Antagonistic interaction between TTA-A2 and paclitaxel for anti-cancer effects by complex formation with T-type calcium channel

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

Keywords:

• A549
• Lung cancer
• paclitaxel
• TTA-A2
• T-type calcium channel
• synergistic/antagonistic effect

Acknowledgements

This work was supported by the IMPRINT under Grant [no. 5450]; UGC JRF fellowship under Grant [Ref no: 21/12/2014(ii)EU-V]; and Department of biotechnology under Grant [DBT/2015/IIT-R/349]. Authors thank Macromolecular Crystallographic Unit (MCU), a Central Facility at Institute Instrumentation Centre (IIC), IIT Roorkee for computational work.

Disclosure statement

Authors declare no conflict of interest.

Data availability statement

The data supporting the study are available from the corresponding author on request. The data are not made publicly available due to privacy or ethical restrictions.