Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
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Fecha
2020
Autores
Vargas, José Eduardo
Puga, Renato
Lenz, Guido
Trindade, Cristiano
Filippi-Chiela, Eduardo
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Editor
Hindawi
Resumen
Doxorubicin (Doxo) is the most effective chemotherapeutic agent for the treatment of breast cancer. However, resistance to Doxo is
common. Adjuvant compounds capable of modulating mechanisms involved in Doxo resistance may potentiate the effectiveness of
the drug. Resveratrol (Rsv) has been tested as an adjuvant in mammary malignancies. However, the cellular and molecular
mechanisms underlying the effects of cotreatment with Doxo and Rsv in breast cancer are poorly understood. Here, we
combined in vitro and in silico analysis to characterize these mechanisms. In vitro, we employed a clinically relevant
experimental design consisting of acute (24 h) treatment followed by 15 days of analysis. Acute Rsv potentiated the long-lasting
effect of Doxo through the induction of apoptosis and senescence. Cells that survived to the cotreatment triggered high levels of
autophagy. Autophagy inhibition during its peak of activation but not concomitant with Doxo+Rsv increased the long-term
toxicity of the cotreatment. To uncover key proteins potentially associated with in vitro effects, an in silico multistep strategy
was implemented. Chemical-protein networks were predicted based on constitutive gene expression of MCF7 cells and
interatomic data from breast cancer. Topological analysis, KM survival analysis, and a quantitative model based on the
connectivity between apoptosis, senescence, and autophagy were performed. We found seven putative genes predicted to be
modulated by Rsv in the context of Doxo treatment: CCND1, CDH1, ESR1, HSP90AA1, MAPK3, PTPN11, and RPS6KB1. Six
out of these seven genes have been experimentally proven to be modulated by Rsv in cancer cells, with 4 of the 6 genes in MCF7
cells. In conclusion, acute Rsv potentiated the long-term toxicity of Doxo in breast cancer potentially through the modulation of
genes and mechanisms involved in Doxo resistance. Rational autophagy inhibition potentiated the effects of Rsv+Doxo, a
strategy that should be further tested in animal models.