1. La silibina, un potencial agente radiosensibilizante en el tratamiento del cáncer de vejiga invasor

BARBARA P. PRACK MC CORMICK ; DENISE BELGOROSKY ; YANINA V. LANGLE ; ADRIANA G. PAZ ; ANA M. EIJÁN ; EDUARDO O. SANDES

Buenos Aires

Congreso; 12° Congreso Argentino de Física Médica, 1° Congreso de Física Médica de las Américas & 1° Congreso de Medicina Nuclear y Diagnóstico por Imágenes de la AATMN; 2014

SOCIEDAD DE FISICA MEDICA DE LAS AMERICAS

SILYBIN AS A POTENTIAL RADIOSENSITIZING AGENT FOR THE TREATMENT OF INVASIVE BLADDER CANCER Barbara P. Prack Mc Cormick1, Denise Belgorosky1, Yanina V. Langle1, Adriana G. Paz2, Ana M. Eijan1, Eduardo O. Sandes1. 1 Instituto de Oncología ?Ángel H. Roffo? - Universidad de Buenos Aires - Argentina. 2 Servicio de cobaltoterapia Hospital Municipal de Oncología ?Marie Curie? - GCBA - Argentina 1Av San Martín 5481 1417 DTB - CABA - Argentina eosandes@yahoo.com.ar 2Patricias Argentinas 750 1405 BWU - CABA - Argentina PAPER CATEGORY Diagnostic Radiology Nuclear Medicine X Radiation Therapy Radiation Protection Other AATMN ABSTRACT Introduction: Radiotherapy (RT) and chemotherapy are conservative therapeutic options for the treatment of multiple tumors including bladder cancer (BCa). However, RT damages adjacent normal tissue and also some tumors show radioresistance. Therefore, it is necessary to search for adjuvant agents which potentially can optimize the effect of RT. It was proposed that the transcription factor NF-kB, which activates survival pathways in response to RT, could be a therapeutic target. Objectives: Considering that flavonoids can block the activity of NF-kB, we analyzed the ability of the flavonoid silybin (Sb) to improve the antitumor effect of RT on two variants of a murine BCa model, invasive (MB49-I) and non muscle invasive (MB49). Material and Methods: We assed: 1) cell viability at different doses of RT (0-2-4 and 8 Gy) and/or Sb (0-150 µM) by MTS assay, 2) radiosensitization by clonogenic assay, 3) activation of NF-kB signaling pathway by western blot and gene reporter assays, 4) tumor growth in C57BL/6J mice treated with Sb (400 mg/kg/day, gavage: 5 d/wk) and/or RT (3 Gy/day, 2 v/wk , total dose = 18 Gy). Results: In vitro experiments showed that Sb alone induced dose-dependent cytotoxicity (ED50: MB49-I = 104 µM, MB49 = 120 µM). At 120 h of treatment, MB49-I showed enhanced response to RT (4 and 6 Gy) when it was combined with 40 or 60 µM Sb (p ≤ 0.001), the effect was lower in MB49. In clonogenic assays, Sb (60 µM) induced higher radiosensitization in MB49-I (2 Gy 2 Gy + Sb vs. p = 0.01) compared to MB49. At the molecular level, NF-kB activation was triggered by RT alone in MB49-I, this effect was reverted by Sb. In vivo, the combined treatment of RT and Sb, induced tumor shrinkage (slope = -4.238) and increased survival in mice bearing MB49-I tumor, and growth retardation in MB49 (RT vs SbRT p = 0.01). Conclusions: Our results show that Sb has more radiosensitizing activity in the invasive bladder cancer cell line MB49-I than in the non invasive MB49 and its mechanism of action involves NF-kB pathway inactivation. These data suggest that Sb could be a potential adjuvant agent for the conservative treatment of invasive BCa.