Catechol-O-methyltransferase as a target for melanoma destruction?
Catechols may interfere in melanogenesis by causing increased levels of toxic quinones. Several catechols and known inhibitors of the enzyme catechol-O-methyltransferase (COMT) were therefore tested for their toxicity towards a pigmented melanoma cell line, UCLA-SO-(M14). The inhibition of thymidine incorporation as a result of exposure to the compounds was measured. All agents were compared to 4-hydroxyanisole (4HA), a depigmenting agent extensively studied as an antimelanoma drug. The compounds were also tested on the epithelial cell line, CNCM-I-(221) in the presence and absence of tyrosinase. All the compounds were more effective than 4HA towards the M14-cells at either 10(-4) M or 10(-5) M. The toxicity of 4HA towards the 221-cells was shown to be completely dependent on the presence of tyrosinase. Effects of the test agents on the 221-cells were also observed in the absence of tyrosinase. Although some of them were shown to be good substrates for tyrosinase only small changes in toxicity were observed as a result of the presence of the enzyme in comparison with 4HA. No direct correlation of the toxicity of the agents and COMT inhibition was observed. The possible mode of action of the compounds through inhibition of COMT and interference in melanogenesis is discussed together with other possibilities and factors involved.
Smit
N P
NP
Department of Dermatology, University of Amsterdam, The Netherlands.
Latter
A J
AJ
Naish-Byfield
S
S
Westerhof
W
W
Pavel
S
S
Riley
P A
PA
D000840:Anisoles / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000302:isolation & purification; D065098:Catechol O-Methyltransferase Inhibitors; D016923:Cell Death; D002458:Cell Fractionation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology*; D014442:Monophenol Monooxygenase / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000840:Anisoles; D000970:Antineoplastic Agents; D065098:Catechol O-Methyltransferase Inhibitors; C009760:mequinol; D014442:Monophenol Monooxygenase; D002394:Catechol O-Methyltransferase; D013936:Thymidine