Novel chemotherapeutics with marked and selective antitumor activity are essential to develop, particularly those that can overcome resistance to established
therapies.
Iron (Fe) is critical for cell-cycle progression and
DNA synthesis and potentially represents a novel molecular target for the design of new
anticancer agents. The aim of this study was to evaluate the antitumor activity and Fe chelation efficacy of a new class of Fe
chelators using human
tumors. In this investigation, the
ligands showed broad antitumor activity and could overcome resistance to established
antitumor agents. The in vivo efficacy of the most effective
chelator identified, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (
Dp44mT), was assessed by using a panel of human xenografts in nude mice. After 7 weeks, net growth of a
melanoma xenograft in Dp44mT-treated mice was only 8% of that in mice treated with vehicle. In addition, no differences in these latter animals were found in hematological indices between Dp44mT-treated mice and controls. No marked systemic Fe depletion was observed comparing Dp44mT- and vehicle-treated mice, probably because of the very low doses required to induce anticancer activity.
Dp44mT caused up-regulation of the Fe-responsive
tumor growth and
metastasis suppressor Ndrg1 in the
tumor but not in the liver, indicating a potential mechanism of selective anticancer activity. These results indicate that the novel Fe
chelators have potent and broad antitumor activity and can overcome resistance to established chemotherapeutics because of their unique mechanism of action.