Abstract
Aim: Chemoresistance is a prevalent issue in cancer treatment. Paclitaxel (PTX) is a microtubule-binding anticancer drug used in various cancer treatments. However, cancer cells often show chemoresistance against PTX with the help of P-glycoprotein (Pgp) - a drug efflux pump. It has also been observed that overexpressed T-type calcium channels (TTCCs) maintain calcium homeostasis in cancer cells, and calcium has a role in chemoresistance. Therefore, the aim of this study was to test the adjuvant role of TTA-A2, a TTCC blocker, in enhancing the anticancer effect of PTX on the A549 lung adenocarcinoma cell line. Methods: Morphology assay, calcium imaging assay, clonogenic assay, apoptosis assay, and real-time polymerase chain reaction (real-time PCR) were performed to find the adjuvant role of TTA-A2. Samples were treated with PTX at 10 nM concentration and TTA-A2 at 50 and 100 nM concentrations. PTX and TTA-A2 were used in the combination treatment at 10 and 100 nM concentrations, respectively. Results: Immunocytochemistry confirmed the expression of TTCC in A549 cells. Morphology assay showed altered morphology of A549 cells. The adjuvant role of TTA-A2 was observed in the calcium imaging assay in spheroids, in the clonogenic assay in monolayers, and in the apoptosis assay in both cultures. With real-time PCR, it was observed that, even though cells express the mRNA of Pgp, it is non-significant upon treatment with PTX and TTA-A2. Conclusion: TTA-A2 can be used as an adjuvant to reduce chemoresistance in cancer cells as well as to enhance the anticancer effect of the standard anticancer drug PTX. Being a potent TTCC inhibitor, TTA-A2 may also enhance the anticancer effects of other anticancer drugs.
Highlights
Cancer has a significant impact on mortality worldwide
The adjuvant role of TTA-A2 was observed in the calcium imaging assay in spheroids, in the clonogenic assay in monolayers, and in the apoptosis assay in both cultures
TTA-A2 can be used as an adjuvant to reduce chemoresistance in cancer cells as well as to enhance the anticancer effect of the standard anticancer drug PTX
Summary
Cancer has a significant impact on mortality worldwide. At least 14 million cancer patients and 8 million cancer deaths are recorded every year[1]. Paclitaxel (PTX), a microtubule-binding agent, is widely used in the treatment of various cancers[3,4,5,6], such as lung[7], ovarian[8], breast[9], and prostate cancer[10]. It binds to the microtubule β-tubulin subunit and stabilizes its structure, thereby preventing microtubule depolymerization. Cancer cells acquire resistance to PTX through the action of Pglycoprotein (Pgp), a drug efflux pump[12,13,14] Calcium signaling is another factor known to induce chemoresistance in cells[14,15]
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