Therapeutic induction of apoptosis is an important goal of anticancer
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 antiapoptotic survival factors and thus represent a novel molecular target for anticancer intervention. Here, we demonstrate the
tumor cell-specific apoptogenicity of carbonyl scavengers, which act by covalently trapping RCS, against human (A375, G361, and LOX) and murine (
B16) melanoma cell lines. A structure-activity relationship study identified nucleophilic carbonyl scavenger pharmacophores as the functional determinants of apoptogenic antimelanoma activity of structurally diverse agents such as 3,3-dimethyl-D-cysteine and
aminoguanidine. Previous 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 antimelanoma
drug design.