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

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Abstract

Purpose

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 investigate 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 phosphorylation 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 proliferation 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 significantly 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 provoked 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.

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Data availability

Data will be available on request to Dr. Isabel Lüthy (isabel.luthy@gmail.com).

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Acknowledgements

MJ was a fellow from the Instituto Nacional del Cáncer, MSR and EMR doctoral and postdoctoral fellows from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), CDB is a researcher from the Hospital de Alta Complejidad SAMIC—El Calafate and AB, CPP and IAL from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). This work was funded by the Instituto Nacional del Cáncer (INC), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) PIP 2022-100 and Agencia Nacional de Promoción Científica y Tecnológica PICT 2016-0193, PICT 2019-01631, PICT 2021-417 and PICT 2021-604, all from Argentina.

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Jabloñski, M., Rodríguez, M.S., Rivero, E.M. et al. The Beta2-adrenergic agonist salbutamol synergizes with paclitaxel on cell proliferation and tumor growth in triple negative breast cancer models. Cancer Chemother Pharmacol 92, 485–499 (2023). https://doi.org/10.1007/s00280-023-04586-9

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