Received for publication September 1, 2005.
Revised October 4, 2005.
Accepted for publication October 5, 2005.

Anti-Melanoma Activity of Apoptogenic Carbonyl Scavengers

Abstract

Therapeutic induction of apoptosis is an important goal of anti-cancer drug design. Cellular carbonyl stress mediated by endogenous reactive carbonyl species (RCS) such as glyoxal and methylglyoxal (MG) affects proliferative signaling and metastasis of human tumor cells. Recent research suggests that RCS produced constitutively during increased tumor cell glycolysis may be anti-apoptotic survival factors and thus represent a novel molecular target for anti-cancer intervention. Here, we demonstrate the tumor cell specific apoptogenicity of carbonyl scavengers, which act by covalently trapping RCS, against human (A375, G361, LOX) and murine (B16) melanoma cell lines. A structure activity relationship study identified nucleophilic carbonyl scavenger pharmacophores as the functional determinants of apoptogenic anti-melanoma activity of structurally diverse agents such as 3,3-dimethyl-D-cysteine and aminoguanidine. Earlier work has demonstrated that covalent adduction of protein-arginine residues in the mitochondrial permeability transition (MPT) pore and heat shock protein 27 by intracellular MG, produced in tumor cell glycolysis, inhibits mitochondrial apoptosis and enhances cancer cell survival. Indeed, in various melanoma cell lines, carbonyl scavenger induced apoptosis was antagonized by pretreatment with the membrane-permeable RCS phenylglyoxal (PG). Carbonyl scavenger induced apoptosis was associated with early loss of mitochondrial transmembrane potential, and cyclosporin A antagonized the effects of carbonyl scavengers, suggesting a causative role of MPT pore opening in carbonyl scavenger apoptogenicity. Consistent with RCS-inhibition of mitochondrial apoptosis in melanoma cells, staurosporine-induced apoptosis also was suppressed by PG pretreatment. Our results suggest that carbonyl scavengers acting as direct molecular antagonists of RCS are promising apoptogenic prototype agents for anti-melanoma drug design.

Key words: apoptosis, carbonyl scavenger, carbonyl stress, melanoma, methylglyoxal, mitochondrial transmembrane potential