ANTI-TUMOR ACTIONS OF CYTOTOXIC DRUGS PLUS MUSCARINIC AGONISTS ON HUMAN TRIPLE NEGATIVE BREAST CANCER CELLS

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

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

The administration of low doses of cytotoxic drugsalone or combined with repurposing drugs scheduled with short inter-doseintervals is called metronomic therapy (MT). MT is a new strategy in cancertreatment, since it exhibits high effectiveness and low incidence of sideeffects. We previously demonstrated that the activation of muscarinic receptors(M) can modulate breast cancer cell viability. Triple negative (TN) breasttumors are highly aggressive, and the effectiveness of pharmacologicaltreatment is low probably due to the absence of a specifictarget.  Here, we analyzed the effect ofa combination of subthreshold concentrations of a muscarinic agonist, carbachol(CARB) or arecaidine propargyl ester (APE) (non- selective or selective for M2subtype respectively) with paclitaxel (PX) or doxorubicin (DX), two cytotoxicdrugs used in breast cancer treatment, on MDA-MB231 or MDA-MB468 TN tumor-derivedcell lines. By MTT assay we observed on MDA-MB231 cells that the combination ofPX+CARB or PX+APE reduced cell viability (23.9±2.5%; 23.5±7.1% respect tocontrol; p<0.05). When we combined these muscarinic agonists with anothercytotoxic drug, DX, we also observed a reduction in cell viability (DX+CARB: 27.4±4.2%;DX+APE: 30.7±1.6%; p<0.001 vs. control). To confirm these results we analyzedthe effect of these drugs on another TN cell line, MDA-MB468, obtaining similarresults (PX+CARB: 50.3±2.4%; PX+APE: 26.9±3.6%; p<0.001 vs. control). Whenwe combined CARB or APE with DX we observed the same effect (DX+CARB: 21.1±0.7%;DX+APE: 31.2±0.9%; p<0.05 vs. control). None of the combined treatments hadeffect on the non tumorigenic cell line, MCF-10A. These results suggest that the combination of low dosesof cytotoxic drugs with muscarinic agonists can reduce cell viability and couldbe used as a new strategy to treat TN breast tumors in humans.