Iron Chelators: Development of Novel Compounds with High and Selective Anti-Tumour Activity

Abstract

Targeting essential nutrients (eg., those required for DNA synthesis) to inhibit cancer cell growth is a well established therapeutic strategy. A good example is the highly successful folate antagonist, methotrexate. However, up until recently, strategies to target iron which is also crucial for DNA synthesis have not been systematically explored to develop agents for the treatment of cancer. Over the last 15 years, our laboratory has embarked upon structure-activity studies designed to develop novel Fe chelators with anti-cancer efficacy. These studies have led to the development of the dipyridyl thiosemicarbazone chelators that show potent and selective anti-cancer activity and which overcome resistance to other cytotoxic agents. This class of compounds include the chelator, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which at optimal doses markedly inhibits tumour growth and is well tolerated. Moreover, this ligand does not induce overt Fe-depletion in vivo, probably because very low doses (0.4 mg/kg) are effective at inhibiting tumour growth. Importantly, our compounds are far more active and less toxic than the chelator, Triapine®, that is being assessed in a wide variety of international clinical trials. A vital part of the mechanism of action of these compounds is their ability to form a redox-active Fe complex that generates radicals to inhibit tumour growth. Due to their relatively high lipophilicity and low molecular weight of this class of compounds, oral activity may be expected in addition to their well known efficacy via the intravenous route.

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

“…While iron chelators were originally designed to be ROS-scavenging antioxidants and chemoprotectants in heart cells, some have been shown to induce excess ROS generation in cancer cells. As anticancer agents, iron chelators have shown marked and selective activity in several in vitro and in vivo test systems (131,209). Doxorubicin targets top2a and topoisomerase 2 beta (top2b).…”

Novel Second-Generation Di-2-Pyridylketone Thiosemicarbazones Show Synergism with Standard Chemotherapeutics and Demonstrate Potent Activity against Lung Cancer Xenografts after Oral and Intravenous Administration in Vivo

“…3−5 Consequently, due to this increased Fe requirement, neoplastic cells compared to their normal counterparts express higher levels of the transferrin receptor 1 that delivers iron from the Fe transport protein, transferrin (Tf). 1,2 Considering the key role of Fe in tumor cell growth, the development of novel Fe-binding drugs (chelators) is a promising anticancer strategy, 1,5,6 as demonstrated by the entrance into clinical trials of the anticancer agent, 3aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). However, this chelator results in relatively low antitumor activity and its dose-limiting side effects such as methemoglobinemia and hypoxia have seriously limited its clinical potential.…”

An Iron Regulatory Gene Signature Predicts Outcome in Breast Cancer

“…In animal models, high dietary iron increased the rate of tumor formation (4, 5); conversely, a low iron diet led to less rapid growth of tumor xenografts (6, 7) and reduced spontaneous mammary tumors in rats (7). This has led to the exploration of agents that restrict iron availability, such as iron chelators and anti-transferrin receptor antibodies, as anti-tumor agents (8, 9). …”