Effects of the monoamine oxidase inhibitor, tranylcypromine, on induction of HL60 cell differentiation by hexamethylene bisacetamide and N-acetyl-1,6-diaminohexane.
Hexamethylene bisacetamide (HMBA) is converted by successive deacetylation and oxidation reactions to four major metabolites; in vitro, the initial deacetylated metabolite, N-acetyl-1,6-diaminohexane (NAD-AH), is more potent than HMBA (Synder, S.W.; Egorin, M.J.; Geelhaar, L.A.; Hamburger, A.W.; Callery, P.S. Cancer Res. 48:3613-3616; 1988). We propose that monoamine oxidase (MAO) catalyzed metabolism of NADAH to 6-acetamidohexanoic acid (AcHA) is an inactivation pathway and, therefore, investigated whether blocking such metabolism with the MAO inhibitor, tranylcypromine, would potentiate induction of cell differentiation by HMBA and NADAH. Tranylcypromine, at concentrations up to 30 micrograms/mL, did not inhibit HL60 cell growth and did not induce differentiation of HL60 cells. Tranylcypromine did, however, produce concentration-dependent enhancement of HMBA- and NADAH-induced differentiation. In contrast, 30 micrograms/mL of tranylcypromine did not effect the ability of dimethylsulfoxide, at concentrations between 0.25% and 1.25%, to induce differentiation of HL60 cells. Tranylcypromine, at 30 micrograms/mL, did not change cellular concentrations of HMBA or NADAH but did reduce intracellular concentrations of AcHA, consistent with inhibition of MAO catalyzed conversion of NADAH to AcHA. These results support the hypothesis that MAO catalyzed metabolism of NADH to AcHA is an inactivation pathway and may provide the basis for a clinical trail in which HMBA metabolism is modulated with concurrent tranylcypromine therapy.
Snyder
S W
SW
Division of Development Theraputics, University of Maryland Cancer Center, Baltimore 21201.
Egorin
M J
MJ
Zuhowski
E G
EG
Schimpff
E C
EC
Callery
P S
PS
D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D014191:Tranylcypromine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects
D000081:Acetamides; D014191:Tranylcypromine; C050895:N-acetyl-1,6-diaminohexane; C014026:hexamethylene bisacetamide; D004121:Dimethyl Sulfoxide