Effect of paclitaxel in combination with the beta2 adrenergic agonist salbutamol on breast cancer MDA-MB-231 cell line growing in vivo: Mechanist of action

Abstract

Breast cancer is the leading cancer death cause of women in Ar- gentina. Beta2 adrenergic receptors have been described in several breast cancer cell lines and tumors. We have previously described (SAIC 2016, abstract 723) that the beta2 adrenergic agonist sal- butamol exerted in vitro a synergic effect with paclitaxel inhibiting cell proliferation. The aim of the present study was to assess the in vivo effect of the combination of paclitaxel and salbutamol in the triple-negative MDA-MB-231 cell line growing in nude mice. Both salbutamol (daily sc 1.2 mg/kg/day) and paclitaxel (10 mg/kg/week, ip in two injections) significantly inhibited tumor growth. Moreover, their combination inhibited very significantly this parameter. For ex- ample, day 63 (mean ± SEM in mm2): control tumors: 46,5 ± 9,70, n=8; paclitaxel: 32.4 ± 6,40, n=7, p<0.05; salbutamol 29.3 ± 7.58, n=7, p<0.05. Paclitaxel + salbutamol 9.33 ± 2.45, n=9, p<0.0001 against control, p<0.05 against each individually. The coefficient of drug interaction indicated synergism since the value obtained is < 1 (0.010, p<0.0005 in interaction by two-way ANOVA). In order to assess the mechanism of action, several in vitro exper- iments were performed. Paclitaxel diminished cell viability (trypan blue essay), while salbutamol diminished pERK/ERK ratio (using WB) and the expression of cyclin D1 gene (RT-qPCR). Moreover, both drugs enhanced apoptosis (acridine orange ethidium bromide staining assay). In preliminary results, salbutamol completely re- versed the increase of MDR1 (ABCB1) expression induced by pacli- taxel. This could account for the synergic effect of both drugs. These results suggest that the doses of chemotherapeutic drugs adminis- tered to patients in some triple negative (claudin-low) tumors could be reduced in the presence of salbutamol, diminishing their toxicity.