Defining the role of echinocandin catechol functional groups in the development of secondary hepatocellular carcinoma.

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Julius JM, Gaikwad A, Lowry A, Lewis RE, Lozano RD, Dalrymple JL, Coleman RL, Smith JA

Defining the role of echinocandin catechol functional groups in the development of secondary hepatocellular carcinoma.

J Antimicrob Chemother. 2012 Feb;67(2):422-9. doi: 10.1093/jac/dkr494. Epub 2011 Nov 30.

PubMed ID

22129592 [ View in PubMed

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Abstract

OBJECTIVES: To determine whether the catechol functional group on echinocandins decreases the catechol-O-methyltransferase (COMT) metabolism of catechol oestrogens (CEs) and the potential role of this functional group in the development of hepatocellular cancer. METHODS: Human COMT expression was measured by RT-PCR in a panel of selected human cancer cell lines and human hepatocytes. An ex vivo human hepatocyte model was employed to evaluate the metabolism of 17-beta-oestradiol to CEs in the presence of a catechol (B(0)C) versus a non-catechol echinocandin (B(0)) compound. COMT inhibition assays were conducted to evaluate the metabolism of CEs in the presence of B(0)C or B(0). Oestrogen receptor expression in human hepatic carcinoma cells was evaluated by RT-PCR and western blotting. Cell proliferation assays were used to evaluate the impact of B(0) or B(0)C on cancer cell growth. RESULTS: MCF-7 and Hep-G2 cells and human hepatocytes expressed variant Met/Met COMT. At clinically relevant concentrations, only B(0)C significantly increased CE levels in the COMT inhibition assays, to 90.0 muM compared with 79.8 muM in the untreated controls (P = 0.032). A high concentration (500 mug/mL) of B(0)C decreased COMT expression to 79%, 94% and 90% of untreated, baseline control levels in the three cell lines, respectively. B(0)C and B(0) did not increase cell growth in the cancer cell lines evaluated. CONCLUSIONS: At clinically achievable concentrations only B(0)C significantly inhibited COMT activity and increased CE concentrations. Short-term exposure did not alter the rate of cancer cell growth. Confirmation is needed to determine the clinical impact of long-term exposure to and the use of echinocandins with catechol functional groups.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Micafungin	Catechol O-methyltransferase	Protein	Humans	Unknown	Substrate	Details