Singh Vishal, Verma Suman, Fatima Fiza, Samanta Sintu Kumar, Varadwaj Pritish Kumar, Sahoo Amaresh Kumar
Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Allahabad 211015, Uttar Pradesh,India.
Department of Biotechnology, Rani Durgavati Vishwavidyalaya, Jabalpur, Madhya Pradesh 482001, India.
ACS Omega. 2023 Oct 3;8(41):38025-38037. doi: 10.1021/acsomega.3c03640. eCollection 2023 Oct 17.
Treatment of triple-negative breast cancer (TNBC) is very challenging as only few therapeutic options are available, including chemotherapy. Thus, a constant search for new and effective approaches of therapy that could potentially fight against TNBC and mitigate side effects is "turn-on". Recently, multitarget therapy has come up with huge possibilities, and it may possibly be useful to overcome several concurrent challenges in cancer therapy. Herein, we proposed the inhibition of both Topoisomerase II enzyme and p53-MDM2 (p53 cavity in MDM2) protein complex by the same bioactive molecules for multitarget therapy. RNA-seq analysis was performed to get a network of essential proteins involved in the apoptosis pathway by considering the triple-negative breast cancer cell line (MDA-MB-231). All of the untreated duplicate sample data were retrieved from NCBI (GSC149768). Further, via screening, potent bioactive molecules were screened out to target both Topo II and the p53-MDM2 complex. The results of ligand-based screening involving docking, MMGBSA, ADME/T, MD simulation, and PCA suggested that resveratrol, a plant bioactive molecule, showed more potential binding in the same cavity of target proteins compared with doxorubicin for Topo IIα (5GWK) and etoposide for the second protein target (p53-MDM2 complex; 4OQ3) as the control drug. This is also evident from the in vitro validation in case of triple-negative breast cancer cell lines (MDA-MB-231) and Western blotting analysis. Thus, it paves the scope of multitargeting against triple-negative breast cancer.
三阴性乳腺癌（TNBC）的治疗极具挑战性，因为只有包括化疗在内的少数治疗选择。因此，不断寻找能够对抗TNBC并减轻副作用的新的有效治疗方法很有必要。最近，多靶点治疗展现出了巨大潜力，它可能有助于克服癌症治疗中的几个同时存在的挑战。在此，我们提出用相同的生物活性分子抑制拓扑异构酶II和p53-MDM2（MDM2中的p53腔）蛋白复合物，以进行多靶点治疗。通过对三阴性乳腺癌细胞系（MDA-MB-231）进行RNA测序分析，以获得参与凋亡途径的必需蛋白网络。所有未处理的重复样本数据均从NCBI（GSC149768）检索。此外，通过筛选，筛选出了针对拓扑异构酶II和p53-MDM2复合物的强效生物活性分子。基于配体的筛选结果，包括对接、MMGBSA、ADME/T、分子动力学模拟和主成分分析，表明植物生物活性分子白藜芦醇与作为对照药物的拓扑异构酶IIα（5GWK）的阿霉素和第二个蛋白质靶点（p53-MDM2复合物；4OQ3）的依托泊苷相比，在靶蛋白的同一腔中显示出更强的潜在结合能力。这在三阴性乳腺癌细胞系（MDA-MB-231）的体外验证和蛋白质印迹分析中也很明显。因此，它为针对三阴性乳腺癌的多靶点治疗开辟了道路。
