Autophagy-dependent apoptosis is triggered by a semi-synthetic [6]-gingerol analogue in triple negative breast cancer cells

Abstract

Triple negative breast cancer (TNBC) is very aggressive and lacks specific therapeutic targets, having limited treatment options and poor prognosis. [6]-gingerol is the most abundant and studied compound in ginger, presenting diverse biological properties such as antitumor activity against several types of cancer, including breast cancer. In this study, we show that the semi-synthetic analogue SSi6, generated after chemical modification of the [6]-gingerol molecule, using acetone-2,4-dinitrophenylhydrazone (2,4-DNPH) reagent, enhanced selective cytotoxic effects on MDA-MB-231 cells. Remarkably, unlike the original [6]-gingerol molecule, SSi6 enabled autophagy followed by caspase-independent apoptosis in tumor cells. We found a time-dependent association between SSi6-induced oxidative stress, autophagy and apoptosis. Initial SSi6-induced reactive oxygen species (ROS) accumulation (1h) led to autophagy activation (2-6h), which was followed by caspase-independent apoptosis (14h) in TNBC cells. Additionally, our data showed that SSi6 induction of ROS plays a key role in the promotion of autophagy and apoptosis. In order to investigate whether the observed cell death induction was dependent on preceding autophagy in MDA-MB-231 cells, we used siRNA to knock down LC3B prior to SSi6 treatment. Our data show that LC3B downregulation decreased the number of apoptotic cells after treatment with SSi6, indicating that autophagy is a key initial step on SSi6-induced caspase-independent apoptosis. Overall, the results of this study show that structural modifications of natural compounds can be an interesting strategy for developing antitumor drugs, with distinct mechanisms of actions, which could possibly be used against triple negative breast cancer cells that are resistant to canonical apoptosis-inducing drugs.

6-Gingerol protects cardiocytes H9c2 against hypoxia-induced injury by suppressing BNIP3 expression

“…It has been well demonstrated that 6 G stimulates apoptosis in several cancer cells [11][12][13][14]. Meanwhile, 6 G induced autophagy in human cervical adenocarcinoma cells [15] and induced autophagy to protect human umbilical vein endothelial cells against apoptosis [32] while inhibited autophagy in lung cancer cells [33].…”

“…6-Gingerol (6 G) is a natural chemical compound isolated from ginger (Zingiber officinale). Specifically, 6 G has been indicated to possess potential efficacies against tumour [11][12][13][14][15][16], oxidative stress and inflammation [17][18][19]. Moreover, potent protection of 6 G against hypoxia/reoxygenation-induced injury has been recently elucidated.…”

St. John’s Wort Suppresses Growth in Triple-Negative Breast Cancer Cell Line MDA-MB-231 by Inducing Prodeath Autophagy and Apoptosis

“…In addition, in breast cancer, there are distinct abnormalities in the apoptotic pathway such as Bcl-2 overexpression, which confers resistance to chemotherapy [ 42 ]. Nowadays, accumulating evidence indicates that apoptosis and autophagy may be simultaneously induced by antitumor compounds in order to kill tumor cells in a complex, coordinated, and cooperative manner [ 43 , 44 , 45 ]. In consideration of this, it was of interest to see how the inhibition of autophagy was involved in apoptosis by SJWE treatment.…”

Sandensolide Induces Oxidative Stress-Mediated Apoptosis in Oral Cancer Cells and in Zebrafish Xenograft Model

“…In this study, we found that the cytotoxic effect of sandensolide on OSCC cells partially reversed by NAC and Z-VAD-FMK, suggesting that other pathways may be involved in the activity of this compound. Several studies have demonstrated that the accumulation of ROS induces oxidative damage to the induction of autophagy, leading to subsequent production of apoptotic cell death [ 43 , 44 ]. The cytotoxic effect of sandensolide related to autophagy should be an interesting subject for further investigations.…”