The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells

Abstract

Triple-negative breast cancer (TNBC), which is estrogen receptor (ER)-negative, progesterone receptor‑negative and is also negative for HER2 expression, remains a great clinical challenge due to its strong resistance to chemotherapy at the late stage of treatment and relatively unfavorable prognosis. Gemcitabine has been approved by the FDA/SFDA for use as a first-line therapeutic drug against advanced or metastatic breast cancer. Therefore, the clarification of the mechanisms underlying gemcitabine-acquired resistance is of particular importance for the optimal management of TNBC. A number of studies have revealed that autophagy, which has been found to protect cancer cells from anti-cancer drug-induced death, may contribute to the development of drug resistance. However, the association between autophagy and gemcitabine treatment in TNBC cells has yet to be defined. Our study clearly demonstrates that gemcitabine is able to induce mTOR-independent autophagy in human triple‑negative MDA-MB-231 breast cancer cells. In addition, we demonstrate that autophagy protects MDA-MB-231 cells from gemcitabine-induced cell growth inhibition and apoptosis, indicating that gemcitabine can activate autophagy to impair the sensitivity of MDA-MB‑231 cells. Furthermore, as shown by our results, the inhibition of gemcitabine-induced autophagy by chloroquine shifts the expression of the p53 protein, Bcl-2 family proteins and the relative Bax/Bcl-xL ratio in favor of promoting apoptosis. These results reveal that the inhibition of apoptosis may be one of the mechanisms of autophagy-induced cytoprotection in gemcitabine-treated MDA-MB-231 cells. The apoptotic and autophagic processes constitute a mutual inhibition system and jointly seal the fate of TNBC cells that are exposed to gemcitabine. Thus, our study suggests that the combination of an autophagic inhibitor and gemcitabine as a therapeutic strategy may represent a promising approach with greater clinical efficacy for patients with TNBC. However, extended preclinical trials are required to further determine the positive effects of the inhibition of autophagy on the efficacy of gemcitabine.

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

“…The double sided functions of autophagy implicate its paradoxical roles in anticancer treatments, increasing or diminishing their anticancer activity. However, an increasing amount of evidence suggests that autophagy׳s pro-survival function plays a significant role in chemoresistance in a many different cancer types33, 34, 35, 36, 37, 38.…”

Exosomes as a Surrogate Marker for Autophagy in Peripheral Blood, Correlative Data from Phase I Study of Chloroquine in Combination with Carboplatin/Gemcitabine in Advanced Solid Tumors

“…Even though, its role in cancer development, progression, and metastases has been widely described with a vast amount of data, most of these data were obtained from in vitro and mice models (Kuma et al, 2004;Komatsu et al, 2006;Mizushima et al, 2008;Zou et al, 2013;Chen et al, 2014a;Lowry et al, 2015). The main focus is to establish connection to other process by monitoring effects on their biomarkers.…”

Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer

“…Evidences reported that blockage of autophagy increased the sensitivity of chemotherapy, radiotherapy, and EGFR target therapy in NSCLC cells [17–19]. Chen et al reported that inhibiting the cytoprotective autophagy induced by gemcitabine enhanced apoptosis in TNBC cells [20]. Cufi et al found that autophagy was involved in HER2-targeted therapy in breast cancer, and was associated with drug resistance [21].…”