ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
MRP4 ASSOCIATION WITH 5FU AND GEMCITABINE RESISTANCE IN PANCREATIC CANCER
Autor/es:
YANEFF, A; CAROZZO, A; DAVIO, C; DI SIERVI, N; SAHORES, A; MAY, M; SHAYO, C; GOMEZ, N
Reunión:
Congreso; XLVIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE FARMACOLOGÍA EXPERIMENTAL; 2016
Resumen:
Pancreaticductal adenocarcinoma (PDAC) ranks among the most lethal of human malignanciesdue to several factors: there are no early detection markers, has extensivelocal tumor invasion, early systemic dissemination, and extremely poor responseto chemotherapy and radiation treatment. Gemcitabine (GEM) became the referenceregimen for advanced pancreatic cancer after a randomized trial showedsignificant improvement in the median overall survival as comparedwithfluorouracil (5FU) administered as an intravenous bolus. This chemotherapytreatment reduces primary tumor burden, but patients have an overall survivalnot longer than six months. Our laboratory has validated a membrane transporter(MRP4) as a new therapeutic target in pancreatic cancer and its associationwith cAMP efflux. Both gene silencing (shRNA) and pharmacological inhibition(MK571) leads to lower tumorigenicity, malignancy and proliferation in PDACmodels both on in vivo and in vitro assays. The hypothesis of our work is that 5FUand GEM cause an adaptation of the tumor, overexpressing MRP4, increasing theirlevel of invasion and malignancy. We performed a kinetic cAMP transport assayto assess MRP4 activity in the presence of these two chemotherapeutic agents inPANC-1 cell line, concluding that they do not significantly affect the flow ofcAMP. In proliferation concentration-response curves, neither MK571 nor MRP4gene specific silencing modified 5FU or GEM sensitivity after 72 hourstreatment. Interestingly, we observed an increase in MRP4 mRNA levels of up tosix times (p<0,01) in cel ls treated 96 hours with IC50 concentrations ofthese chemotherapeutic agents. Therefore, these results may explain one of thecauses of chemotherapy failure, despite of decreasing the size of the primarytumor. The adaptation of neoplastic cells by treatm ent with 5FU or GEMinvolved an increase of MRP4 conferring them greater invasiveness andaggressive behavior.