Abstract
Purpose
The iron chelator Dp44mT is a potent topoisomerase IIα inhibitor with novel anticancer activity. Doxorubicin (Dox), the current front-line therapy for breast cancer, induces a dose-limiting cardiotoxicity, in part through an iron-mediated pathway. We tested the hypothesis that Dp44mT can improve clinical outcomes of treatment with Dox by alleviating cardiotoxicity.
Methods
The general cardiac and renal toxicities induced by Dox were investigated in the presence and absence of Dp44mT. The iron chelating cardioprotectant Dexrazoxane (Drz), which is approved for this indication, was used as a positive control. In vitro studies were carried out with H9c2 rat cardiomyocytes and in vivo studies were performed using spontaneously hypertensive rats.
Results
Testing of the GI50 profile of Dp44mT in the NCI-60 panel confirmed activity against breast cancer cells. An acute, toxic dose of Dox caused the predicted cellular and cardiac toxicities, such as cell death and DNA damage in vitro and elevated cardiac troponin T levels, tissue damage, and apoptosis in vivo. Dp44mT alone caused insignificant changes in hematological and biochemical indices in rats, indicating that Dp44mT is not significantly cardiotoxic as a single agent. In contrast to Drz, Dp44mT failed to mitigate Dox-induced cardiotoxicity in vivo.
Conclusions
We conclude that although Dp44mT is a potent iron chelator, it is unlikely to be an appropriate cardioprotectant against Dox-induced toxicity. However, it should continue to be evaluated as a potential anticancer agent as it has a novel mechanism for inhibiting the growth of a broad range of malignant cell types while exhibiting very low intrinsic toxicity to healthy tissues.
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Acknowledgments
This study was funded by the intramural research program of the Food and Drug Administration and the National Cancer Institute. We thank Dr. Yves Pommier (NCI) for helpful discussions and Dr. Melanie Simpson (NCI) for critical reading of the manuscript. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the U.S. Food and Drug Administration.
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280_2011_1587_MOESM1_ESM.eps
Fig. S1 Anticancer cytotoxicity profile of Dp44mT. The NCI 60 panel of cancer cell lines was treated with increasing concentrations of Dp44mT in order to evaluate the relative sensitivities to the drug in different tissue types. Cell lines are depicted graphically by their tissue of origin. Red asterisks indicate tissue types that were most sensitive to the drug. Supplementary material 1 (EPS 11951 kb)
280_2011_1587_MOESM2_ESM.eps
Fig. S2 Anticancer cytotoxic profile of Dp44mT. The GI50 value for each cell line and tissue type tested is shown. Bars protruding to the right indicate increased sensitivity to Dp44mT while bars protruding to the left indicate increased resistance. (EPS 4519 kb)
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Rao, V.A., Zhang, J., Klein, S.R. et al. The iron chelator Dp44mT inhibits the proliferation of cancer cells but fails to protect from doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats. Cancer Chemother Pharmacol 68, 1125–1134 (2011). https://doi.org/10.1007/s00280-011-1587-y
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DOI: https://doi.org/10.1007/s00280-011-1587-y