Vitamin E Protects against Lipid Peroxidation and Rescues Tumorigenic Phenotypes in Cowden/Cowden-like Patient-Derived Lymphoblast Cells with Germline SDHx Variants

Purpose: Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid, and other cancers. Germline variations in succinate dehydrogenase genes (SDHx) occur in approximately 10% PTEN mutation-negative CS and CS-like (CSL) individuals (SDHvar+). We previously showed that SDHx variants result in elevated reactive oxygen species (ROS), disruption of nicotinamide adenine dinucleotide (NAD) equilibrium, and destabilization of p53 hence apoptosis resistance in CS/CSL patient-derived lymphoblastoid cells. In the present study, we sought to address the tumorigenic impacts of increased ROS and the potential of protecting SDHvar+ cells with antioxidants. Experimental Design: We measured the lipid peroxidation levels in patient-derived SDHvar+ lymphoblastoid cells and sequenced 74 controls or SDHvar+ germline DNA samples for mitochondrial hypervariable region II (HVRII) polymorphisms. SDHvar+ lymphoblastoid cells were treated with various antioxidants to check p53 expression and sub-G(1) cell population with cell-cycle analysis. Results: We showed that elevated ROS results in higher lipid peroxidation in SDHvar+ cells. Accumulation of polymorphisms in mitochondrial HVRII was observed in SDHvar+ samples. Interestingly, alpha-tocopherol (vitamin E) treatment, but not other antioxidants, rescued SDHvar+ cells from apoptosis resistance and protected SDHvar+ cells from oxidative damage such as decreased lipid peroxidation as well as partially recovered p53 expression and NAD/NADH levels. Conclusions: We conclude that disruption of complex II because of SDHx variants leads to increased ROS generation, specifically accompanied by lipid peroxidation. The lipid soluble antioxidant alpha-tocopherol can selectively protect SDHvar+ cells from oxidative damage, apoptosis resistance, and rebalance redox metabolites NAD/NADH. Clin Cancer Res; 18(18); 4954-61. (c) 2012 AACR.