedCrossRefGoogle Scholar
  42. Kumar, D., Shankar, S., & Srivastava, R. K. (2014). Rottlerin induces autophagy and apoptosis in prostate cancer stem cells via PI3K/Akt/mTOR signaling pathway. Cancer Letters, 343(2), 179–189.PubMedCrossRefGoogle Scholar
  43. Kumar, A., Singh, U. K., & Chaudhary, A. (2015). Targeting autophagy to overcome drug resistance in cancer therapy. Future Medicinal Chemistry, 7(12), 1535–1542.PubMedCrossRefGoogle Scholar
  44. Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274–293.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Leng, S., Hao, Y., Du, D., Xie, S., Hong, L., Gu, H., et al. (2013). Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy. International Journal of Cancer, 133(12), 2781–2790.PubMedGoogle Scholar
  46. Levy, J. M., & Thorburn, A. (2011). Targeting autophagy during cancer therapy to improve clinical outcomes. Pharmacology and Therapeutics, 131(1), 130–141.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Li, T. L., Su, L., Zhong, N., Hao, X. X., Zhong, D. S., Singhal, S., et al. (2013). Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells. Autophagy, 9(7), 1057–1068.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Liang, X. H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., et al. (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature, 402(6762), 672–676.PubMedCrossRefGoogle Scholar
  49. Liu, R., Li, J., Zhang, T., Zou, L., Chen, Y., Wang, K., et al. (2014). Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking. Autophagy, 10(7), 1241–1255.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Liu, T., Song, Y., Chen, H., Pan, S., & Sun, X. (2010). Matrine inhibits proliferation and induces apoptosis of pancreatic cancer cells in vitro and in vivo. Biological and Pharmaceutical Bulletin, 33(10), 1740–1745.PubMedCrossRefGoogle Scholar
  51. Lu, Y., Dong, S., Hao, B., Li, C., Zhu, K., Guo, W., et al. (2014). Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A. Autophagy, 10(11), 1895–1905.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Maira, S. M., Stauffer, F., Schnell, C., & Garcia-Echeverria, C. (2009). PI3K inhibitors for cancer treatment: Where do we stand? Biochemical Society Transactions, 37(Pt 1), 265–272.PubMedCrossRefGoogle Scholar
  53. Marino, G., Niso-Santano, M., Baehrecke, E. H., & Kroemer, G. (2014). Self-consumption: The interplay of autophagy and apoptosis. Nature Reviews Molecular Cell Biology, 15(2), 81–94.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Marino, G., Salvador-Montoliu, N., Fueyo, A., Knecht, E., Mizushima, N., & Lopez-Otin, C. (2007). Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. Journal of Biological Chemistry, 282(25), 18573–18583.PubMedCrossRefGoogle Scholar
  55. Mathew, R., Karantza-Wadsworth, V., & White, E. (2007). Role of autophagy in cancer. Nature Reviews Cancer, 7(12), 961–967.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Mauvezin, C., & Neufeld, T. P. (2015). Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A/SERCA-dependent autophagosome-lysosome fusion. Autophagy, 11(8), 1437–1438.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Maycotte, P., & Thorburn, A. (2011). Autophagy and cancer therapy. Cancer Biology and Therapy, 11(2), 127–137.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Miller, W. H., Jr., Schipper, H. M., Lee, J. S., Singer, J., & Waxman, S. (2002). Mechanisms of action of arsenic trioxide. Cancer Research, 62(14), 3893–3903.PubMedGoogle Scholar
  59. Nagelkerke, A., Bussink, J., Geurts-Moespot, A., Sweep, F. C., & Span, P. N. (2015). Therapeutic targeting of autophagy in cancer. Part II: Pharmacological modulation of treatment-induced autophagy. Seminars in Cancer Biology, 31, 99–105.PubMedCrossRefGoogle Scholar
  60. Nakamura, M., Kikukawa, Y., Takeya, M., Mitsuya, H., & Hata, H. (2010). Clarithromycin attenuates autophagy in myeloma cells. International Journal of Oncology, 37(4), 815–820.PubMedCrossRefGoogle Scholar
  61. Nam, H. Y., Han, M. W., Chang, H. W., Lee, Y. S., Lee, M., Lee, H. J., et al. (2013). Radioresistant cancer cells can be conditioned to enter senescence by mTOR inhibition. Cancer Research, 73(14), 4267–4277.PubMedCrossRefGoogle Scholar
  62. Niu, X., Li, S., Wei, F., Huang, J., Wu, G., Xu, L., et al. (2014). Apogossypolone induces autophagy and apoptosis in breast cancer MCF-7 cells in vitro and in vivo. Breast Cancer, 21(2), 223–230.PubMedCrossRefGoogle Scholar
  63. Nomura, T., & Katunuma, N. (2005). Involvement of cathepsins in the invasion, metastasis and proliferation of cancer cells. The Journal of Medical Investigation, 52(1–2), 1–9.PubMedCrossRefGoogle Scholar
  64. Pattingre, S., & Levine, B. (2006). Bcl-2 inhibition of autophagy: A new route to cancer? Cancer Research, 66(6), 2885–2888.PubMedCrossRefGoogle Scholar
  65. Plumbridge, T. W., & Brown, J. R. (1978). Studies on the mode of interaction of 4′-epi-adriamycin and 4-demethoxy-daunomycin with DNA. Biochemical Pharmacology, 27(14), 1881–1882.PubMedCrossRefGoogle Scholar
  66. Polivka, J., Jr., & Janku, F. (2014). Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacology and Therapeutics, 142(2), 164–175.PubMedCrossRefGoogle Scholar
  67. Powis, G., Bonjouklian, R., Berggren, M. M., Gallegos, A., Abraham, R., Ashendel, C., et al. (1994). Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Research, 54(9), 2419–2423.PubMedGoogle Scholar
  68. Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., et al. (2003). Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. Journal of Clinical Investigation, 112(12), 1809–1820.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Racoma, I. O., Meisen, W. H., Wang, Q. E., Kaur, B., & Wani, A. A. (2013). Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS One, 8(9), e72882.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Renna, M., Schaffner, C., Brown, K., Shang, S., Tamayo, M. H., Hegyi, K., et al. (2011). Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. Journal of Clinical Investigation, 121(9), 3554–3563.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Ristic, B., Bosnjak, M., Arsikin, K., Mircic, A., Suzin-Zivkovic, V., Bogdanovic, A., et al. (2014). Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells. Experimental Cell Research, 326(1), 90–102.PubMedCrossRefGoogle Scholar
  72. Ronan, B., Flamand, O., Vescovi, L., Dureuil, C., Durand, L., Fassy, F., et al. (2014). A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nature Chemical Biology, 10(12), 1013–1019.PubMedCrossRefGoogle Scholar
  73. Rubiolo, J. A., Lopez-Alonso, H., Martinez, P., Millan, A., Cagide, E., Vieytes, M. R., et al. (2014). Yessotoxin induces ER-stress followed by autophagic cell death in glioma cells mediated by mTOR and BNIP3. Cellular Signalling, 26(2), 419–432.PubMedCrossRefGoogle Scholar
  74. Salabei, J. K., Balakumaran, A., Frey, J. C., Boor, P. J., Treinen-Moslen, M., & Conklin, D. J. (2012). Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy. Toxicology and Applied Pharmacology, 262(3), 265–272.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Seglen, P. O., & Gordon, P. B. (1982). 3-Methyladenine: Specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proceedings of the National Academy of Sciences of the United States of America, 79(6), 1889–1892.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Shao, Y., Gao, Z., Marks, P. A., & Jiang, X. (2004). Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 101(52), 18030–18035.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Shimizu, S., Kanaseki, T., Mizushima, N., Mizuta, T., Arakawa-Kobayashi, S., Thompson, C. B., et al. (2004). Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biology, 6(12), 1221–1228.PubMedCrossRefGoogle Scholar
  78. Shimizu, S., Konishi, A., Nishida, Y., Mizuta, T., Nishina, H., Yamamoto, A., et al. (2010). Involvement of JNK in the regulation of autophagic cell death. Oncogene, 29(14), 2070–2082.PubMedCrossRefGoogle Scholar
  79. Shimizu, S., Yoshida, T., Tsujioka, M., & Arakawa, S. (2014). Autophagic cell death and cancer. International Journal of Molecular Sciences, 15(2), 3145–3153.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Sosa, M. S., Bragado, P., Debnath, J., & Aguirre-Ghiso, J. A. (2013). Regulation of tumor cell dormancy by tissue microenvironments and autophagy. Advances in Experimental Medicine & Biology, 734, 73–89.CrossRefGoogle Scholar
  81. Takahashi, A., Kimura, F., Yamanaka, A., Takebayashi, A., Kita, N., Takahashi, K., et al. (2014). Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell International, 14, 53.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Tamai, M., Matsumoto, K., Omura, S., Koyama, I., Ozawa, Y., & Hanada, K. (1986). In vitro and in vivo inhibition of cysteine proteinases by EST, a new analog of E-64. Journal of Pharmacobio-Dynamics, 9(8), 672–677.PubMedCrossRefGoogle Scholar
  83. Tanida, I., Minematsu-Ikeguchi, N., Ueno, T., & Kominami, E. (2005). Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy, 1(2), 84–91.PubMedCrossRefGoogle Scholar
  84. Thorburn, A., Thamm, D. H., & Gustafson, D. L. (2014). Autophagy and cancer therapy. Molecular Pharmacology, 85(6), 830–838.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Thorne, C. A., Hanson, A. J., Schneider, J., Tahinci, E., Orton, D., Cselenyi, C. S., et al. (2010). Small-molecule inhibition of Wnt signaling through activation of casein kinase 1alpha. Nature Chemical Biology, 6(11), 829–836.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Umezawa, H., Aoyagi, T., Morishima, H., Matsuzaki, M., & Hamada, M. (1970). Pepstatin, a new pepsin inhibitor produced by Actinomycetes. Journal of Antibiotics, 23(5), 259–262.PubMedCrossRefGoogle Scholar
  87. Vlahos, C. J., Matter, W. F., Hui, K. Y., & Brown, R. F. (1994). A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). Journal of Biological Chemistry, 269(7), 5241–5248.PubMedGoogle Scholar
  88. Voss, V., Senft, C., Lang, V., Ronellenfitsch, M. W., Steinbach, J. P., Seifert, V., et al. (2010). The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Molecular Cancer Research, 8(7), 1002–1016.PubMedCrossRefGoogle Scholar
  89. Wang, Y., Kuramitsu, Y., Tokuda, K., Baron, B., Kitagawa, T., Akada, J., et al. (2014). Gemcitabine induces poly (ADP-ribose) polymerase-1 (PARP-1) degradation through autophagy in pancreatic cancer. PLoS One, 9(10), e109076.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Wang, Z., Zhang, J., Wang, Y., Xing, R., Yi, C., Zhu, H., et al. (2013). Matrine, a novel autophagy inhibitor, blocks trafficking and the proteolytic activation of lysosomal proteases. Carcinogenesis, 34(1), 128–138.PubMedCrossRefGoogle Scholar
  91. Watanabe, M., Adachi, S., Matsubara, H., Imai, T., Yui, Y., Mizushima, Y., et al. (2009). Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation. International Journal of Cancer, 124(1), 55–67.PubMedCrossRefGoogle Scholar
  92. Wei, Y., Kadia, T., Tong, W., Zhang, M., Jia, Y., Yang, H., et al. (2010). The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Autophagy, 6(7), 976–978.PubMedCrossRefGoogle Scholar
  93. Wirth, M., Joachim, J., & Tooze, S. A. (2013). Autophagosome formation—The role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage. Seminars in Cancer Biology, 23(5), 301–309.PubMedCrossRefGoogle Scholar
  94. Wong, V. K., Li, T., Law, B. Y., Ma, E. D., Yip, N. C., Michelangeli, F., et al. (2013). Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells. Cell Death & Disease, 4, e720.CrossRefGoogle Scholar
  95. Wu, L., & Yan, B. (2011). Discovery of small molecules that target autophagy for cancer treatment. Current Medicinal Chemistry, 18(12), 1866–1873.PubMedCrossRefGoogle Scholar
  96. Yamamoto, S., Tanaka, K., Sakimura, R., Okada, T., Nakamura, T., Li, Y., et al. (2008). Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anticancer Research, 28(3A), 1585–1591.PubMedGoogle Scholar
  97. You, D., Kim, Y., Jang, M. J., Lee, C., Jeong, I. G., Cho, Y. M., et al. (2015). KML001 induces apoptosis and autophagic cell death in prostate cancer cells via oxidative stress pathway. PLoS One, 10(9), e0137589.PubMedPubMedCentralCrossRefGoogle Scholar
  98. Yu, H. C., Lin, C. S., Tai, W. T., Liu, C. Y., Shiau, C. W., & Chen, K. F. (2013). Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation. Journal of Biological Chemistry, 288(25), 18249–18259.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Yue, W., Hamai, A., Tonelli, G., Bauvy, C., Nicolas, V., Tharinger, H., et al. (2013). Inhibition of the autophagic flux by salinomycin in breast cancer stem-like/progenitor cells interferes with their maintenance. Autophagy, 9(5), 714–729.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Zhang, X. Q., Huang, X. F., Hu, X. B., Zhan, Y. H., An, Q. X., Yang, S. M., et al. (2010). Apogossypolone, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces autophagy of PC-3 and LNCaP prostate cancer cells in vitro. Asian Journal of Andrology, 12(5), 697–708.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Zhang, C., Richon, V., Ni, X., Talpur, R., & Duvic, M. (2005). Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: Relevance to mechanism of therapeutic action. Journal of Investigative Dermatology, 125(5), 1045–1052.PubMedCrossRefGoogle Scholar
  102. Zhou, M., & Wang, R. (2013). Small-molecule regulators of autophagy and their potential therapeutic applications. ChemMedChem, 8(5), 694–707.PubMedCrossRefGoogle Scholar
  103. Zhu, X. X., Yao, X. F., Jiang, L. P., Geng, C. Y., Zhong, L. F., Yang, G., et al. (2014). Sodium arsenite induces ROS-dependent autophagic cell death in pancreatic beta-cells. Food and Chemical Toxicology, 70, 144–150.PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.State Key Laboratory of Bioorganic and Natural Products ChemistryShanghai Institute of Organic Chemistry, Chinese Academy of SciencesShanghaiP.R. China

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