33 Androgen deprivation therapy prevents recurrence of bladder cancer

INTRODUCTION AND OBJECTIVES: Hyaluyronic acid (HA) and HYAL-1 hyaluronidase family of molecules are potential markers for BCa diagnosis and predicting prognosis and promote tumor growth and metastasis. 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. Epithelial mesenchymal transition (EMT) is the hallmark of invasion and metastasis. Since HA promotes tumor metastasis and EMT, we evaluated the expression of EMT markers in bladder tissues and antitumor effects of 4-MU in BCa models. METHODS: Quantitative PCR was used to measure mRNA expression of EMT genes (B-catenin, Twist, and Snail) in 66 bladder tissue specimens (27 normal; 39 tumor); follow-up: 26þ/-4.3 months; median 20 months. The effect of 4-MU (40 e 120 mg/ml) on cell proliferation, apoptosis, intracellular signaling, and the expression of HA receptors, and EMT genes were examined in BCa cell lines, 253J-Lung and HT1376. HA addition and mAkt overexpression were conducted to delineate the mechanism of action of 4-MU. Effect of 4-MU on tumor growth was analyzed in subcutaneous xenografts. RESULTS: Among the EMT genes, Snail and Twist were differentially expressed in BCa tissues when compared to normal bladder (P 3-fold) when treatment was started either on the day of tumor cell injection or after tumors became palpable. No weight loss or serum or organ toxicity was observed in treated mice. CONCLUSIONS: This study shows that expression of EMT determinants correlates with clinical outcome. Furthermore, the nontoxic dietary supplement 4-MU has potent antitumor activity and reverses EMT.