Search

Epithelial to mesenchymal transition (EMT) plays a key role in tumor progression and metastasis as a crucial event for cancer cells to trigger the metastatic niche. Transforming growth factor-β (TGF-β) has been shown to play an important role as an EMT inducer in various stages of carcinogenesis. Previous reports had shown that antitumor vanadium inhibits the metastatic potential of tumor cells by reducing MMP-2 expression and inducing ROS-dependent apoptosis. However, the role of vanadium in (TGF-β)-induced EMT remains unclear. In the present study, we report for the first time on the inhibitory effects of vanadium on (TGF-β)-mediated EMT followed by down-regulation of ex vivo cancer stem cell markers. The results demonstrate blockage of (TGF-β)-mediated EMT by vanadium and reduction in the mitochondrial potential of tumor cells linked to EMT and cancer metabolism. Furthermore, combination of vanadium and carboplatin (a) resulted in synergistic antitumor activity in ex vivo cell cultures, and (b) prompted G0/G1 cell cycle arrest and sensitization of tumor cells to carboplatin-induced apoptosis. Overall, the findings highlight the multifaceted antitumor action of vanadium and its synergistic antitumor efficacy with current chemotherapy drugs, knowledge that could be valuable for targeting cancer cell metabolism and cancer stem cell-mediated metastasis in aggressive chemoresistant tumors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cadmium (Cd) is a well-known metal carcinogen associated with tumor formation and carcinogenesis. It has been shown to induce cancer through various cellular mechanisms involving inhibition of DNA repair, abnormal gene expression, induction of oxidative stress, and triggering apoptosis. It is well-established that the H-ras oncogene is involved in the process of carcinogenesis with direct effects on cellular proliferation and tumorigenesis. Given the biotoxicity of cadmium and its association with carcinogenesis, the effect of that metal ion (Cd(II)) was investigated, in a concentration-dependent fashion, on cell viability, cell proliferation, caspase-3 mediated apoptosis and H-ras gene expression in human breast cancer epithelial MCF-7 cells transfected with the H-ras oncogene (wild type and G12V mutation). The findings show a significant modulation effect of cadmium on H-ras gene expression accompanied by up-regulation of caspase-3-related apoptosis in the concentration range of 100-1000 nΜ cadmium. Concurrently, there is a decrease in MCF-7 proliferation. Collectively, the results a) indicate an interplay of cadmium with H-ras(wt and G12V), with cadmium exhibiting a significant concentration-dependent effect on the modulation of H-ras expression, cell viability and proliferation, and b) project distinctly interwoven roles for both cadmium and H-ras in aberrant physiologies in cancer cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

It is well known that iron dysregulation is involved in a number of processes involving genetic and non-genetic factors leading to neurodegeneration. Molecules bearing iron or influencing iron metabolism reflect directly into the levels of that redox active metal, present as Fe(II)/Fe(III), in the brain. In turn, iron level variations are associated with chemical reactivity disrupting iron homeostasis, generating variable neurotoxic iron forms and contributing to the vulnerability of cells toward oxidative stress and neuronal death in Alzheimer's disease (AD). Efforts to delineate the interactions of neurotoxic Fe(III) with low molecular mass substrates, relevant to cellular processes, led to the discovery of specific well-defined binary iron-quinate (FeQ) species. Poised to investigate the specific effects of a) well-defined forms of labile soluble Fe(III), b) the nature and chemistry of the ligand bound to Fe(III), and c) a natural metal ion binder - quinic acid - acting as a potential neuroprotectant toward iron toxicity, FeCl(3), FeQ, and free quinate were employed in in vitro studies involving primary rat hippocampal cultures. Three hour and 24-hour exposures of such cultures to Fe(III) reveal significant differential effects on both glial and neuronal cell survival linked to neurotoxicity of the specific yet variably composed complex forms of iron. The use of quinic acid both in the free and bound form to Fe(III) a) exemplifies essential structural and chemical attributes of naturally encountered metal ion binders promoting well-defined interactions with neurotoxic Fe(III), and b) signifies the potential linkage of labile Fe(III) chemical reactivity in neurodegeneration with natural substrate neuroprotection., (Copyright © 2012 Elsevier Inc. All rights reserved.)