School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China.
J Med Chem. 2023 Jul 27;66(14):9537-9560. doi: 10.1021/acs.jmedchem.3c00213. Epub 2023 Jul 6.
Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the enzyme has been recognized as one of the important factors in inducing anthracycline (ANT) resistance in cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of over DOX cytotoxicity was demonstrated and . Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.
醛酮还原酶 1C3（AKR1C3）与肿瘤的发生和化疗耐药有关。该酶的催化活性已被认为是诱导癌细胞中蒽环类药物（ANT）耐药的重要因素之一。抑制 AKR1C3 的活性可能为恢复 ANT 耐药性癌症的化疗敏感性提供一种有前途的方法。在此，开发了一系列含联苯的 AKR1C3 抑制剂。最佳类似物 选择性地阻断 AKR1C3 介导的阿霉素（DOX）在 MCF-7 转染细胞模型中的还原。此外， 与 DOX 联合处理显著协同增强了 MCF-7 细胞中 AKR1C3 过表达的 DOX 细胞毒性，并逆转了 DOX 耐药性。 和 进一步证明了 对 DOX 细胞毒性的潜在协同作用。我们的研究结果表明，抑制 AKR1C3 可能增强 ANTs 的治疗效果，甚至表明 AKR1C3 抑制剂可能作为有效的佐剂，用于克服癌症治疗中 AKR1C3 介导的化疗耐药性。
