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Glucuronides of antitumor agents C‐1311 and C‐1305 modulate cytotoxicity in cancer cells
Author(s) -
Pawlowska Monika,
Chu Rong,
Bratton Stacie M,
Augustin Ewa,
Mazerska Zofia,
Chambers Timothy C.,
Radominska-Pandya Anna
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.966.2
Subject(s) - cytotoxicity , glucuronidation , transfection , cell cycle , recombinant dna , gene isoform , apoptosis , cancer cell , cell culture , cell , in vitro , biology , chemistry , cancer , cancer research , microbiology and biotechnology , biochemistry , microsome , gene , genetics
These studies focus on two anti‐tumor compounds, C‐1311, an imidazoacridinone (IA), which has been selected for Phase II clinical trials, and C‐1305, a triazoloacridinone (TA), which is in extended preclinical studies. Our recent studies with human recombinant UDP‐glucuronosyltransferase (UGTs) revealed that these compounds are metabolized by the 1A10 isoform (UGT1A10), with the higher rate of glucuronidation C‐1305. Experiments with KB‐3 and MCF‐7 cells transiently transfected with UGT1A10 (50% efficiency) were carried out to investigate the effects of this isoform on cell cytotoxicity and cell cycle progression following C‐1311 and C‐1305 treatment. After transfection, cellular levels of C‐1311 and C‐1305 glucuronides were identified by HPLC‐ESI‐MS and their rate of production was time and concentration dependent. MTT assay revealed that sensitivity of cells with UGT1A10 overexpression compared to wild type increased by 31% in KB‐3 and by 40% in MCF‐7 cells only in the presence of C‐1305. Treatment of KB‐3 and MCF‐7 cells overexpressing UGT1A10 with C‐1305 led to the appearance of sub‐G1 population, suggesting apoptosis commitment. Collectively, these data indicate that the glucuronide of C‐1305 might be biologically active and its activity may contribute to overall cytotoxicity and pharmacology in these cancer cells.