D-penicillamine and other low molecular weight thiols: review of anticancer effects and related mechanisms

Abstract

Low molecular weight thiols (LMWTs) like N-acetyl cysteine, D-penicillamine, captopril, Disulfiram and Amifostine, etc. have been used as chemo-preventive agents. Recent studies have reported cell growth inhibition and cytotoxicity in several different types of cancer cells following treatment with several LMWTs. Cytotoxic and cytostatic effects of LMWTs may involve interaction of the thiol group with cellular lipids, proteins, intermediates or enzymes. Some of the mechanisms that have been proposed include a p53 mediated apoptosis, thiyl radical induced DNA damage, membrane damage through lipid peroxidation, anti-angiogenic effects induced by inhibition of matrix metalloproteinase enzymes and angiostatin generation. LMWTs are strong chelators of transition metals like copper, nickel, zinc, iron and cobalt and may cause metal co-factor depletion resulting in cytotoxicity. Oxidation of thiol group can also generate cytotoxic reactive oxygen species (ROS).

Keywords: ACE; Angiogenesis; Apoptosis; D-pen; D-penicillamine; DSF; DTT; Disulfiram; Dox; ECGF; ECM; Free radical; GSH; HA; LMWTs; LPS; Lipid peroxidation; MMP; N-acetyl cysteine; NAC; PDTC; Prx; RNS; ROS; SOD; TGF; TM; Tetrathiomolybdate; angiotensin converting enzyme; dithiothreitol; doxorubicin; endothelial cell growth factor; extracellular matrix; glutathione; hyaluronic acid; lipopolysaccharides; low molecular weight thiols; matrix metalloproteinases; p53; peroxiredoxin; pyrrolidine dithiocarbamate; reactive nitrogen species; reactive oxygen species; superoxide dismutase; tPA; tissue plasminogen activator; tumor growth factor.