Metabolic transformation of antitumor acridinone C-1305 but not C-1311 via selective cellular expression of UGT1A10 increases cytotoxic response: implications for clinical use. - Publication - Bridge of Knowledge

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Metabolic transformation of antitumor acridinone C-1305 but not C-1311 via selective cellular expression of UGT1A10 increases cytotoxic response: implications for clinical use.

Abstract

The acridinone derivates C-1305 and C-1311 are promising antitumor agents with high activity against several experimental cellular and tumor models and which are under evaluation in pre-clinical and early phase clinical trials. Recent evidence from our laboratories has indicated that both compounds were conjugated by several UGT isoforms with the most active being extrahepatic UGT1A10. The present studies were designed to test the ability and selectivity of UGT1A10 in the glucuronidation of acridinone antitumor agents in a cellular context. We show that in KB-3 cells, a HeLasubline lacking expression of any UGT isoforms, both C-1305 and C-1311 undergo metabolic transformation to the glucuronidated forms upon overexpression of UGT1A10. Furthermore, UGT1A10 overexpression significantly increased the cytotoxicity of C-1305 but not C-1311, suggesting that the glucuronide was more potent than the C-1305 parent compound. We also show that both compounds cause cell cycle arrest at S and G2 phases without evidence of mitotic arrest, consistent with DNA as the major target. These findings contribute to our understanding of the mechanisms of action of these agents and are of particular significance as data for C-1305 contradict the dogma that glucuronidation typically plays a role in detoxification or deactivation. In summary, these studies suggest that extrahepatic UGT1A10 plays an important role in the metabolism and the bioactivation of C-1305, and constitutes the basis for further mechanistic studies on the mode of action of this drug, as well as translational studies on the role of this enzyme in regulation of C-1305 toxicity in cancer.

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Category:
Articles
Type:
artykuł w czasopiśmie wyróżnionym w JCR
Published in:
DRUG METABOLISM AND DISPOSITION no. 41, pages 414 - 421,
ISSN: 0090-9556
Language:
English
Publication year:
2013
Bibliographic description:
Pawłowska M., Chu R., Fedejko-Kap B., Augustin E., Mazerska Z., Radominska-Pandya A., Chambers T.: Metabolic transformation of antitumor acridinone C-1305 but not C-1311 via selective cellular expression of UGT1A10 increases cytotoxic response: implications for clinical use.// DRUG METABOLISM AND DISPOSITION. -Vol. 41, nr. 2 (2013), s.414-421
DOI:
Digital Object Identifier (open in new tab) 10.1124/dmd.112.047811
Verified by:
Gdańsk University of Technology

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