title: Modulation of CYP3A4 activity and induction of apoptosis, necrosis and senescence by the anti-tumour imidazoacridinone C-1311 in human hepatoma cells.
abstract: 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.
authors: Chemical Faculty, Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, Narutowicza Str. 11/12, 80-233 Gdańsk, Poland. ewa.augustin@pg.gda.pl
authors: Ewa
authors: E
authors: Augustin
authors: Monika
authors: M
authors: Pawłowska
authors: Joanna
authors: J
authors: Polewska
authors: Agnieszka
authors: A
authors: Potega
authors: Zofia
authors: Z
authors: Mazerska
mesh_terms: D000609:Aminoacridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C098965:C 1311