Small-Molecule Regulators of Autophagy as Potential Anti-cancer Therapy
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 thu
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Small-Molecule Regulators of Autophagy as Potential Anti-cancer Therapy Qing Li, Mi Zhou, and Renxiao Wang
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
3.1
Introduction
Autophagy plays an essential role in normal physiology. Under normal conditions, autophagy occurs at basal levels to maintain cellular homeostasis by removing longlived or misfolded proteins and clearing damaged or dysfunctional organelles. Under starved conditions, autophagy can be induced to digest dysfunctional proteins and organelles more rapidly, which will help cell to survive (Green and Levine 2014). It is also well known that autophagy may protect cell by overcoming adversities,
Q. Li • M. Zhou • R. Wang (*) State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P.R. China e-mail: [email protected] © Springer International Publishing Switzerland 2016 J.-M. Yang (ed.), Targeting Autophagy in Cancer Therapy, Current Cancer Research, DOI 10.1007/978-3-319-42740-9_3
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such as starvation, chemotherapies or radiotherapies. Autophagy can also exhibit cytotoxicity in certain condition, e.g. when apoptosis is blocked (Gewirtz 2014). In this chapter, we will briefly introduce the molecular mechanism of autophagy and its dual role in anti-cancer therapy development. We will also review the public reported small-molecule regulators of autophagy, including autophagy inhibitors and autophagy inducers, discovered as potential anti-cancer therapies.
3.2
The Process of Autophagy
The known pathway of autophagy includes induction, formation and elongation of isolation membrane, autophagosome completion, fusion of autophagosome and lysosome, and degradation in autolysosome (Fig. 3.1). Autophagy is regulated by a “pre-initiation” ULK complex, which includes ULK1, FIP200 and ATG13. The ULK complex then activates Class III PI3K complex, which requires the disruption of binding of anti-apoptotic Bcl-2 proteins to Beclin 1 and is also regulated by AMPK. The Class III PI3K complex generates Phosphatidylinositol 3-phosphate
Fig. 3.1 The process of autoph
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