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Dual-target platinum(IV) complexes reverse cisplatin resistance in triple negative breast via inhibiting poly(ADP-ribose) polymerase (PARP-1) and enhancing DNA damage

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单位： [1]Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China. [2]Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, China.

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关键词： Cisplatin resistance PARP inhibitors Platinum(IV) complex Multifunctional anticancer agent

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Platinum(II)-based drugs play an important role in many chemotherapeutic protocols, but their further clinical applications are hindered by the development of drug resistance and serious side effects. Therefore, to reverse cisplatin (CDDP) resistance in tandem with reduced side effects, nine novel platinum(IV) complexes modified with key pharmacophore of Olaparib were synthesized and evaluated for biological activities. Among them, the optimal complex 8-2 showed good inhibitory activity against PARP-1 and superior anticancer effects over CDDP on parental (MDA-MB-231, IC50 = 1.13 μM) and CDDP -resistant triple-negative breast cancer (TNBC) cell line (MDA-MB-231/CDDP, IC50 = 1.72 μM). Detailed mechanisms revealed that compared with Olaparib and CDDP, the enhanced intracellular accumulation of 8-2 could efficiently reverse CDDP resistance in MDA-MB-231/CDDP cells via inhibiting DNA repair-associated mechanisms, enhancing DNA damage, and activating mitochondrion-dependent apoptosis pathway. Furthermore, 8-2 obtained higher tumor growth inhibition rate (64.1 %) than CDDP (26.5 %) in MDA-MB-231/CDDP xenografts, but it did not induce significant toxicity in vivo and in intro, making it a potential drug candidate for the treatment of TNBC.Copyright © 2023 Elsevier Inc. All rights reserved.

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出版当年[2022]版：

大类 | 1 区

化学

小类 | 1 区有机化学 2 区生化与分子生物学

最新[2025]版：

大类 | 2 区医学

小类 | 1 区有机化学 2 区生化与分子生物学

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出版当年[2021]版：

Q1 CHEMISTRY, ORGANIC Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

最新[2023]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CHEMISTRY, ORGANIC

影响因子： 4.5 最新[2023版] 4.7 最新五年平均 5.307 出版当年[2021版] 5.321 出版当年五年平均 5.275 出版前一年[2020版] 5.1 出版后一年[2022版]

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第一作者单位： [1]Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.

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