Effect of thymoquinone on pharmacokinetics of 5-fluorouracil in rats and its effect on human cell line in vitro

Abstract

Thymoquinone (TQ) is one of the components extracted from Nigella sativa seeds and has antioxidant, anti-inflammatory, and anticancer effects. We evaluated the effect of TQ on 5-fluorouracil (5-FU) pharmacokinetics (PK) in vivo and in vitro on human colorectal cancer cell line. Ten Adult male Wistar rats were assigned to two groups. TQ treated group received intraperitoneal TQ once daily for 14 consecutive days (5 mg/kg). Both groups received intraperitoneal 5-FU (50 mg/kg) on day 15 and blood samples were collected from retro-orbital plexus. The pharmacokinetics parameters were analyzed using high-performance liquid chromatography (HPLC). Moreover, various concentrations of 5-FU, TQ, and combination of 5-FU and TQ were added to the HT-29 cell line and cell viability was measured using 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The maximum serum concentration ( Cmax), area under the curve (AUC), and time of maximum concentration ( Tmax) of 5-FU in TQ treated group were significantly increased approximately by 61, 60, and 24% compared to the control group, respectively. The combination of 5-FU with TQ (0.284 mM) showed a greater inhibitory effect on HT-29 cell growth compared to the alone 5-FU (0.027 and 0.055 mM) administration. TQ increases the AUC, Cmax, and Tmax of 5-FU and has a synergistic effect on the PK of 5-FU. Moreover, low concentration of TQ enhances the inhibitory effects of 5-FU on cell growth in colorectal cancer cell line. This synergistic effect might enhance the anticancer effects of low concentration of 5-FU, leading to drug dose reduction and reduced systemic toxicity of this chemotherapeutic agent.

In Vitro Assessment of the Cytotoxic Effect of 5-Fluorouracil, Thymoquinone and their Combination on Tongue Squamous Cell Carcinoma Cell Line

“…In this investigation, the MTT assay was employed, It was performed as it is one of the dependable techniques for evaluating cellular viability. Furthermore, it is renowned for its discerning detection of cellular proliferation, as it quantifies the rate of cellular growth through the utilization of a linear correlation between cellular activity and absorbance [19].…”

Thymoquinone: A Promising Therapeutic Agent for the Treatment of Colorectal Cancer

“…In addition, the combination was found to decrease the expression of protumor genes, such as WNT, β-catenin, NF-κB, COX-2, inducible nitric oxide synthase (iNOS), VEGF, and increase the expression of antitumor genes, namely dickkopf-1 (DKK-1), cyclin dependent kinase inhibitor 1A (CDNK-1A), TGF-β1, TGF-βRII, Smad4 and glutathione peroxidase (GPx) [135]. Eftekhar and colleagues [136] reported similar findings. They showed that co-exposure of HT-29 cells to 5-FU and TQ resulted in greater cell inhibition than when the substances were used alone.…”

“…They showed that co-exposure of HT-29 cells to 5-FU and TQ resulted in greater cell inhibition than when the substances were used alone. They also showed that TQ has a synergistic effect on the pharmacokinetics of 5-FU [136]. TQ's effect on CRC and cancer stem cells, considered the most resistant to 5-FU, has also been studied.…”

Potential anticancer properties and mechanisms of thymoquinone in colorectal cancer

“…Notably, the combined administration of TQ and 5-FU resulted in an enhanced cytotoxic effect compared to the individual suppressive impact of 5-FU. 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 ].…”