Abstract
Tumor cell resistance to anti-cancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin in T24R2 cells, a T24-derived cell line. Treatment with cordycepin or cisplatin (2 μg/mL) alone failed to induce cell death in T24R2 cells, but combination treatment with these drugs significantly induced apoptosis through mitochondrial pathways, including depolarization of mitochondrial membranes, decrease in anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1, and increase in pro-apoptotic proteins Bak and Bax. High expression levels of MDR1 were the cause of cisplatin resistance in T24R2 cells, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on transcription factor Ets-1 in T24R2 cells. Although correlation exists between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr38 phosphorylated form (pThr38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 levels and reduced MDR1 transcription, probably through its effects on PI3K signaling, inducing the resensitization of T24R2 cells to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of cancer in patients with resistance to anti-cancer drugs.
Highlights
Chemotherapy is far the most effective cancer treatment, the clinical response of a patient to this treatment varies widely, and survival is often unsatisfactory
We investigated the mechanism of cordycepin-mediated resensitization to cisplatin in T24R2 cells, a cisplatin-resistant cell line derived from the T24 human bladder cancer cell line [14], suggesting that cordycepin may be developed as a candidate for combination therapy combinations in patients with cisplatin resistance
While cordycepin-induced cytotoxicity in T24R2 cells was slightly increased at a high dose of cordycepin (50 μg/mL), combination treatment with cordycepin and cisplatin significantly induced cell death starting at 20 μg/mL of cordycepin
Summary
Chemotherapy is far the most effective cancer treatment, the clinical response of a patient to this treatment varies widely, and survival is often unsatisfactory. The best studied mechanism of drug resistance in tumor cells is an increased efflux of anti-cancer drugs This mechanism is very effective in preserving intracellular drug concentrations below the apoptosis-triggering threshold by using a variety of ATP-dependent active drug transporters, such as multidrug resistance protein 1 (MDR1), breast cancer resistant protein (BCRP), and multi-drug resistance-associated protein 1 (MRP1) [5,6]. These transmembrane active transporters play an important role in recognizing anti-cancer drugs, and in detoxifying intracellular compartments by pumping these drugs out. Targeting active drug transporters such as MDR1, for example, can resensitize drug-resistant tumor cells to anti-cancer drugs [7,8]
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