MP44-11 BIOMARKER-DRIVEN TARGETED ORAL TREATMENT STRATEGY FOR BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I1 Apr 2017MP44-11 BIOMARKER-DRIVEN TARGETED ORAL TREATMENT STRATEGY FOR BLADDER CANCER Daley Schimmelpfennig, Michael W. Kemper, Soum D. Lokeshwar, Andre Jordan, and Vinata B. Lokeshwar Daley SchimmelpfennigDaley Schimmelpfennig More articles by this author , Michael W. KemperMichael W. Kemper More articles by this author , Soum D. LokeshwarSoum D. Lokeshwar More articles by this author , Andre JordanAndre Jordan More articles by this author , and Vinata B. LokeshwarVinata B. Lokeshwar More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1342AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hyaluronic acid (HA) family of molecules, HA-synthases (HAS-1,2,3), HA-receptors (CD44, RHAMM) and hyaluronidase (HYAL-1) are markers for bladder cancer (BCa) diagnosis and predicting prognosis. HA-family promotes tumor growth and metastasis by inducing epithelial mesenchymal transition (EMT). 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. We evaluated the expression of HA family and EMT markers in bladder tissues and antitumor effects of 4-MU in preclinical models of BCa. METHODS mRNA expression of HA-family and EMT genes (beta-catenin, Twist, and Snail) in 72 bladder tissue specimens (28 normal; 44 tumor); follow-up: 20.3+/-2.5 months, was measured by QPCR. The effect of 4-MU (0-0.6 mM) on cell growth, apoptosis, HA-signaling were examined in BCa cell lines by Q-PCR, immunoblotting, proximal ligation and PI-3K activity assays. Effect of oral administration of 4-MU (100, 200-mg/kg) on tumor growth was analyzed in preclinical models. RESULTS HAS-1, -2 -3, HYAL-1 and Snail levels were 10-20-fold elevated in BCa tissues as compared to normal bladder (P<0.001). In univariate analysis, HAS-1, -2, HYAL-1 and Twist levels correlated with metastasis (P<0.001); HYAL-1 was an independent predictor of metastasis. 4-MU inhibited cell proliferation, chemotactic motility and invasion in a dose-dependent manner; 50-70% inhibition at IC50 (0.4 mM) for HA-synthesis inhibition. 4-MU induced apoptosis (>3-fold) via the death receptor pathway. 4-MU downregulated HA-signaling; mRNA and/or protein levels of CD44, RHAMM, p-Akt, beta-catenin, p-beta-catenin(S552), snail and twist were downregulated by 3-5-fold, but pßcatenin((T41/S45), pGSK-3alpha/beta and E-cadherin levels were elevated. 4-MU also inhibited CD44/PI-3K complex formation and PI-3K activity. HA addition or mAkt expression attenuated 4-MU effects. In xenograft studies, 4-MU oral treatment abrogated growth of established HT1376 tumors (vehicle, day 35: 766+/-221 mm3; 4-MU: 128+/-61, day 50). No weight loss or serum or organ toxicity was observed in treated mice. CONCLUSIONS This study demonstrates that HA-family and signaling is upregulated in BCa and can be specifically targeted for treatment by a non-toxic dietary supplement. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e567-e568 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Daley Schimmelpfennig More articles by this author Michael W. Kemper More articles by this author Soum D. Lokeshwar More articles by this author Andre Jordan More articles by this author Vinata B. Lokeshwar More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...