<br>膳食生物活性二吲哚甲烷通过调节 ABCB1/P-gp 外排转运蛋白增强 Centchroman 对乳腺癌细胞的治疗功效,The Journal of Nutritional Biochemistry

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膳食生物活性二吲哚甲烷通过调节 ABCB1/P-gp 外排转运蛋白增强 Centchroman 对乳腺癌细胞的治疗功效
The Journal of Nutritional Biochemistry ( IF 4.8 ) Pub Date : 2021-04-25 , DOI: 10.1016/j.jnutbio.2021.108749
Dhanamjai Penta ₁ , Priya Mondal ₁ , Jagadish Natesh ₁ , Syed Musthapa Meeran ₁

Affiliation

药物外流转运蛋白的过度表达通常与癌症治疗中的多药耐药性相关。在这里，我们首次研究了二吲哚甲烷 (DIM)（一种富含十字花科蔬菜的膳食生物活性物质）通过调节人乳腺癌细胞中的药物外流转运蛋白来增强 Centchroman (CC) 功效的能力。 CC是一种选择性雌激素受体调节剂，对乳腺癌具有良好的治疗效果。 DIM 和 CC 的组合可协同抑制乳腺癌细胞的细胞增殖并诱导细胞凋亡。这种新颖的组合也阻碍了人类乳腺癌细胞的干细胞性。分子对接分析表明，DIM 与 ABCB1 (P-gp) 和 ABCC1 (MRP1) 药物外排转运蛋白的底物结合位点表现出很强的结合亲和力。 DIM 增加了乳腺癌细胞中 Hoechst 和 Calcein（分别是 P-gp 和 MRP1 的底物）的细胞内积累。此外，DIM 刺激 P-gp ATP 酶活性，这表明 DIM 与 P-gp 的底物结合结构域结合，从而抑制其外排活性。有趣的是，DIM 通过抑制 P-gp 和 MRP1 的表达以及活性来提高 CC 的细胞内浓度。 CC 的细胞内保留增加了其抗乳腺癌的功效。总体而言，DIM（一种膳食生物活性物质）通过调节乳腺癌细胞中的药物流出 ABC 转运蛋白来增强 CC 的抗癌效率。因此，基于DIM的营养保健品和功能食品可以开发作为人类乳腺癌的辅助治疗。

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Dietary bioactive diindolylmethane enhances the therapeutic efficacy of centchroman in breast cancer cells by regulating ABCB1/P-gp efflux transporter

Overexpression of drug efflux transporters is commonly associated with multidrug-resistance in cancer therapy. Here for the first time, we investigated the ability of diindolylmethane (DIM), a dietary bioactive rich in cruciferous vegetables, in enhancing the efficacy of Centchroman (CC) by modulating the drug efflux transporters in human breast cancer cells. CC is a selective estrogen receptor modulator, having promising therapeutic efficacy against breast cancer. The combination of DIM and CC synergistically inhibited cell proliferation and induced apoptosis in breast cancer cells. This novel combination has also hindered the stemness of human breast cancer cells. Molecular docking analysis revealed that DIM had shown a strong binding affinity with the substrate-binding sites of ABCB1 (P-gp) and ABCC1 (MRP1) drug-efflux transporters. DIM has increased the intracellular accumulation of Hoechst and Calcein, the substrates of P-gp and MRP1, respectively, in breast cancer cells. Further, DIM stimulates P-gp ATPase activity, which indicates that DIM binds at the substrate-binding domain of P-gp, and thereby inhibits its efflux activity. Intriguingly, DIM enhanced the intracellular concentration of CC by inhibiting the P-gp and MRP1 expression as well as activity. The intracellular retaining of CC has increased its efficacy against breast cancer. Overall, DIM, a dietary bioactive, enhances the anticancer efficiency of CC through modulation of drug efflux ABC-transporters in breast cancer cells. Therefore, DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy against human breast cancer.

更新日期：2021-04-25

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