Thymoquinone chemosensitizes human colorectal cancer cells to imatinib via uptake/efflux genes modulation

摘要

Imatinib (IM) is a pharmaceutical drug that inhibits tyrosine kinase enzymes that are responsible for the activation of many proteins by signal transduction cascades as c-Abl, c-Kit and the platelet-derived growth factor (PDGF) receptor. Thymoquinone (TQ) is an active constituent of Nigella sativa seeds. Thymoquinone benefits are attributed to its medicinal uses as antioxidant, anticancer and antimicrobial agent. This study aimed to investigate the impact of using TQ with IM in the HCT116 human colorectal cancer cell line model. The HCT116 cells were treated with IM or/and TQ in non-constant ratios, in which the fixed concentrations of TQ (5, 10 or 20 mu mol/L) were co-treated with various concentrations of IM (7.5-120 mu mol/L) for 24, 48 and 72 hours. Imatinib-TQ interaction was analysed using CompuSyn software. The IC50 values for IM were 105, 72 mu mol/L after 48 and 72 hours, respectively, and were significantly reduced to 7.3, 7 and 5.5 mu mol/L after combination with TQ (10 mu mol/L) and to 5.8, 5.6 and 4.6 mu mol/L after combination with TQ (20 mu mol/L) to 24, 48 and 72 hours, respectively. The combination index (CI) and dose reduction index (DRI) values indicate a significant synergism in HCT-116 cells at different treatment time points. Thymoquinone significantly enhances the cellular uptake of IM in HCT116 cells in a time and concentration-dependent manner. A significant downregulation in ATP-binding cassette (ABC) subfamily B member 1 (ABCB1), ABC subfamily G member 2 (ABCG2) and human organic cation transporter 1 (hOCT1) genes was observed in the cells exposed to IM+TQ combination as compared to IM alone, which resulted in a substantial elevation in uptake/efflux ratio in combination group. In conclusion, TQ potentiates IM efficacy on HCT116 cells via uptake/efflux genes modulation.