Abstract
Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide. In this study, we investigated the effect and mechanism of Artesunate (ART), a traditional Chinese medicine, on inducing apoptosis of human bladder cancer cells. In vivo antitumor activity was investigated in bladder cancer in rat by subcutaneous injection of different concentration of ART. The effect of ART on growth inhibition and apoptosis of bladder cancer cells was evaluated using dimethylthiazoly-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. Cyclooxygenase-2 (COX-2) and miR-16 expression levels were determined with real-time PCR. The concentrations of prostaglandin E2 (PGE2) in the supernatants of bladder cancer cells were measured with an ELISA kit. The miR-16 inhibitor or mimic were transfected into cells to up- or down-regulate miR-16 expression. ART efficiently inhibited orthotopic tumor growth in the bladder cancer rat, which is accompanied with an increase of miR-16 expression and a decrease of COX-2 expression. In vitro, ART could induce cytotoxicity and apoptosis in bladder cancer cells, but presented a much lighter toxicity effect against normal human urothelial cells. ART significantly increased miR-16 expression and decreased the expression of COX-2 and the production of PGE2. More importantly, down-regulation of miR-16 expression could reverse the effect of ART on apoptosis and COX-2 expression in bladder cells. Moreover, exogenous PGE2 could inhibit apoptosis of bladder cancer cells treated with ART. In conclusion, ART can elicit an anti-tumor effect against bladder cancer by up-regulation of miR-16 expression, which resulted in the decrease of COX-2 expression and PGE2 production. Hence, ART might be an effective drug for the treatment of bladder cancer.
Highlights
Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide [1]
In order to determine whether ART can induce apoptosis of bladder cancer cells, we evaluated caspase-3 activity
We found that ART inhibited the COX-2 expression of bladder cancer cells and prostaglandin E2 (PGE2) production in a dose-dependent manner, which could be restored by miR-16 inhibitor (Figure 6C)
Summary
Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide [1]. The traditional strategies only modestly improve response and the 5-year survival rate in patients with invasive and metastatic bladder cancer is still very low [2]. Chemotherapy is regarded as an effective approach in the prevention of human cancer death, side effects limit the use of this treatment [3]. It is urgent to find effective drugs that prolong survival and improve quality of life, without damaging normal cells. Improving our understanding of the molecular events involved in the progression of bladder cancer is beneficial for the identification of potential molecular targets for new therapeutic strategies.
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