Novel Polypyridyl chelators deplete cellular zinc and destabilize the X‐linked inhibitor of apoptosis protein (XIAP) prior to induction of apoptosis in human prostate and breast cancer cells

Abstract

X-linked inhibitor of apoptosis protein, XIAP, inhibits the initiation and execution phases of the apoptotic pathway. XIAP is the most potent member of the inhibitor of apoptosis protein (IAP) family of the endogenous caspase inhibitors. Therefore, targeting XIAP may be a promising strategy for the treatment of apoptosis-resistant malignancies. In this study we systematically studied the relationships of chemical structures of several novel ligands to their zinc-binding ability, molecular target XIAP, and tumor cell death-inducing activity. We show that treatment of PC-3 prostate cancer and MDA-MB-231 breast cancer cells with these membrane-permeable zinc-chelators with different zinc affinities results in varying degrees of XIAP depletion. Following decreased level of XIAP expression, we also show apoptosis-related caspase activation and cellular morphological changes upon treatment with strong zinc-chelators N4Py and BnTPEN. Addition of zinc has a full protective effect on the cells treated with these chelators, while iron addition has only partial protection that, however, can be further increased to a comparable level of protection as zinc by inhibition of ROS generation, indicating that cell death effects mediated by iron- but not zinc-complexes involve redox cycling. These findings suggest that strong zinc-chelating agents may be useful in the treatment of apoptosis-resistant human cancers.

Zinc and zinc transporters in prostate carcinogenesis

“…94, 95 Indeed, TPEN-mediated XIAP depletion coincides with increased activation of the apoptosis-mediating caspase 3 and caspase 9, as well as increased sensitization of apoptosis-resistant tumour cells to subsequent treatment with TNF-related apoptosis-inducing ligand (TRAIL). 93 These findings were also supported by Zuo et al , 96 who demonstrated that novel polypyridyl chelators deplete cellular zinc and destabilize XIAP in human prostate and breast cancer cells. In light of the fact that prostate cancer cells are unable to counteract zinc chelation, a new potential therapeutic avenue opens for exploration.…”

Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling

“…All specimens were formalin fixed, sectioned, stained with haematoxylin and eosin and examined through microscopy. Pathological staging was performed by Dr Chang according to the international staging system for lung cancer 67 .…”

In vitro evaluation of metal chelators as potential metallo- β -lactamase inhibitors

“…Also, polypyridyls are acyclic chelators that have proven their ability to treat apoptosis‐resistant human cancer in vitro due to their strong zinc chelating properties (Zuo et al . ). Examples of polypyridyls (Fig.…”

“…) include di‐(2‐picolyl) amine (DPA) and N,N,N′,N ‐tetrakis (2‐pyridymethyl) ethylenediamine (TPEN) which has a higher affinity for zinc metals than DPA (Zuo et al . ). The zinc chelating properties of TPEN have been studied both in vitro and in vivo , but there is very little information in the literature on the MBL inhibition properties of these acyclic chelators (Adler et al .…”