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

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.

• Authors: Ewa Augustin, Barbara Borowa-Mazgaj, Agnieszka Kikulska, Milena Kordalewska, Monika Pawłowska
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 34 Issue 1 Pg. 146-56 (Jan 2013) ISSN: 1745-7254 [Electronic] United States
• PMID: 23160340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acridines
• Antineoplastic Agents
• C 1305
• Cytotoxins
• Triazoles
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Caspases

Topics

• Acridines (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• CHO Cells
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cricetinae
• Cricetulus
• Cytochrome P-450 CYP3A (genetics)
• Cytotoxins (pharmacology)
• Humans
• Triazoles (pharmacology)
• Up-Regulation