A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

Abstract

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 vehicletreated 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.cancer ͉ di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone ͉ Ndrg1

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…Chelators are widely investigated because of their therapeutic potential in the treatment of metal overload and diseases related to imbalanced metal homeostasis including hemochromatosis, β-thalassemia, Alzheimer's or Parkinson's diseases and cancer [8,9,12,70].…”

“…According to this model, increased glycolysis compensates for the higher energy demand created by the "futile cycling" of the transporter [79,81,82], but the oxidative stress associated with oxidative phosphorylation ultimately results in the selective apoptosis of MDR cells [83]. ROS have not only been implicated in the paradoxical sensitivity of resistant cells, but also in the mechanism of toxicity of chelators [8,12,13].…”

“…The increased proliferation of cancer cells results in an elevated demand for metal ions, which creates a vulnerability that can be exploited therapeutically [8][9][10][11]. The toxicity of chelators is M A N U S C R I P T…”

Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance–linked ABCG2 transporter

“…Thiosemicarbazone-related compounds are well-known to have active antiviral, antibacterial, antimalarial, and antihypertensive properties (42), as well as antitumor activity that can overcome resistance to chemotherapeutics (19,43). Recently, we reported that the small-molecule thiosemicarbazone NSC73306 is significantly more cytotoxic to cells that overexpress P-glycoprotein than to cells that do not, and this unique property is directly proportional to functional P-glycoprotein protein expression (19).…”

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

“…Many cancers exhibit an increased requirement for iron, presumably because of the need for iron as a cofactor in proteins essential to sustain growth and proliferation (1–3). Modulation of iron-regulatory proteins affects growth of lung tumor xenografts (4, 5), and agents that deplete iron are currently under investigation as anticancer therapies (6–9). …”