Title: An Emerging Molecular Target in Melanoma: Cellular Carbonyl Stress and the Inhibition of Mitochondrial Survival Pathways by Carbonyl Scavenger Agents
Volume: 1
Issue: 3
Author(s): Georg T. Wondrak, Myron K. Jacobson and Elaine L. Jacobson
Affiliation:
Keywords:
apoptosis, carbonyl scavenger, carbonyl stress, melanoma, mitochondrial permeability transition pore, receptor for advanced glycation endproducts
Abstract: Therapeutic induction of apoptosis is an important goal of anti-cancer drug design. Here, we review briefly the emerging role of cellular carbonyl stress in melanoma proliferative control, antiapoptotic survival signaling, progression, and metastasis. Cellular carbonyl stress mediated by endogenous reactive carbonyl species (RCS) such as glyoxal, methylglyoxal (MG), and malondialdehyde has been implicated in proliferative signaling and metastasis of human tumor cells. RCS-derived protein-epitopes called advanced glycation endproducts (AGEs) formed from chemical reaction between RCS and tissue proteins are abundant in melanoma tissue, and AGEs are potent ligands of RAGE, a membrane receptor involved in melanoma proliferation and metastasis. In addition to the established role of AGE-RAGE signaling in many human malignancies, increasing experimental evidence supports the hypothesis that RCS, originating from increased tumor cell glycolysis and mitochondrial oxidative stress, are small molecular anti-apoptotic effectors targeting the mitochondrial permeability transition pore (MPTP). We also discuss the emerging role of RCS as novel molecular targets for chemotherapeutic intervention, and provide preliminary experimental evidence that carbonyl scavengers, specific molecular antagonists of RCS, may represent a novel class of anti-melanoma therapeutics.
