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.
journal_name
Acta Pharmacol Sinjournal_title
Acta pharmacologica Sinicaauthors
Augustin E,Borowa-Mazgaj B,Kikulska A,Kordalewska M,Pawłowska Mdoi
10.1038/aps.2012.132subject
Has Abstractpub_date
2013-01-01 00:00:00pages
146-56issue
1eissn
1671-4083issn
1745-7254pii
aps2012132journal_volume
34pub_type
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