Co-administration of nobiletin and tetrahydrocurcumin enhanced the cytotoxicity to breast cancer through inhibiting CYP1A1 enzyme: from the perspective of pharmacokinetic interactions.

BACKGROUND & OBJECTIVES: The introduction of traditional Chinese medicine to the treatment of breast cancer increases the risk of adverse herb-herb interactions. Both nobiletin and tetrahydrocurcumin (THC) have been demonstrated to inhibit breast cancer progression, which makes them easily co-prescribed. This study evaluated the co-administration of nobiletin and THC, aiming to assess their synergistic effect in inhibiting breast cancer and reveal the potential mechanism.

MATERIALS & METHODS: A single dosage of nobiletin and its co-administration with THC were performed in rats. The pharmacokinetic profiling of nobiletin was analyzed under the two administration strategies. Rat liver microsomes were employed for evaluating the metabolic stability of nobiletin and the activity of CYP1A1 with the probe-substance assay. The cytotoxicity of nobiletin and its combination with THC was evaluated in MCF-7 cells with the help of the CCK8 assay.

RESULTS

Co-administration strategy significantly changed the pharmacokinetics of nobiletin with the increasing Cmax (187.00 ± 9.27 vs. 145.87 ± 8.16 mg/L), prolonging t (22.01 ± 5.46 vs. 12.16 ± 1.20 h), and decreasing clearance rate (0.039 ± 0.01 vs. 0.062 ± 0.01 L/h/kg). THC increased the metabolic stability of nobiletin and enhanced its inhibitory effect on breast cancer cell growth. Additionally, THC also improved the cytotoxicity of nobiletin to MCF-7 cells, with the IC value decreased from 27.38 to 6.52 µM. Significant inhibition of CYP1A1 was observed under the treatment of THC.

CONCLUSION

Co-administration of nobiletin with THC increased its systemic exposure and enhanced its cytotoxicity to breast cancer. The inhibited activity of CYP1A1 was considered the underlying mechanism of their interaction.