title: Autophagy contributes to modulating the cytotoxicities of Bcl-2 homology domain-3 mimetics.
abstract: The dysregulation of apoptosis is a key step in developing cancers, and mediates resistance to cancer therapy. Commitment to apoptosis is caused by permeabilization of the outer mitochondrial membrane, a process regulated by the interactions between different proteins of Bcl-2 family. Furthermore, Bcl-2 family proteins also bind to the endoplasmic reticulum, where they modulate autophagy, another important pathway regulating cell survival and death. Dysregulation of Bcl-2 family has been demonstrated in a wide spectrum of human cancers, including gastrointestinal cancers. Therefore, targeting the Bcl-2 family of proteins represents a promising therapeutic approach for these malignancies. Recent advances have yielded small molecules that have close structural or functional similarity to BH3-only proteins and are therefore named BH3 mimetics. Of these BH3 mimetics, obatoclax, (-)-gossypol, and ABT-263 are currently in clinical trials for multiple cancers. Growing evidence indicates that these BH3 mimetics not only induce apoptosis, but also regulate autophagy which may serve as a pro-survival or pro-death mechanism to counteract or mediate the cytotoxicity of BH3 mimetics. This review discusses the role of autophagy in cell-fate decision upon BH3 mimetics treatment. Further exploration of our understanding of the association between autophagy and cellular outcomes in response to BH3 mimetics treatment will likely offer improved therapies for patients with cancer.
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: yule0423@gmail.com.
authors.forename: Le
authors.initials: L
authors.lastname: Yu
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007211:Indoles; D018716:Molecular Mimicry; D054730:Protein Interaction Domains and Motifs; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013449:Sulfonamides; C520962:obatoclax; C528561:navitoclax
keywords: Apoptosis; Autophagy; BH3 mimetics; Bcl-2 family; Cancer therapy