Thymoquinone synergizes gemcitabine anti-breast cancer activity via modulating its apoptotic and autophagic activities

Abstract

The use of anti-cancer adjuvant therapy is rationalized by potentiating the efficacy, and/or protecting from major side effects of chemotherapeutics. Thymoquinone (TQ) is a naturally occurring compound with cumulative evidence of anti-cancer properties. In this study, we assessed the chemomodulatory potential of TQ to gemcitabine (GCB) against human breast adenocarcinoma (MCF-7), and ductal carcinoma (T47D) cells. TQ showed cytotoxic effects against MCF-7 and T47D with IC50’s of 64.9 ± 14 µM and 165 ± 2 µM, respectively. The IC50’s of GCB against MCF-7 and T47D were 0.9 ± 0.18 µM and 14.3 ± 2.8 µM and were significantly reduced after combination with TQ to 0.058 ± 12 µM and 2.3 ± 0.2 µM, respectively. The CI- values were indicative of synergism in MCF-7 and T47D cells (0.15 and 0.30, respectively). Further investigation showed that GCB caused significant anti-proliferative effect reflected by increasing cell population in S-phase in both cell lines. TQ potentiated GCB-induced anti-proliferative activity in both cell lines. GCB induced considerable apoptosis in T47D cell line, and TQ significantly increased GCB-induced apoptotic effects by 1.5 to 3.6 folds. Interestingly, GCB, TQ and their combination induced significant autophagic cell death in the apoptosis defected MCF-7 cells. In addition, TQ, GCB and their combination depleted breast cancer associated stem cell (CD44(+)/CD24(−)/(low)) clone within MCF-7 and T47D cells by 3.8% to 27.5%. In conclusion, TQ showed promising chemomodulatory effects to GCB against breast cancer cells via inducing apoptosis, necrosis and autophagy, in addition to depleting tumor associated resistant stem cell fraction.

Design and synthesis of novel phenylaminopyrimidines with antiproliferative activity against colorectal cancer

“…Putting the killing prole of these compounds (Table 1) in consideration, we suggest that, HCT-116 and HT-29 CRC cells are escaping apoptosis via autophagy shunting. In other words and similar to what was observed in our previous study on breast cancer cells, 28 autophagy is considered here to be an apoptosis escape shelter. 27,29,30…”

Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets

“…Increased autophagic cell death has also been observed to synergize with the caspase-dependent apoptotic cell death in SASVO3 cells. A similar role for TQ in inducing both apoptotic and autophagic cell death with the resultant potentiation of the anti-proliferative effects of Gemcitabine has been noted in MCF7 breast cancer cells [117]. In LoVo colon cancer cells, TQ can induce autophagic cell death through pathways involving the activation of JNK and p38 MAPK [118].…”

Molecular Insights Into Therapeutic Potential of Autophagy Modulation by Natural Products for Cancer Stem Cells

“…However, salinomycin, a polyether ionophore antibiotic, eliminated BCSCs induction of lipid oxidation, mitochondrial dysfunction, and oxidative stress (Zhao et al, 2019). Thymoquinone, derived from Nigella sativa, increases the cytotoxicity in breast cancer cell lines via autophagy stimulation (Bashmail et al, 2018). Curcumin, natural phytochemical, preventing the proliferation of BCSCs along with decreasing the bulk breast cancer cells (Li and Zhang, 2014).…”