Modulation of CYP3A4 activity and induction of apoptosis, necrosis and senescence by the antitumor imidazoacridinone C-1311 in human hepatoma cells
Abstrakt
There is increasing evidence that the expression level of drug metabolic enzymes affects the final cellular response following drug treatment. Moreover, anti-tumour agents may modulate enzymatic activity and/or cellular expression of metabolic enzymes in tumour cells. We investigated the influence of CYP3A4 overexpression on the cellular response induced by the anti-tumour agent C-1311 in hepatoma cells. C-1311-mediated CYP3A4 activity modulation and the effect of CYP3A4 overexpression on C-1311 metabolism were also examined. Experiments were performed using the HepG2 cell line and its CYP3A4-overexpressing variant, Hep3A4. DAPI staining, cell cycle analysis, phosphatidylserine externalization, and senescence-associated (SA)--galactosidase expression were used to monitor the cellular effects following C-1311 exposure. C-1311 cellular metabolism and CYP3A4 activity were investigated by high-performance liquid chromatography. C-1311 metabolism was found to be very low in both hepatoma cell lines and slightly influenced by CYP3A4 expression. Interestingly, C-1311 was an effective inhibitor of CYP3A4 enzymatic activity, with no impact on its protein levels. C-1311 cytotoxicity was significantly lower in Hep3A4 cells than in HepG2 cells. Cell cycle analysis revealed that HepG2 cells underwent a rather stable G2/M arrest, whereas CYP3A4-overexpressing cells accumulated slightly in this compartment. C-1311-treated cells died through apoptosis and necrosis, whereas surviving cells underwent cellular senescence; however, these effects occurred faster and to a greater extent in Hep3A4 cells. Although CYP3A4 did not influence C-1311 metabolism, changes in CYP3A4 levels affected the C-1311-induced cellular response in hepatoma cells. Therefore, inter-patient differences in CYP3A4 levels should be considered when assessing the potential therapeutic effects of C-1311.
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- Kategoria:
- Publikacja w czasopiśmie
- Typ:
- artykuł w czasopiśmie wyróżnionym w JCR
- Opublikowano w:
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CELL BIOLOGY INTERNATIONAL
nr 37,
wydanie 2,
strony 109 - 120,
ISSN: 1065-6995 - Język:
- angielski
- Rok wydania:
- 2013
- Opis bibliograficzny:
- Augustin E., Pawłowska M., Polewska J., Potęga A., Mazerska Z.: Modulation of CYP3A4 activity and induction of apoptosis, necrosis and senescence by the antitumor imidazoacridinone C-1311 in human hepatoma cells// CELL BIOLOGY INTERNATIONAL. -Vol. 37, iss. 2 (2013), s.109-120
- Weryfikacja:
- Politechnika Gdańska
wyświetlono 116 razy