Abstract
BackgroundChemoresistance is one of the most leading causes for tumor progression and recurrence of bladder cancer. Reactive oxygen species (ROS) plays a key role in the chemosensitivity of cancer cells. In the present study, emodin (1,3,8-trihydroxy-6-methylanthraquinone) was applied as a ROS generator in combination with cisplatin in T24 and J82 human bladder cancer cells.MethodsCell viability and apoptosis rate of different treatment groups were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM). The expression of transporters was measured at both the transcription and translation levels using PCR and western blotting. In vitro findings were confirmed by in vivo experiments using tumor-bearing mice. The expression of multidrug resistance-associated protein 1 (MRP1) in tumour tissue was measured using immunohistochemistry and side effects of the emodin/cisplatin co-treatment were investigated by histological examination.ResultsEmodin increased the cellular ROS level and effectively enhanced the cisplatin-induced cytotoxicity of T24 and J82 human bladder cancer cells through decreasing glutathione-cisplatin (GSH-cisplatin) conjugates. It blocked the chemoresistance of T24 and J82 cells to cisplatin through suppressing the expression of MRP1. This effect was specific in T24 and J82 cells but not in HCV-29 normal bladder epithelial cells. Consistent with in vitro experiments, emodin/cisplatin co-treatment increased the cell apoptosis and repressed the MRP1 expression in xenograft tumors, and without obvious systemic toxicity.ConclusionsThis study revealed that emodin could increase the cisplatin-induced cytotoxicity against T24 and J82 cells via elevating the cellular ROS level and downregulating MRP1 expression. We suggest that emodin could serve as an effective adjuvant agent for the cisplatin-based chemotherapy of bladder cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2640-3) contains supplementary material, which is available to authorized users.
Highlights
Chemoresistance is one of the most leading causes for tumor progression and recurrence of bladder cancer
Effects of emodin co-treated with cisplatin on T24 and J82 cells viability According to the cell viability test (Additional file 3: Figure S1 and Additional file 4: Figure S2), the cisplatin concentration of 1.5 μg/ml was selected as an appropriate dose for investigating chemotherapeutic sensitivity at 24 h for T24 cells, and 1 μg/ml for J82 cells
We investigated the expressions of multiple drug resistance 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), MRP2, copper transporter receptor 1 (CTR1), ATP7A, ATP7B, and ATP binding cassette subfamily G member 2 (ABCG2) in T24 and J82 bladder cancer cells treated with emodin and cisplatin alone or in combination
Summary
Chemoresistance is one of the most leading causes for tumor progression and recurrence of bladder cancer. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) was applied as a ROS generator in combination with cisplatin in T24 and J82 human bladder cancer cells. Cisplatin-contained chemotherapy is commonly used in patients with advanced or metastatic bladder cancer. Chemoresistance is one of the most leading causes for tumor progression and recurrence of bladder cancer [1]. In non-muscle invasive bladder cancer, 30–80 % of cases will recur and 1–45 % will progress to muscle invasion within 5 years [5]. It is necessary to reveal the mechanism of chemoresistance and improve the sensitivity of chemotherapy in bladder cancer
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