In addition to its role as a cofactor in many enzymatic processes, NAD+ regulates key metabolic processes

ne adaptive mechanism used by premalignancies. HIF-1 increases expression of pyruvate dehydrogenase kinase , which inhibits pyruvate dehydrogenase, thereby inhibiting the conversion of pyruvate to acetyl-CoA, the substrate oxidized in the mitochondrial TCA cycle to produce ATP via the electron transport chain. LY341495 chemical information Therefore, in hypoxic environments, PDH activity is inhibited, glucose metabolism shifts from oxidative phosphorylation in the mitochondria to fermentation in the cytoplasm, and glycolytic activity is increased to maintain sufficient ATP production via the quicker but less efficient aerobic glycolysis. This metabolic adaptation leads to suppression of apoptosis, providing a proliferative advantage in cancer cells. Switching of energy metabolism in cancer cells to oxidative phosphorylation can promote apoptosis and increase sensitivity to chemotherapy and radiation. This switch can be J Cancer Res Clin Oncol. Author manuscript; available in PMC 2015 March 01. Garon et al. Page 3 accomplished by activating PDH, which results in increases in the following: pyruvate entry to the mitochondria, acetyl-CoA levels, TCA cycle activity, and reactive oxygen species production. DCA is a small compound with good oral bioavailability that promotes a metabolic shift from cytoplasmic glycolysis to mitochondrial oxidative phosphorylation by inhibiting PDHK. DCA has been used for over 25 years to treat children and adults with mitochondrial disorders. It has shown relatively modest toxicities, mostly limited to neurotoxocity . Several preclinical studies have successfully demonstrated DCA’s anti-tumor activity. A recent clinical trial performed at the University of Alberta found that DCA could be administered safely and effectively after debulking surgery, temozolamide, and radiation in the management of glioblastoma multiforme . DCA achieves 100% bioavailability with excellent central nervous system penetration, increasing its potential in cancers involving the CNS. The half-life of DCA after an oral dose is under an hour, but there is evidence that DCA inhibits its own metabolism, leading to sustained trough levels in the low mM range. We designed this PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19844160 phase II clinical trial to determine the response rate of oral dichloroacetate in patients with previously treated and/or metastatic breast cancer and NSCLC. In addition, we studied the effects of DCA across a panel of 54 NSCLC cell lines. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Patients Patients, Materials and Methods Eligible patients were 18 years old with pathologically confirmed stage IV breast cancer or stage IIIB/IV NSCLC with radiographically measurable disease by RECIST 1.0. Eligible lung cancer patients either demonstrated disease progression despite receiving platinum-based chemotherapy, or refused recommended chemotherapy. Eligible metastatic breast cancer patients received prior anthracycline and taxane-based chemotherapy, hormonal therapy if the tumor was ER positive, and trastuzumab if immunohistochemistry or fluorescent in-situ hybridization demonstrated HER2 amplification. Patients were required to have an Eastern Cooperative Oncology Group Performance Status of 02 . Life expectancy of at least 12 weeks, and adequate bone marrow, hepatic, and renal function were required. Ejection fractions were evaluated using multigated acquisition scan, and only those with normal ejection fractions were included in this study. Patients were excluded for periphe