Muscarinic receptors as therapeutic targets in triple negative breast cancer treatment. Paclitaxel plus carbachol administered in a metronomic schedule.

SANCHEZ, Y; ALEJANDRO ESPAÑOL; SALEM , AGUSTINA; MARÍA E. SALES

Congreso; LXIII REUNION ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACION CLINICA; 2018

We have demonstratedthat the long term activation of muscarinic receptors (MR) decreases tumor cellviability pointing to MR as possible therapeutic targets in breast cancer. Metronomictherapy consists in the administration of low doses of cytotoxic drugs, aloneor combined with repositioning drugs with short intervals inter-doses. Here, weinvestigated the effect that a metronomic combination of paclitaxel (PX) plusthe muscarinic agonist carbachol (CARB) exerts on tumor growth and on ?ATPbinding cassette? (ABC)G2 transporter and epidermal growth factor receptor(EGFR) as mediators of chemotherapy resistance in breast cancer treatment. MDA-MB231cells derived from a triple negative (TN) breast tumor express functional MR,and the combination of subthreshold concentrations of PX (10-8M) plusCARB (10-12M) in 2 cycles of 48 h reduced cell viability by 24% ineach cycle (p<0.05 vs. control; determined by MTT assay), similarly to PX ata pharmacological concentration (10-6M, p<0.05). This effectcould be mediated partially by a decrement in the expression of ABCG2 and EGFR(56±2% and 35±3% respectively vs. control; p<0.01) measured by Western blot.We also analyzed the effect of the systemic administration (i.p.) of PX plusCARB to MDA-MB231 NUDE mice tumor bearers. A significant reduction in tumorgrowth was observed after 2 cycles of treatment (90±19%; p<0.001 vs.untreated tumor bearers). The effect was prevented by treating animals with atropine.This combined treatment has the advantage to not affect non tumorigenic mammaryMCF-10A cells. These results suggest the possibility to consider MR astherapeutic targets in a metronomic therapy schedule in TN breast cancer.