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

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-β-oestradiol to CEs in the presence of a catechol (B ₀C) versus a non-catechol echinocandin (B ₀) compound. COMT inhibition assays were conducted to evaluate the metabolism of CEs in the presence of B ₀C 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 ₀C 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 ₀C significantly increased CE levels in the COMT inhibition assays, to 90.0 μM compared with 79.8 μM in the untreated controls (P = 0.032). A high concentration (500 μg/mL) of B ₀C decreased COMT expression to 79%, 94% and 90% of untreated, baseline control levels in the three cell lines, respectively. B ₀C and B ₀ did not increase cell growth in the cancer cell lines evaluated. Conclusions: At clinically achievable concentrations only B. ₀C 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.