Nair Rakesh Sathish, Potti Manoj Easwaran, Thankappan Ratheeshkumar, Chandrika Sivakumar Krishnankutty, Kurup M R Prathapachandra, Srinivas Priya
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud, Thiruvananthapuram, Kerala, India.
Department of Applied Chemistry, Cochin University of Science and Technology, Kochin, Kerala, India.
Mol Carcinog. 2017 May;56(5):1501-1514. doi: 10.1002/mc.22610. Epub 2017 Jan 18.
Novel chelated metal complexes were synthesized from carbohydrazones to thiocarbohydrazones using metal-based drug designing platforms and their combination effect with Pb, a naphthaquinone were analyzed for anticancer activity in breast cancer cell lines. A panel of BRCA1 wild-type and mutated breast cancer cells: MCF-7 (BRCA1 /ER ), MDA-MB-231 (BRCA1 /ERα ), HCC-1937 (BRCA1 /ERα ), HCC1937/wt BRCA1, MX1 (BRCA1 /ERα ), and MDA-MB-436 (BRCA1 /ERα ) were screened for anti-cancer activity. Cu (HL)(HSO ) · H O]SO · 6 H O (CS2) is the most potent anticancer agent among the copper carbohydrazone and thiocarbohydrazone complexes analyzed in this study. It can be suggested that the presence of sulphate, as pharmacologically active centre, can induce cytotoxicity more effectively when compared to chlorine, bromine, perchlorate, and methanol. This is the first report demonstrating that CS2 can bind to DNA by hindering BamH1 activity and could induce DNA double strand breaks as evidenced by γ-H2AX expression. In addition to this, CS2 could also act as a Topo II inhibitor at a much lower concentration than etoposide and induce apoptosis, making it a potent anticancer agent. In combination with Pb, a potent ROS inducer, CS2 could induce synergistic anti-cancer activity in HR/ BRCA1 defective breast cancer cells. This is the first study reporting the mechanism involved in the induction of apoptosis for a metal chelated copper carbohydrazone complex and its combination effects with Pb in HR defective, BRCA1 mutated breast cancer cells.
使用基于金属的药物设计平台，从 carbohydrazones 到 thiocarbohydrazones 合成了新型螯合金属配合物，并分析了它们与萘醌 Pb 的组合效应在乳腺癌细胞系中的抗癌活性。对一组 BRCA1 野生型和突变型乳腺癌细胞：MCF-7（BRCA1 /ER ）、MDA-MB-231（BRCA1 /ERα ）、HCC-1937（BRCA1 /ERα ）、HCC1937/wt BRCA1、MX1（BRCA1 /ERα ）和 MDA-MB-436（BRCA1 /ERα ）进行了抗癌活性筛选。Cu(HL)(HSO ) · H O]SO · 6 H O（CS2）是本研究分析的铜 carbohydrazone 和 thiocarbohydrazone 配合物中最有效的抗癌剂。可以认为，作为药理活性中心的硫酸盐的存在，与氯、溴、高氯酸盐和甲醇相比，能更有效地诱导细胞毒性。这是第一份报告表明 CS2 可以通过阻碍 BamH1 活性与 DNA 结合，并如 γ-H2AX 表达所证明的那样诱导 DNA 双链断裂。除此之外，CS2 还可以在比依托泊苷低得多的浓度下作为拓扑异构酶 II 抑制剂并诱导细胞凋亡，使其成为一种有效的抗癌剂。与强效 ROS 诱导剂 Pb 联合使用时，CS2 可以在 HR/BRCA1 缺陷的乳腺癌细胞中诱导协同抗癌活性。这是第一项报道金属螯合铜 carbohydrazone 配合物诱导细胞凋亡的机制及其在 HR 缺陷、BRCA1 突变的乳腺癌细胞中与 Pb 的联合效应的研究。
