Faculty of Pharmacy, University of Science & Technology, Omdurman, Sudan.
Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Molecules. 2022 Sep 9;27(18):5858. doi: 10.3390/molecules27185858.
The chemotherapy of tumors is frequently limited by the development of resistance and severe side effects. Phytochemicals may offer promising candidates to meet the urgent requirement for new anticancer drugs. We screened 69 phytochemicals, and focused on gedunin to analyze its molecular modes of action. Pearson test-base correlation analyses of the logIC values of 55 tumor cell lines of the National Cancer Institute (NCI), USA, for gedunin with those of 91 standard anticancer agents revealed statistically significant relationships to all 10 tested microtubule inhibitors. Thus, we hypothesized that gedunin may be a novel microtubule inhibitor. Confocal microscopy, cell cycle measurements, and molecular docking in silico substantiated our assumption. Agglomerative cluster analyses and the heat map generation of proteomic data revealed a subset of 40 out of 3171 proteins, the expression of which significantly correlated with sensitivity or resistance for the NCI cell line panel to gedunin. This indicates the complexity of gedunin's activity against cancer cells, underscoring the value of network pharmacological techniques for the investigation of the molecular modes of drug action. Finally, we correlated the transcriptome-wide mRNA expression of known drug resistance mechanism (ABC transporter, oncogenes, tumor suppressors) logIC values for gedunin. We did not find significant correlations, indicating that gedunin's anticancer activity might not be hampered by classical drug resistance mechanisms. In conclusion, gedunin is a novel microtubule-inhibiting drug candidate which is not involved in multidrug resistance mechanisms such as other clinically established mitotic spindle poisons.
肿瘤的化疗常常受到耐药性和严重副作用的发展的限制。植物化学物质可能为满足新抗癌药物的迫切需求提供有希望的候选物。我们筛选了 69 种植物化学物质，并专注于研究格尔丁宁，以分析其作用机制。美国国立癌症研究所（NCI）55 种肿瘤细胞系的 logIC 值与 91 种标准抗癌药物的格尔丁宁的 Pearson 测试基础相关分析显示出与所有 10 种测试的微管抑制剂有统计学显著关系。因此，我们假设格尔丁宁可能是一种新型的微管抑制剂。共聚焦显微镜、细胞周期测量和计算机分子对接证实了我们的假设。蛋白质组学数据的凝聚聚类分析和热图生成显示出 3171 种蛋白质中的 40 种蛋白质子集，其表达与格尔丁宁对 NCI 细胞系的敏感性或耐药性显著相关。这表明格尔丁宁对癌细胞活性的复杂性，突出了网络药理学技术在研究药物作用机制中的价值。最后，我们将已知耐药机制（ABC 转运蛋白、癌基因、肿瘤抑制基因）的转录组 mRNA 表达与格尔丁宁的 logIC 值进行了相关性分析。我们没有发现显著相关性，表明格尔丁宁的抗癌活性可能不受经典耐药机制的影响。总之，格尔丁宁是一种新型的微管抑制剂候选药物，它不涉及其他临床确立的有丝分裂纺锤体毒物等多药耐药机制。
