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. 2025 Aug 4;16(1):1465.
doi: 10.1007/s12672-025-03229-0.

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

Hongming Song  1 , Fengqin Gao  2 , Zhaohe Niu  3 , Xiangping Liu  4 , Xingang Wang  3 , Weihong Cao  3 , Haibo Wang  5
Affiliations

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

Hongming Song et al. Discov Oncol. .

Abstract

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 t1/2 (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 IC50 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.

Keywords: CYP450; Co-administration; Cytotoxicity; Drug-drug interaction; Pharmacokinetic; Synergistic effect.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study had been approved by the Ethics Committee of The Affiliated Hospital of Qingdao University. The study was conducted in agreement with the ARRIVE guidelines. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Plasma concentration-time curve of nobiletin indicating its pharmacokinetic profile under the treatment of a single dosage of nobiletin and co-administration with THC in rats
Fig. 2
Fig. 2
Cell growth (a), concentration-dependent inhibition evaluation (b), and total cell apoptosis rate (c) of MCF-7 cells under the treatment of a single dosage of nobiletin (10 µM) and co-administration with THC (10 µM). *P < 0.05, ****P < 0.0001
Fig. 3
Fig. 3
Concentration-dependent inhibition of CYP1A1 evaluated in rat liver microsomes under 5, 10, 25, 50, and 100 µM THC (a). The inhibition model of CYP1A1 by THC was evaluated by Linear-Burk analysis (b)
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