Abstract

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 in-silico result, we further tested these drugs in a 3D spheroid model of A549, a lung adenocarcinoma cell line. The in-silico 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 in vitro 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

摘要

研究表明，与健康细胞相比，在癌细胞中，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) - 一种小管结合抗癌剂作为阳性对照。阻断 TTCC 已显示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 治疗还可以减少细胞内的细胞内钙信号传导。因此，PTX 有可能与钙通道相互作用。因为，药物-药物相互作用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。确认在计算机模拟结果中，我们在肺腺癌细胞系 A549 的 3D 球体模型中进一步测试了这些药物。计算机模拟结果表明，与 TTCC-native 相比，两种药物 TTA-A2 和 PTX 可以在 TTCC 的同一位点相互作用形成更稳定的复合物。体外实验结果表明，药物同时使用时，药物之间存在拮抗作用。通过使用顺序处理，在用 PTX 处理之前，球体被 TTA-A2 致敏。结果表明序贯治疗有助于克服两种药物之间的拮抗作用。

由 Ramaswamy H. Sarma 传达