Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo - PubMed (original) (raw)

Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo

Yu Bai et al. Cancer Sci. 2010 Feb.

Abstract

Resveratrol, a naturally occurring polyphenolic antioxidant compound present in grapes and red wine, has been reported to hold various biochemical responses. In this preliminary study, we evaluate the chemopreventive potential of resveratrol against bladder cancer and its mechanism of action. Treatment of bladder cancer cells with resveratrol resulted in a significant decrease in cell viability. Resveratrol induced apoptosis through the modulation of Bcl-2 family proteins and activation of caspase 9 and caspase 3 followed by poly(ADP-ribose) polymerase degradation. Treatment with resveratrol led to G(1) phase cell cycle arrest in T24 cells by activation of p21 and downregulation of cyclin D1, cyclin-dependent kinase 4, and phosphorylated Rb. Resveratrol also inhibited the phosphorylation of Akt, whereas the phosphorylation of p38 MAPK was enhanced. In addition, resveratrol treatment decreased the expression of vascular endothelial growth factor and fibroblast growth factor-2, which might contribute to the inhibition of tumor growth on the bladder cancer xenograft model. These findings suggest that reveratrol could be an important chemoprevention agent for bladder cancer.

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Figures

Figure 1

Figure 1

Cytotoxicity effects of resveratrol on T24 bladder cancer cells. Cell proliferation and viability were determined by an MTT assay. Reduced cell viability was observed with resveratrol treatment (25–250 μ

m

) at 12, 24, and 48 h. The data are presented as mean ± SD.

Figure 2

Figure 2

Dose‐dependent apoptosis induced by treatment with resveratrol in T24 bladder cancer cells. Cells treated with various concentrations of resveratrol were double‐stained with annexin V and PI and analyzed by flow cytometry. The gate setting distinguished between living (bottom left), necrotic (top left), early apoptotic (bottom right), and late apoptotic (top right) cells.

Figure 3

Figure 3

Cell cycle analysis of T24 bladder cancer cells treated with resveratrol. Cells were cultured with different concentrations of resveratrol for 24 h and then stained with propidium iodide. The DNA content was analyzed by flow cytometry. G1, S, and G2 indicate cell cycle phases.

Figure 4

Figure 4

Expression of proteins changed in cells treated with different concentrations of resveratrol for 24 h. (A) Resveratrol upregulated the expression of WAF‐1/p21 but downregulated the expression of cyclin D1, cyclin‐dependent kinase 4 (CDK4), and phosphorylated (p‐) Rb. (B) Resveratrol inhibited Akt phosphorylation and enhanced p38 MAPK activation. (C) Resveratrol inhibited the expression of anti‐apoptotic gene products Bcl‐2 and Bcl‐xL but upregulated the expression of apoptotic gene product Bax. The levels of p‐Bad at Ser112 and Ser136 were decreased by treatment with resveratrol. (D) Resveratrol treatment activated caspase 3 and caspase 9 and resulted in a cleavage of poly(ADP‐ribose) polymerase (PARP). The data shown here are from a representative experiment repeated three times with similar results.

Figure 5

Figure 5

Effects of resveratrol on bladder cancer xenografts in vivo. (A) Tumor volume growth in nude mice treated with i.p. injection of resveratrol (20 mg/kg per day) for 4 weeks. The data are presented as mean ± SD. Daily average tumor volumes for each group were compared throughout the course of the experiment using ANOVA. (B) Photographs show the implanted tumors in representative mice at the day 28.

Figure 6

Figure 6

Resveratrol inhibited the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor‐2 (FGF‐2) in both T24 bladder cancer cells and tumor tissue. Gene expression was analyzed by RT‐PCR. Representative data are shown from three independent experiments with identical results.

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