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

Abstract

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 µmol/L) were co‐treated with various concentrations of IM (7.5–120 µmol/L) for 24, 48 and 72 hours. Imatinib‐TQ interaction was analysed using CompuSyn software. The IC50 values for IM were 105, 72 μmol/L after 48 and 72 hours, respectively, and were significantly reduced to 7.3, 7 and 5.5 μmol/L after combination with TQ (10 μmol/L) and to 5.8, 5.6 and 4.6 μmol/L after combination with TQ (20 μmol/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.

Therapeutic potential of thymoquinone in combination therapy against cancer and cancer stem cells

“…Resistance to IM was reported to develop in cancer patients through several mechanisms including the modulation of the expression of drug efflux and influx transporters[ 101 , 102 ]. In a study conducted by Thabet et al [ 103 ], TQ was found to improve the anti-proliferative and apoptotic effects of IM in colorectal cancer cells in vitro . Interestingly, this was accompanied by a significant decrease in the expression of the drug transporters ATP-binding cassette (ABC) subfamily B member (ABCB) 1, ABCG2 and human organic cation transporter 1 leading to a significant increase in IM uptake /efflux ratio compared to IM alone.…”

Potential anticancer properties and mechanisms of thymoquinone in colorectal cancer

“…This combination demonstrated a significant suppressive effect at 5-FU concentrations of 0.027 and 0.055 mM, suggesting that TQ could potentially amplify the growth-suppressive effects of 5-FU on cancer cells [ 127 ]. The concurrent administration of 30 μM imatinib, a tyrosine kinase inhibitor, and 10 μM TQ resulted in the suppression of ABCB1, ABCG2, and hOCT1, thereby enhancing the uptake of imatinib in HCT-116 cells [ 128 ]. The combination of 20 and 40 µM TQ with 0.2 µM cisplatin amplified the cytotoxicity of cisplatin in HCT-116 and COLO205 cells.…”

Targeting PI3K/Akt signaling in prostate cancer therapy

“…Thymoquinone has been employed in treatment of various cancers such as lung tumor, breast tumor and colorectal tumor, among others. Thymoquinone can affect various signaling networks in cancer therapy that PI3K/Akt signaling is among them and it can be used as a chemo‐sensitizer agent (Alam et al 2022; Karim et al 2022; Thabet et al 2021; Abd‐Rabou et al 2021). A recent experiment has employed docetaxel and thymoquinone in treatment of prostate cancer.…”