Assesment of an Oxidant-Based Strategy to Target Cancer Cells

Abstract

Many cancer cell lines concentrate vitamin C, and in combination with vitamin K3 generate a redox-cycling that induces over-production of ROS, thus this treatment provides an oxidant challenge to cancer cells that spares non-cancer cells (Verrax et al, 2009). Because mitochondria are targets of oxidative damage by ROS, Vit K3/C treatment was predicted to induce mitochondrial dysfunction, subsequent Ca2+ homeostasis dysregulation and cell death. However, effectiveness of this treatment for breast and neuroendocrine cancer cell lines has not been investigated. Thus, we compared mitochondrial function, Ca2+ dynamics and cell viability prior to and following Vit K3/C treatment in human neuroendocrine and breast cancer cell lines. Ca2+-, ψm- and ROS-sensitive dyes were used to measure mitochondrial mass, energy state and changes Ca2+ dynamics. This study indicated that mitochondrial membrane potential was reduced in both carcinoid and breast cancer cell lines after VitK3/C treatment. Mitochondrial superoxide levels were significantly increased only in breast cancer cell lines after VitK3/C treatment and were correlated with cell death. In contrast, mitochondrial dysregulation was more effective at altering Ca2+ signaling in neuroendocrine than in breast cancer cell lines. Treatment with Vit K3/C significantly reduced Ca2+ entry and diminished the frequency and maintenance of Ca2+ oscillations. Although Vit K3/C treatment was found to be generally toxic to both breast and neuroendocrine cancer cell lines, it was less effective at inducing cell death in neuroendocrine cancer cells. Thus, these data indicate that the oxidative treatment regimen may not be universally effective for all types of cancers. Moreover, the mechanism of toxicity appears to be associated with a direct oxidant challenge to mitochondria. Further study will determine if this treatment approach alone or in combination with other therapies will be a useful strategy to combat cancer in patients.