CEFYBO   02669
CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
M2 receptor activation inhibits cell growth and survival in human breast cancer
Autor/es:
ALEJANDRO ESPAÑOL; DI BARI, MARIA; CRISTOFARO, ILARA; MARÍA E. SALES; TATA, ADA
Reunión:
Congreso; Anticancer Drug Action and Drug Resistance: from Cancer Biology to the Clinic. EACR-AACR-SIC 2015; 2015
Resumen:
 Introduction. The involvement ofmuscarinic receptors in the modulation of tumor growth and progression has beenlargely demonstrated in several tumor types.  Recently we demonstrated that the M2 agonist,Arecaidine Propargyl Ester (APE) arrests cell proliferation and inducesapoptosis in glioblastoma and urothelial bladder cancer cells. In this work weinvestigated the effects mediated by M2 receptors  in breast cancer cell lines and the combinedeffect of APE with paclitaxel, a conventional breast cancer drug. Materials and Methods. MCF-7 and MDA-MB-231 cell lines werecultured in DMEM supplemented with 10% FBS. MTT assay and trypan blue staining were used to evaluate cellviability and cell death respectively. M2 silencing (by siRNA) was used toconfirm the ability of M2 agonist to selectively bind this receptor. Transcriptlevels for muscarinic receptors, EGFR and multidrug efflux pumps (e.g. ATPbinding cassette, ABC) were analyzed by RT-PCR.Results. We  detected  the expression of M2 receptor subtype byRT-PCR analysis and protein  expressionwas confirmed by western blot analysis both in MCF-7 and MDA-MB-231 cell lines,being higher in MDA-MB-231 than in MCF-7 cells. The M2 agonist APE, addedat  micromolar concentration, decreasedcell growth in a time and dose dependent manner in both cell lines. The effectappeared more evident in MDA-MB-231 than in MCF-7 cells. Thesilencing of M2 receptor abolished the M2 agonist effect confirming that APEselectively binds M2 receptors. Interestingly, low doses of APE plus paclitaxeladministered to the cell cultures caused a significant decrease of cell growth.The combined effect of the two drugs presents a synergism of potentiation. Finallythe co-treatment with both drugs negatively modulates the mRNA levels of ABC(G2 type) and EGFR. Conclusions. Thedata obtained suggest that M2 receptor agonist APE may represent a newinteresting therapeutic tool in breast cancer therapy as well as in other tumortypes (glioblastoma, bladder cancer and neuroblastoma).  Its ability to decrease ABC  efflux pumps and EGFR expression also suggestthat APE may reduce cell chemoresistance and make the tumor cells moreresponsive to conventional drugs (e.g. paclitaxel)