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Adenosine Overcomes Triple Negative Breast Cancer Resistance to Platin-Derived Chemotherapeutic Drugs
* 1 , 1 , 2 , 3 , * 1
1  LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
2  LAQV/REQUIMTE, Laboratory of Bromatology and Hydrology, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal Faculty of Nutrition and Food Science, University of Porto, 4150-180 Porto, Portugal
3  ICBAS – Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, 4050-313 Porto, Portugal
Academic Editor: Maria Emília Sousa


Triple negative breast cancer (TNBC), a poor survival cancer has high resistance to therapy, with low drug efficacy. Adenosine is present in high concentrations in tumor microenvironment. Recently, adenosine was found to sensitize ovarian cisplatin-resistant cancer. This work aims at addressing if adenosine can sensitize TNBC resistance to platinum drugs. Concomitant/preincubation of adenosine with cisplatin or carboplatin induced cell proliferation in TNBC cisplatin-sensitive (MDA) and -resistant (MDA/R) cells (using Lionheart-FX microscope). Phosphorylation of ERK or NF-κB pathways and cAMP production were evaluated (AlphaScreen assays). Data analyzed with One-way ANOVA t-test. Results: concomitant or preincubation of adenosine (300, 600, 700 µM) with cisplatin reduced resistance in MDA/R, with proliferation levels approaching those observed in MDA. In MDA, endogenous and exogenous adenosine have no effect over ERK phosphorylation; in MDA/R, exogenous adenosine lowers ERK phosphorylation. NF-κB phosphorylation was induced by A3R and A2BR tonic activation in MDA and MDA/R, respectively, increasing survival - exogenous adenosine inactivates this via. Tonically cAMP production was altered in MDA and MDA/R, revealing inhibitory and stimulatory effects in cAMP production by A1R and A2BR, respectively, in MDA/R. By contrast, exogenous adenosine revealed that adenosine receptors in MDA contribute differently while in MDA/R all receptor subtypes have a similar contribution to cAMP production. Thus, adenosine contributes to overcome platinum-derived resistance in TNBC, involving the inactivation of NF-κB pathway and decrease of ERK phosphorylation (partially mediated by A3R). Fund FCT (UIDB/QUI/50006/2020).

Keywords: Adenosine; P1-Receptors; Carboplatin; cisplatin; TNBC, Cancer Resistance; A2B Receptor