Istradefylline modulates purinergic enzymes and reduces malignancy-associated factors in B16F10 melanoma cells.

Autor:	da Silva JLG; Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia E Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Av. Roraima, 1000, Prédio 20, Santa Maria, RS, 97105-900, Brazil.; Programa de Pós-Graduação Em Bioquímica Toxicológica, Centro de Ciências Naturais E Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil., Viana AR; Programa de Pós-Graduação Em Nanociências, Laboratório de Biociências, Universidade Franciscana, Santa Maria, RS, Brazil., Passos DF; Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia E Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Av. Roraima, 1000, Prédio 20, Santa Maria, RS, 97105-900, Brazil.; Programa de Pós-Graduação Em Bioquímica Toxicológica, Centro de Ciências Naturais E Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil., Krause LMF; Centro de Ciências da Saúde, Departamento de Morfologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil., Miron VV; Programa de Pós-Graduação Em Bioquímica Toxicológica, Centro de Ciências Naturais E Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil., Schetinger MRC; Programa de Pós-Graduação Em Bioquímica Toxicológica, Centro de Ciências Naturais E Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil., Pillat MM; Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia E Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Av. Roraima, 1000, Prédio 20, Santa Maria, RS, 97105-900, Brazil., Palma TV; Programa de Pós-Graduação Em Bioquímica Toxicológica, Centro de Ciências Naturais E Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil., Leal DBR; Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia E Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Av. Roraima, 1000, Prédio 20, Santa Maria, RS, 97105-900, Brazil. dbitencourtrosaleal@gmail.com.; Programa de Pós-Graduação Em Bioquímica Toxicológica, Centro de Ciências Naturais E Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil. dbitencourtrosaleal@gmail.com.
Jazyk:	angličtina
Zdroj:	Purinergic signalling [Purinergic Signal] 2023 Dec; Vol. 19 (4), pp. 633-650. Date of Electronic Publication: 2022 Dec 16.
DOI:	10.1007/s11302-022-09909-8
Abstrakt:	ATP and adenosine exert pivotal roles in the development, maintenance, and metastatic spreading of melanoma. The action of such key melanoma tumor microenvironment (TME) constituents might be complementary or opposed, and their effects are not exclusive to immune cells but also to other host cells and tumor cells. The effects of ATP are controlled by the axis CD39/73, resulting in adenosine, the main actor in the TME, and A2A is the crucial mediator of its effects. We evaluated ATP and adenosine signaling through A2A on B16F10 melanoma cells using istradefylline (IST) (antiparkinsonian A2A antagonist) and caffeine (CAF) treatments after exposure to ATP and adenosine. Adenosine increased melanoma cell viability and proliferation in a concentration-dependent manner. ATP increases viability only as a substrate by CD39 to produce adenosine. Both IST and CAF are toxic to B16F10 cells, but only IST potentialized paclitaxel-induced cytotoxic effects, even decreasing its IC50 value. IST positively modulated CD39 and CD73 expression. CD39 activity was increased, and E-ADA was reduced, indicating that the melanoma cells promoted compensatory feedback in the production and maintenance of adenosine levels. A2A antagonism by IST reduced the factors associated with malignancy, like migration, adhesion, colony formation, and the capacity to produce melanin. Moreover, IST significantly increases nitric oxide (NO) production, which correlates to a decline in melanoma cell viability by apoptotic events. Altogether, our results suggest that adenosine signaling through A2A is essential for B16F10 cells, and its inhibition by IST causes compensatory purinergic enzymatic modulations. Furthermore, IST is a promising therapy that provides new ways to improve current melanoma treatments. (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze:	MEDLINE
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