Abstract
BackgroundMetal chelators have gained much attention as potential anti-cancer agents. However, the effects of chelators are often linked solely to their capacity to bind iron while the potential complexation of other trace metals has not been fully investigated. In present study, we evaluated the effects of various lipophilic aroylhydrazone chelators (AHC), including novel compound HNTMB, on various ovarian cancer cell lines (SKOV-3, OVCAR-3, NUTU-19).MethodsCell viability was analyzed via MTS cytotoxicity assays and NCI60 cancer cell growth screens. Apoptotic events were monitored via Western Blot analysis, fluorescence microscopy and TUNEL assay. FACS analysis was carried out to study Cell Cycle regulation and detection of intracellular Reactive Oxygen Species (ROS)ResultsHNTMB displayed high cytotoxicity (IC50 200-400 nM) compared to previously developed AHC (oVtBBH, HNtBBH, StBBH/206, HNTh2H/315, HNI/311; IC50 0.8-6 μM) or cancer drug Deferoxamine, a hexadentate iron-chelator (IC50 12-25 μM). In a NCI60 cancer cell line screen HNTMB exhibited growth inhibitory effects with remarkable differences in specificity depending on the cell line studied (GI50 10 nM-2.4 μM). In SKOV-3 ovarian cancer cells HNTMB treatment led to chromatin fragmentation and activation of the extrinsic and intrinsic pathways of apoptosis with specific down-regulation of Bcl-2. HNTMB caused delayed cell cycle progression of SKOV-3 through G2/M phase arrest. HNTMB can chelate iron and copper of different oxidation states. Complexation with copper lead to high cytotoxicity via generation of reactive oxygen species (ROS) while treatment with iron complexes of the drug caused neither cytotoxicity nor increased ROS levels.ConclusionsThe present report suggests that both, non-complexed HNTMB as a chelator of intracellular trace-metals as well as a cytotoxic HNTMB/copper complex may be developed as potential therapeutic drugs in the treatment of ovarian and other solid tumors.
Highlights
Metal chelators have gained much attention as potential anti-cancer agents
Novel compound HNTMB (Fig. 2), displayed superior cytotoxicity (72 h treatment, IC50 of 200 nM for SKOV-3, 400 nM for OVCAR-3 and NUTU-19) (Fig. 1) when compared to all other 5 aroylhydrazone chelators (AHC) tested which were highly cytotoxic only at higher drug concentrations with IC50 values between 800 nM and 6 μM depending on the cell line or compound studied
The objective of the present study was to investigate the potential of six different lipophilic aroylhydrazone chelators (AHC) including novel compound HNTMB as anti-tumor drugs and to analyze modes of action leading to cell death of ovarian cancer cells following HNTNB treatment
Summary
Metal chelators have gained much attention as potential anti-cancer agents. the effects of chelators are often linked solely to their capacity to bind iron while the potential complexation of other trace metals has not been fully investigated. While re-treatment with a platinum-based agent is possible for some women, overall response rates to second line chemotherapeutic agents are 15-30% and treatment of recurrent ovarian carcinoma is mainly directed at palliation [3,4,5,6]. Treatment strategies against tumors that developed resistance to standard chemotherapeutic agents, most notably platinum analogs, include non-platinum drugs with increased activity and response rates. Chelating drugs and chelator metal complexes are used for the prevention, diagnosis and treatment of cancer and chelating compounds with high affinity for iron or copper have been suggested as potential anti-tumor agents [7]. In previous studies the effects of chelating drugs were often linked solely to their capacity to complex iron while the potential complexation of other trace metals was not discussed or analyzed. One rationale for the anti-tumor activity of chelators is a higher Fe utilization by cancer cells and often elevated concentrations of trace metals, of copper, in tumor patients [8,9,10]
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