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Maria E. Sales

Maria E. Sales

University of Buenos Aires, Argentina

Title: Muscarinic modulation of paclitaxel actions on human breast cancer

Biography

Biography: Maria E. Sales

Abstract

Cholinergic modulation of tumor progression has been described in differentexperimental models. In our laboratory, we demonstrated that long term treatment of murine mammary tumors with the non-selective agonist, carbachol (CARB) promotes cell death through the activation of muscarinic (M) receptors. We studied the effect of acombination of sub threshold doses of CARB (10-12M) with paclitaxel (PX) (10-8M) acytotoxic agent used in the treatment of breast cancer, on MDA-MB231 cells derived from a human triple negative breast tumor. The combination of CARB+PX reduced cell viability by 27±3% (p <0.01 vs. control). In addition, the combination of the M2 selective agonist, arecaidine (ARE) (12.5 ıM) that promotes cell death in glioblastomas, with PX (10-9M) produced a similar reduction in cell viability (24±7%; p<0.05) effect that was not observed with drugs added separately. By Western blot we detected the expression of M receptors (M5> M1=M2). The silencing of M2 receptor with a specific siRNA increased cell viability to control values. ARE+PX also reduced by 98ı7% mRNA levels of the drug transporter ABCG2 and by 97ı8% the expression of the epidermal growth factor receptor (p<0.001 vs. control). The combination did not modify the viability of MCF-10A cells derived from human normal mammary gland that do not express M receptors. These results suggest that M receptors could be considered as therapeutic targets in breast cancer and that the combination of cholinergic agonists plus cytotoxic agents, as PX may represent a novel therapeutic tool for the treatment of this illness