title: Inhibiting autophagy increases epirubicin's cytotoxicity in breast cancer cells.
abstract: Chemotherapy, radiotherapy, and endocrinotherapy are documented to induce autophagy among breast cancer cells, but the role of autophagy in this disease has been attributed as cytoprotective as well as tumor-suppressing. Thus we studied MDA-MB-231 and SK-BR-3 breast cancer cell lines treated with epirubicin (EPI) to assess autophagy and apoptosis. We found out that EPI induced apoptosis and autophagy in both cell lines. The lysosomal inhibitor bafilomycin A1 inhibited cellular autophagy and enhanced EPI-triggered apoptosis, perhaps due to inhibition of autolysosome formation, which then inhibited autophagic effects of engulfing and clearing damaged mitochondria. This inhibition increased mitochondrial cytochrome C release which augmented epirubicin-induced caspase-dependent apoptosis and cytotoxicity. In addition, the lysosomal neutralizing agent ammonia chloride (AC), and Atg7 knockdown by siRNA, could inhibit epirubicin-triggered autophagy, enhance cytotoxicity, and increase caspase-9- and caspase-3-dependent apoptosis. Thus, autophagy plays a prosurvival role in EPI-treated MDA-MB-231 and SK-BR-3 cells, and autophagy inhibition can potentially reverse this effect and increase the cytotoxicity of EPI.
authors: Laboratory of Molecular Diagnosis of Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.|State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Wei
authors: W
authors: Guo
authors: Laboratory of Molecular Diagnosis of Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Yu
authors: Y
authors: Wang
authors: Laboratory of Molecular Diagnosis of Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Zhu
authors: Z
authors: Wang
authors: Laboratory of Molecular Diagnosis of Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.|State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Yan-Ping
authors: YP
authors: Wang
authors: Laboratory of Molecular Diagnosis of Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.|State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors: Hong
authors: H
authors: Zheng
mesh_terms: D000643:Ammonium Chloride / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000071182:Autophagosomes / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D015251:Epirubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells
chemical_list: D018942:Macrolides; D000643:Ammonium Chloride; D015251:Epirubicin; C040929:bafilomycin A1; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9
keywords: Autophagy; bafilomycin A1; breast cancer; cytotoxicity; epirubicin