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CYP3A4 overexpression enhances the cytotoxicity of the antitumor triazoloacridinone derivative C-1305 in CHO cells.


Acta Pharmacol Sin. 2012 Nov 19;


Authors: Augustin E, Borowa-Mazgaj B, Kikulska A, Kordalewska M, Pawłowska M


Abstract

Aim:To examine how the higher expression level of CYP3A4 isoenzyme influenced the cytotoxicity of the antitumor triazoloacridinone derivative C-1305 in Chinese hamster ovary (CHO) cells.Methods:Three CHO cell lines were examined: wild-type CHO cells; CHO-HR cells with overexpression of human cytochrome P450 reductase (CPR); and CHO-HR-3A4 cells with coexpression of human CYP3A4 and CPR. Cellular responses caused by C-1305 were monitored using DAPI staining, cell cycle analysis, phosphatydilserine externalization analysis and SA-β-galactosidase expression analysis. Cell viability was assessed with simultaneous FDA and PI staining.Results:Treatment with C-1305 for 72 h exhibited different levels of cytotoxicity in the 3 cell lines, and the values of IC80 in CHO, CHO-HR and CHO-HR-3A4 cells were 0.087±0.005, 0.032±0.0001, and 0.064±0.0095 μmol/L, respectively. The cell cycle analysis revealed that both CHO and CHO-HR cells underwent transient G(2)/M arrest, whereas CHO-HR-3A4 cells did not accumulate in this phase. Prolonged exposure up to 120 h caused time-dependent increase in the sub-G(1) fraction in all the 3 cell lines. Treatment with C-1305 caused cell death through apoptosis and necrosis. However, these processes were more pronounced in the transfected CHO cells than in the wild-type cells. The cells surviving after C-1305 exposure underwent senescence.Conclusion:CYP3A4 overexpression potently enhances the cellular responses (apoptosis, necrosis and senescence) caused by C-1305 in CHO cells.

PMID: 23160340 [PubMed - as supplied by publisher]