Targeting phenethyl isothiocyanate to mitochondria in lung carcinogenesis

Disruption of normal mitochondrial bioenergetics and oxidative phosphorylation represents an early event during oncogenesis by changing the energy metabolism of precancerous and cancerous cells. Phenethyl isothiocyanate (PEITC), a natural compound present in cruciferous vegetables, has been shown to inhibit the development of several types of cancer in animal models. PEITC has been shown to inhibit oxidative phosphorylation and to induce cancer cell apoptosis through a mitochondria-dependent mechanism and ROS formation, suggesting the role of mitochondrial bioenergetic function and redox homeostasis in oncogenesis. This provides the rationale for conjugating PEITC to a targeting agent that drives it into mitochondria to specifically study the role of mitochondrial function and ROS formation in lung cancer development and to increase the efficacy of PEITC. Preliminary studies demonstrate that mitochondria-targeted PEITC (Mito-PEITC) is a significantly more potent inhibitor of lung carcinogenesis in mice. We hypothesize that lung oncogenesis and metastasis depend on mitochondrial respiration and that Mito-PEITC is a novel, potent inhibitor of lung carcinogenesis and metastasis acting primarily through mitochondrial mechanisms. This hypothesis will be tested using three specific aims. Aim 1 will evaluate the preventive potential and mechanisms of action of Mito-PEITC in vitro. We will use Mito-PEITC and lung cancer cells with genetically modified expression of the members of the mitochondrial electron transport chain to decipher the oncogenic mechanism and evaluate the mechanisms of action of Mito-PEITC. Aim 2 will determine preventive efficacy of Mito-PEITC on lung tumor initiation and progression in A/J mice. Aim 3 will determine the in vivo mechanism and the efficacy of Mito-PEITC to inhibit lung cancer brain metastasis. We will use state-of-the-art in vitro and in vivo assays, including small animal imaging technology to monitor the growth of primary tumors (magnetic resonance imaging) and engraftment of metastatic cells. Innovative approaches for in vivo monitoring of changes in cancer cell bioenergetics and cellular oxidant production (bioluminescence imaging) will be employed. Defining mitochondrial mechanisms of lung oncogenesis and brain metastasis and developing a novel, well-tolerated efficacious agent for prevention and treatment of lung cancer will be highly significant.