The Beta2-adrenergic agonist salbutamol synergizes with paclitaxel on cell proliferation and tumor growth in triple negative breast cancer models

JABLOÑSKI, MARTINA; RODRÍGUEZ, MARÍA SOL; RIVERO, EZEQUIEL MARIANO; BRUQUE, CARLOS DAVID; VANZULLI, SILVIA; BRUZZONE, ARIANA; PÉREZ PIÑERO, CECILIA; LÜTHY, ISABEL ALICIA

CANCER CHEMOTHERAPY AND PHARMACOLOGY

SPRINGER

Lugar: Berlin; Año: 2023

0344-5704

AbstractPurpose Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with chemotherapy, resulting in significant side-effects. We aimed to inves- tigate if the dose of chemotherapeutic drugs could be diminished by co-administering it with the β2-agonist salbutamol. Methods Cell proliferation was measured by thymidine incorporation; gene expression, by real-time PCR and protein phos- phorylation by WB. Apoptosis was assessed by acridine orange / ethidium bromide and TUNEL tests. Public patient databases were consulted. Cells were inoculated to nude mice and their growth assessed.Results The β2-agonist salbutamol synergizes in MDA-MB-231 cells in vitro with paclitaxel and doxorubicin on cell prolif- eration through ADRB2 receptors, while the β-blocker propranolol does not. The expression of this receptor was assessed in patient databases and other cell lines. Triple negative samples had the lowest expression. Salbutamol and paclitaxel decreased MDA-MB-231 cell proliferation while their combination further inhibited it. The pathways involved were analyzed. When these cells were inoculated to nude mice, paclitaxel and salbutamol inhibited tumor growth. The combined effect was sig- nificantly greater. Paclitaxel increased the expression of MDR1 while salbutamol partially reversed this increase. Conclusion While the effect of salbutamol was mainly on cell proliferation, suboptimal concentrations of paclitaxel pro- voked a very important enhancement of apoptosis. The latter enhanced transporter proteins as MDR1, whose expression were diminished by salbutamol. The expression of ADRB2 should be assessed in the biopsy or tumor to eventually select patients that could benefit from salbutamol repurposing.