Sharma Rajni, Gatchie Linda, Williams Ibidapo S, Jain Shreyans K, Vishwakarma Ram A, Chaudhuri Bhabatosh, Bharate Sandip B
Natural Products Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK.
Bioorg Med Chem Lett. 2017 Dec 15;27(24):5400-5403. doi: 10.1016/j.bmcl.2017.11.013. Epub 2017 Nov 7.
The development of multi-drug resistance to existing anticancer drugs is one of the major challenges in cancer treatment. The over-expression of cytochrome P450 1B1 enzyme has been reported to cause resistance to cisplatin. With an objective to discover cisplatin-resistance reversal agents, herein, we report the evaluation of Glycyrrhiza glabra (licorice) extracts and its twelve chemical constituents for inhibition of CYP1B1 (and CYP1A1) enzyme in Sacchrosomes and live human cells. The hydroalcoholic extract showed potent inhibition of CYP1B1 in both Sacchrosomes as well as in live cells with IC values of 21 and 16 µg/mL, respectively. Amongst the total of 12 constituents tested, quercetin and glabrol showed inhibition of CYP1B1 in live cell assay with IC values of 2.2 and 15 µM, respectively. Both these natural products were found to be selective inhibitors of CYP1B1, and does not inhibit CYP2 and CYP3 family of enzymes (IC > 20 µM). The hydroalcoholic extract of G. glabra and quercetin (4) showed complete reversal of cisplatin resistance in CYP1B1 overexpressing triple negative MDA-MB-468 breast cancer cells. The selective inhibition of CYP1B1 by quercetin and glabrol over CYP2 and CYP3 family of enzymes was studied by molecular modeling studies.
对现有抗癌药物产生多药耐药性是癌症治疗中的主要挑战之一。据报道，细胞色素P450 1B1酶的过度表达会导致对顺铂产生耐药性。为了发现顺铂耐药逆转剂，在此我们报告了光果甘草提取物及其12种化学成分对线粒体微粒体和活的人类细胞中CYP1B1（和CYP1A1）酶的抑制作用评估。水醇提取物在微粒体和活细胞中均显示出对CYP1B1的有效抑制作用，IC值分别为21和16μg/mL。在总共测试的12种成分中，槲皮素和光甘草醇在活细胞测定中对CYP1B1有抑制作用，IC值分别为2.2和15μM。发现这两种天然产物都是CYP1B1的选择性抑制剂，不抑制CYP2和CYP3酶家族（IC>20μM）。光果甘草的水醇提取物和槲皮素（4）在过表达CYP1B1的三阴性MDA-MB-468乳腺癌细胞中显示出顺铂耐药性的完全逆转。通过分子建模研究了槲皮素和光甘草醇对CYP2和CYP3酶家族的CYP1B1选择性抑制作用。
