Sunitinib Inhibits Breast Cancer Cell Proliferation by Inducing Apoptosis, Cell-cycle Arrest and DNA Repair While Inhibiting NF-κB Signaling Pathways
A, Korashy HM, Maayah ZH, Al Anazi FE, Alsaad AM, Alanazi IO, Belali OM, Al-Atawi FO, Alshamsan . 2017
The tyrosine kinase inhibitor sunitinib was recently approved for use against gastrointestinal stromal tumors and advanced renal cell carcinoma. Yet, the protective effect of sunitinib against breast cancer has been poorly investigated. In this study, we investigated the antiproliferative and apoptogenic effects of sunitinib and the possible mechanism involved against the MCF7 human breast cancer cell line. Treatment of MCF7 cells with sunitinib caused concentration-dependent cell growth suppression due to apoptosis. Apoptotic death induced by sunitinib in MCF7 cells was mediated by activation of caspase-3 and p53 mRNA and protein expression and an increase in the percentage of apoptotic cells (40%) as determined by flow cytometry. Apoptosis was associated with a significant inhibition of nuclear factor-kappa B mRNA and protein expression. Mechanistically, blocking of de novo RNA synthesis by actinomycin D significantly inhibited sunitinib-induced expression of p53 mRNA, but not that of caspase-3, indicating involvement of a transcriptional mechanism. This apoptosis-mediated inhibition of MCF7 cell growth was attributed to inhibition of cell cycle-related genes (cyclin D1 and cyclin E2) and arrest of MCF7 cells in the G2/M phase in the cell cycle, allowing up-regulation of expression of DNA repair genes such as x-ray repair cross-complementing protein 1. In addition, sunitinib exhibited concentration-dependent induction of oxidative stress genes (heme oxygenase 1 and glutathione transferase A1) through the nuclear factor erythroid 2-related factor 2 pathway. These findings lead us to propose that sunitinib suppressed the proliferation of MCF7 cells via cell-cycle arrest and apoptotic- and oxidative stress-mediated pathways.
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