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Modulation of CYP3A4 activity and induction of apoptosis, necrosis and senescence by the anti‐tumour imidazoacridinone C‐1311 in human hepatoma cells
Author(s) -
Augustin Ewa,
Pawłowska Monika,
Polewska Joanna,
Potega Agnieszka,
Mazerska Zofia
Publication year - 2013
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.10018
Subject(s) - biology , apoptosis , cyp3a4 , dapi , senescence , cell culture , necrosis , cell cycle , enzyme , microbiology and biotechnology , biochemistry , cytochrome p450 , genetics
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 have 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 have also been examined. With the HepG2 cell line and its CYP3A4‐overexpressing variant, Hep3A4, experiments involving DAPI staining, cell cycle analysis, phosphatidylserine externalisation and senescence‐associated (SA)‐β‐galactosidase expression, were used to monitor the effects of C‐1311 exposure. C‐1311 cellular metabolism and CYP3A4 activity were investigated by high‐performance liquid chromatography. C‐1311 metabolism was very low in both hepatoma cell lines and slightly influenced by CYP3A4 expression. Interestingly, in HepG2 cells, C‐1311 was an effective modulator of CYP3A4 enzymatic activity, being the inhibitor of this isoenzyme in Hep3A4 cells. Cell cycle analysis showed that HepG2 cells underwent a rather stable G 2 /M arrest following C‐1311 exposure, whereas CYP3A4‐overexpressing cells accumulated only slightly in this compartment. C‐1311‐treated cells died by apoptosis and necrosis, whereas surviving cells underwent senescence; however, these effects occurred faster and more intensely in Hep3A4 cells. Although CYP3A4 did not influence C‐1311 metabolism, changes in CYP3A4 levels affected the C‐1311‐induced response in hepatoma cells. Therefore, inter‐patient differences in CYP3A4 levels should be considered when assessing the potential therapeutic effects of C‐1311.