title: Defining the role of echinocandin catechol functional groups in the development of secondary hepatocellular carcinoma.
abstract: OBJECTIVE
  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(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 μM compared with 79.8 μM in the untreated controls (P = 0.032). A high concentration (500 μg/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.
authors: Division of Pharmacy,  The University of Texas MD Anderson Cancer Center, Houston, TX 77030,  USA.
authors: Justin M
authors: JM
authors: Julius
authors: Anjali
authors: A
authors: Gaikwad
authors: Amy
authors: A
authors: Lowry
authors: Russell E
authors: RE
authors: Lewis
authors: Richard D
authors: RD
authors: Lozano
authors: John L
authors: JL
authors: Dalrymple
authors: Robert L
authors: RL
authors: Coleman
authors: Judith A
authors: JA
authors: Smith
mesh_terms: D015153:Blotting, Western; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000556:secondary*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D054714:Echinocandins / Q000737:chemistry / Q000633:toxicity*; D004958:Estradiol / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D009052:Leukemia Virus, Murine; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: D002273:Carcinogens; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D054714:Echinocandins; D004958:Estradiol; D002394:Catechol O-Methyltransferase; C034221:catechol