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Iron chelators can overcome resistance to established chemotherapeutics
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A class of iron chelators with a wide spectrum of potent antitumor
activity that overcomes resistance to chemotherapeutics.
Whitnall M, Howard J, Ponka P, Richardson DR
Proc Natl Acad Sci U S A. 2006 Sep 26;

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.

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