The organotelluride catalyst LAB027 prevents colon cancer growth in the mice

Abstract

Organotellurides are newly described redox-catalyst molecules with original pro-oxidative properties. We have investigated the in vitro and in vivo antitumoral effects of the organotelluride catalyst LAB027 in a mouse model of colon cancer and determined its profile of toxicity in vivo. LAB027 induced an overproduction of H 2 O 2 by both human HT29 and murine CT26 colon cancer cell lines in vitro. This oxidative stress was associated with a decrease in proliferation and survival rates of the two cell lines. LAB027 triggered a caspase-independent, ROS-mediated cell death by necrosis associated with mitochondrial damages and autophagy. LAB027 also synergized with the cytotoxic drug oxaliplatin to augment its cytostatic and cytotoxic effects on colon cancer cell lines but not on normal fibroblasts. The opposite effects of LAB027 on tumor and on non-transformed cells were linked to differences in the modulation of reduced glutathione metabolism between the two types of cells. In mice grafted with CT26 tumor cells, LAB027 alone decreased tumor growth compared with untreated mice, and synergized with oxaliplatin to further decrease tumor development compared with mice treated with oxaliplatin alone. LAB027 an organotelluride catalyst compound synergized with oxaliplatin to prevent both in vitro and in vivo colon cancer cell proliferation while decreasing the in vivo toxicity of oxaliplatin. No in vivo adverse effect of LAB027 was observed in this model. Cell Death and Disease (2011) 2, e191; doi:10.1038/cddis.2011.73; published online 11 August 2011Subject Category: Cancer All living organisms need to maintain a healthy intracellular redox balance in order to survive and to proliferate. 1 Reactive oxygen species (ROS) are natural by-products of aerobic metabolism whose production correlates with normal cell proliferation through the activation of growth-related signaling pathways. 2 Exposure to low levels of ROS can stimulate the growth of many types of mammalian cells, whereas scavengers of ROS suppress normal cell proliferation in human and rodent fibroblasts. 3,4 Furthermore, growth factors trigger the production of hydrogen peroxide (H 2 O 2 ) that leads to mitogenactivated protein kinase activation and DNA synthesis, a phenomenon inhibited by antioxidant molecules. 5,6 Several observations suggest that ROS also participate in carcinogenesis. First, ROS production is increased in cancer cells, and an oxidative stress can induce DNA damages that lead to genomic instability and possibly stimulate cancer progression. 7 Second, elevated ROS levels are responsible for the activation of transcription factors, such as NF-kB and AP-1 during tumor progression. 8 Several studies have shown that different types of cancer cells such as colon, liver, lung, kidney, prostate and skin cancer cells 9-11 display a high proliferation rate associated with an increased endogenous production of ROS and a downregulation of their antioxidant enzymatic systems.On the other hand, ROS can also induce the apoptosis/ necrosis of cancer cells....

The Organotelluride Catalyst (PHTE)2NQ Prevents HOCl-Induced Systemic Sclerosis in Mouse

“…Therefore, (PHTE) 2 NQ induces a lethal oxidative burst in cells with increased levels of intracellular ROS, but it is not a systemic pro-oxidative molecule, as already observed in various cancer models (Fry and Jacob, 2006;Doering et al, 2010;Coriat et al, 2011). Several reports have linked the intracellular oxidative burst and the initiation of the immune response in human or murine models of SSc (Simonini et al, 1999;Harjardo et al, 2010).…”

“…Finally, ROS can stimulate the growth of dermal fibroblasts through the activation of the RAS pathway, which explains the hyperproliferative properties of SSc skin fibroblasts (Svegliati et al, 2005). However, if intracellular ROS can stimulate cell growth, they can also induce cell death beyond a certain threshold, as seen in tumor cells (Laurent et al, 2005;Morgan and Liu, 2010;Coriat et al, 2011;Lonkar and Dedon, 2011). Interestingly, some catalytic agents called ''sensor/effector'' multifunctional redox catalysts can modulate the intracellular redox balance by generating more reactive oxidants or by targeting cysteine residues in proteins.…”

“…These molecules seem to be particularly effective and selective (Fry and Jacob, 2006). Among the ''sensor/effector'' multifunctional redox catalyst agents, quinone-and chalcogen (selenium, tellurium)-containing agents have shown an in vitro cytotoxic activity against various types of tumor cells Coriat et al, 2011;Lilienthal et al, 2011). These observations have prompted us to try these new cytotoxic organotelluride catalysts in the treatment of mouse SSc.…”

“…Within this family of compounds, (PHTE) 2 NQ has been the most widely studied compound in vitro on tumor cells Jamier et al, 2010), and it has also been the only one used in vivo on mice (Coriat et al, 2011). Intracellular oxygen radicals and H 2 O 2 associate with the quinone moiety of the (PHTE) 2 NQ and strongly oxidize cellular thiols in a reaction catalyzed by the tellurium part of the molecule.…”

Sulforaphane induces p53-deficient SW480 cell apoptosis via the ROS-MAPK signaling pathway

“…Colorectal tumors first arise in the large intestine or the rectum, and is the third and second most common cancer in males and females, respectively (7,8). This progressive cancer arises from the accumulation of mutations in tumor suppressor genes and oncogenes, which disrupt the homeostatic balance between cell proliferation and apoptosis (9).…”