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.

Ambra1 modulates the sensitivity of breast cancer cells to epirubicin by regulating autophagy via ATG12

“…Our previous study has found that EPI can induce autophagy in MCF‐7 breast cancer cells, which protects the cells from apoptosis . Guo et al subsequently obtained similar results in MDA‐MB‐231 and SK‐BR‐3 cells. However, Garbar et al report that multiple chemotherapy drugs, including EPI, induced an increase of autophagy in MCF‐7 cells, but not in MDA‐MB‐231 cells.…”

“…[7][8][9] Our previous study has found that EPI can induce autophagy in MCF-7 breast cancer cells, which protects the cells from apoptosis. 29 Guo et al 30 been published on the relationship between autophagy and cancer therapy, the mechanism by which autophagy participates in the treatment of cancer has not yet been fully established. [7][8][9] Here, we found that knockdown of Ambra1 blocked EPI-induced autophagy and increased the sensitivity of breast cancer cells to EPI.…”

Cytotoxic Potential of the Coelomic Fluid Extracted from the Sea Cucumber Holothuria tubulosa against Triple-Negative MDA-MB231 Breast Cancer Cells

“…MDA-MB231 cells are endowed with a constitutively elevated autophagy rate. Inhibition of autophagy was proven to render them susceptible to the lethal effect of chemicals in various experimental conditions (e.g., [18,19,31,32]); on the other hand, lethal effects on this cell line induced by several autophagy inducers have been reported in the literature (e.g., [33,34]).…”

“…This hypothesis is substantiated by the absence of activation of cell death program, as observed after cell exposure to CF preparations. In fact, it is also known that autophagosomal degradation of the damaged mitochondria reduces the intracytoplasmic release of cytochrome C and inhibits the onset of intrinsic apoptosis [32]. It must also be taken into consideration, however, that MDA-MB-231 cells are provided with a mutant p53 and high levels of phospholipase D, both sustaining survival, thereby being intrinsically resistant to apoptosis [40,41].…”

Cell-Free Coelomic Fluid Extracts of the Sea Urchin Arbacia lixula Impair Mitochondrial Potential and Cell Cycle Distribution and Stimulate Reactive Oxygen Species Production and Autophagic Activity in Triple-Negative MDA-MB231 Breast Cancer Cells

“…Autophagy plays a complex and controversial role in breast cancer, operating as either a tumor-suppressor system addressing neoplastic cells to death, or a cancer cell protective system which provides energy and basic elements to allow a fast-proliferative rate in conditions of oxygen and nutrient deficiency [36]. MDA-MB-231 cells are characterized by a constitutively elevated autophagy rate and autophagy restraining has made them vulnerable to cytotoxic treatments in various experimental conditions [20,21,37,38]. On the other hand, it is widely recognized that chemical induction of autophagy can be lethal to MDA-MB231 cells, as reported in some published papers [39,40].…”