Department of Biomedical Engineering, Regenerative Medicine and Stem Cells Laboratory, Indian Institute of Technology Hyderabad, Kandi, Telangana, India.
Department of Biotechnology, Indian Institute of Technology, Hyderabad, Telangana, India.
J Biomol Struct Dyn. 2022 Apr;40(6):2395-2406. doi: 10.1080/07391102.2020.1839558. Epub 2020 Oct 25.
Studies have shown that in cancer cells, there is an increased T-type calcium channel (TTCC) expression compared to healthy cells. Therefore, the studies targeting TTCC for cancer therapy have shown many positive outcomes. Here, we have used TTA-A2- a potent TTCC inhibitor as a test drug, and paclitaxel (PTX)- a tubule-binding anti-cancer agent as a positive control. Blocking TTCC has shown to overcome resistance in cancer cells towards anti-cancer drugs by reducing calcium influx, and some studies have shown that PTX treatment also reduces the intracellular calcium signaling in cells. So, there is a possibility that PTX might be interacting with calcium channels. Since, drug-drug interaction can cause severe side-effects, or alter the actions of each other; we aim to study the interactions among TTA-A2, PTX, and TTCC. In this study, we have used computational analysis to test the binding of TTA-A2 and PTX with TTCC. To confirm the result, we further tested these drugs in a 3D spheroid model of A549, a lung adenocarcinoma cell line. The result showed that both the drugs, TTA-A2 and PTX, could interact at the same site of TTCC to form a higher stable complex as compared to the TTCC-native. The result showed the antagonistic interaction between the drugs when they are used at the same time. By using the sequential treatment, the spheroids were sensitized by TTA-A2, before treating with PTX. The result indicated that sequential treatment could help to overcome the antagonistic interaction between the two drugs. Communicated by Ramaswamy H. Sarma.
研究表明，与健康细胞相比，癌细胞中 T 型钙通道（TTCC）的表达增加。因此，针对 TTCC 进行癌症治疗的研究已经显示出许多积极的结果。在这里，我们使用 TTA-A2——一种有效的 TTCC 抑制剂作为测试药物，紫杉醇（PTX）——一种结合微管的抗癌剂作为阳性对照。阻断 TTCC 已被证明可以通过减少钙内流来克服癌细胞对抗癌药物的耐药性，一些研究表明 PTX 治疗还可以降低细胞内的钙信号转导。因此，PTX 可能与钙通道相互作用。由于药物相互作用可能会导致严重的副作用，或改变彼此的作用；我们旨在研究 TTA-A2、PTX 和 TTCC 之间的相互作用。在这项研究中，我们使用计算分析来测试 TTA-A2 和 PTX 与 TTCC 的结合。为了证实这一结果，我们进一步在 A549（一种肺腺癌细胞系）的 3D 球体模型中测试了这些药物。结果表明，两种药物 TTA-A2 和 PTX 都可以在 TTCC 的同一部位相互作用，形成比 TTCC 天然结构更高稳定的复合物。结果显示，当两种药物同时使用时，它们之间存在拮抗相互作用。通过序贯治疗，在用 PTX 治疗之前，先用 TTA-A2 对球体进行敏化。结果表明，序贯治疗可以帮助克服两种药物之间的拮抗相互作用。由 Ramaswamy H. Sarma 交流。
