Acharya Reetuparna, Deb Pran Kishore, Venugopala Katharigatta N, Pattanayak Shakti Prasad
Division of Advanced Pharmacology, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology (BIT), Mesra, Ranchi 835215, India.
Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology (BIT), Mesra, Ranchi 835215, India.
Pharmaceuticals (Basel). 2024 Dec 6;17(12):1645. doi: 10.3390/ph17121645.
: Breast cancer influences more than 2 million women worldwide annually. Since apoptotic dysregulation is a cancer hallmark, targeting apoptotic regulators encompasses strategic drug development for cancer therapy. One such class of apoptotic regulators is inhibitors of apoptosis proteins (IAP) which are a class of E3 ubiquitin ligases that actively function to support cancer growth and survival. : The current study reports design, synthesis, docking analysis (based on binding to IAP-BIR3 domains), anti-proliferative and anti-tumor potential of the azomethine derivative, 1-(4-chlorophenyl)-N-(4-ethoxyphenyl)methanimine () on breast cancer (in vitro and in vivo) and its possible mechanisms of action. : Strong selective cytotoxic activity was observed in MDA-MB-231, MCF-7, and MDA-MB-468 breast cancer cell lines that exhibited IC50 values, 1.554 µM, 5.979 µM, and 6.462 µM, respectively, without affecting normal breast cells, MCF-10A. For the evaluation of the cytotoxic potential of , immunofluorescence, immunoblotting, and FACS (apoptosis and cell cycle) analyses were conducted. antagonized IAPs, thereby causing MDM2-p53 and Bcl-2-Caspase-mediated intrinsic and extrinsic apoptosis. It also modulated p53 expression causing p21-CDK1/cyclin B1-mediated cell cycle arrest at S and G2/M phases. The in vitro findings were consistent with in vivo findings as observed by reduced tumor volume and apoptosis initiation (TUNEL assay) by IAP downregulation. also produced potent synergistic effects with doxorubicin on tumor inhibition. : Having witnessed the profound anti-proliferative potential of , the possible adverse effects related to anti-cancer therapy were examined following OECD 407 guidelines which confirmed its systemic safety profile and well tolerability. The results indicate the promising effect of as an IAP antagonist for breast cancer therapy with fewer adverse effects.
乳腺癌每年影响全球超过200万女性。由于凋亡失调是癌症的一个标志，靶向凋亡调节因子是癌症治疗战略药物开发的重点。凋亡抑制蛋白（IAP）就是这样一类凋亡调节因子，它是一类E3泛素连接酶，在支持癌症生长和存活方面发挥着积极作用。
当前的研究报告了甲亚胺衍生物1-(4-氯苯基)-N-(4-乙氧基苯基)甲亚胺（）对乳腺癌的设计、合成、对接分析（基于与IAP-BIR3结构域的结合）、抗增殖和抗肿瘤潜力（体内和体外）及其可能的作用机制。
在MDA-MB-231、MCF-7和MDA-MB-468乳腺癌细胞系中观察到了强烈的选择性细胞毒性活性，其IC50值分别为1.554 μM、5.979 μM和6.462 μM，而对正常乳腺细胞MCF-10A没有影响。为了评估的细胞毒性潜力，进行了免疫荧光、免疫印迹和FACS（凋亡和细胞周期）分析。拮抗IAP，从而导致MDM2-p53和Bcl-2-半胱天冬酶介导的内源性和外源性凋亡。它还调节p53表达，导致p21-CDK1/细胞周期蛋白B1介导的细胞周期在S期和G2/M期停滞。体外研究结果与体内研究结果一致，通过IAP下调观察到肿瘤体积减小和凋亡启动（TUNEL检测）。与阿霉素对肿瘤抑制也产生了强大的协同作用。
鉴于见证了的深刻抗增殖潜力，按照经合组织407指南检查了与抗癌治疗相关的可能不良反应，证实了其全身安全性和良好耐受性。结果表明作为一种IAP拮抗剂用于乳腺癌治疗具有良好前景且不良反应较少。
