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.
Highlights
TQ significantly increased GCB-induced apoptotic effects by 1.5 to 3.6 folds
TQ improves the cytotoxicity of GCB in breast cancer cell lines
To study the influence of TQ on the cytotoxic profile of GCB against breast cancer cells, dose response curves of GCB, TQ and their combination were conducted against MCF-7 and T47D cells (Table 1)
Summary
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. 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%. 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. Natural compounds and even crude medicinal plants are believed to be promising source of alternative anti-cancer remedy. Combination of natural compounds with conventional cancer chemotherapy showed promising outcomes and gained the attention of scientists worldwide due to enhancing the anti-cancer efficacy without increasing normal tissue toxicity[14] In our previous work, combination of TQ with cisplatin diminished the resistance fraction to cisplatin and improved its anticancer activity against head and neck cancer cells[15]. The aim of the current work is to investigate the potential chemomodulatory effects of TQ to the cytotoxic profile of GCB against human breast cancer cell lines
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