S known as PFKFB3. Increased PFKFB3 expression results in the production

S known as PFKFB3. Increased PFKFB3 expression results in the production of fructose-2,6,-bisphosphate, a potent allosteric activator of PFK1. Studies suggest that inhibition of PFKFB3 using genetic approaches and small molecule inhibition results in dramatically reduced glycolytic flux and slowed cancer cell growth. Early phase clinical trials are currently underway with small molecule PFKFB3 inhibitors. Another key step in glucose metabolism is the branch point at which glycolysis-derived pyruvate can either be imported into the mitochondria to be oxidized in the TCA cycle, or converted to lactate in the cytosol. The pyruvate dehydrogenase complex, which converts pyruvate to acetyl-CoA in the mitochondria, is responsible for regulating this key junction in pyruvate fate. An important regulator of PDH activity is pyruvate dehydrogenase kinase. PDHK reduces the activity of PDH via inhibitory phosphorylation, resulting in decreased flux of pyruvate into the mitochondria, and increased production of lactate. Several isoforms of PDHK have been shown to be overexpressed in PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19847069 various cancers, and play an important role in maintaining aerobic glycolysis in tumors. Numerous studies have shown that the inhibition of PDHK through RNAi or a small molecule inhibitor, dichloroacetate, caused cancer cell death in vitro and improved outcome in in vivo models of disease. DCA was shown to alter the energetic balance of cancer cells, promoting the oxidation of glucose and consequent production of ROS. DCA has been utilized clinically for the treatment of lactic acidosis, and several clinical trials have explored DCA as an anti-cancer treatment. In a small clinical trial, DCA treatment was associated with radiological DMXB-A web regression of glioblastoma multiforme in some patients, along with reduced proliferation and increased apoptosis of cancer cells. Targeting PDHK with DCA or other novel small molecule inhibitors may be an effective strategy for the inhibition of aerobic glycolysis. The lactate dehydrogenase complex also plays a key role to regulate the fate of pyruvate in cancer. LDH is responsible for the conversion of pyruvate to lactate in the cytosol of the cell, and has increased expression and activity in a variety of cancer types. There are two isoforms of LDH that form tetramers of mixed composition and increased presence of the LDHa isoform is often implicated in Luteolin 7-glucoside web contributing to aerobic Author Manuscript Author Manuscript Author Manuscript Author Manuscript Cancer J. Author manuscript; available in PMC 2016 March 01. Kishton and Rathmell Page 5 glycolysis in cancer cells. Of the isoforms of LDH, LDHa has the highest affinity for pyruvate, along with the highest Vmax for enzymatic activity. Thus, LDHa is able to rapidly convert pyruvate into lactate, completing aerobic glycolysis. There are several hypothesized reasons for cancer cells to overexpress LDHa and to convert pyruvate to lactate. The reaction catalyzed by LDHa results in the production of NAD+, which is critical for maintaining the activity of other proteins in the glycolytic pathway such as GAPDH. Also, studies have shown that LDHa activity is critical for keeping a favorable redox environment in cancer cells. Several research groups have shown that the inhibition of LDHa by small molecule inhibitors or genetic approaches results in slowed cancer cell growth and increased cell death in a variety of types of cancer settings, including hepatocellular carcinoma and breast cancer. There have b.S known as PFKFB3. Increased PFKFB3 expression results in the production of fructose-2,6,-bisphosphate, a potent allosteric activator of PFK1. Studies suggest that inhibition of PFKFB3 using genetic approaches and small molecule inhibition results in dramatically reduced glycolytic flux and slowed cancer cell growth. Early phase clinical trials are currently underway with small molecule PFKFB3 inhibitors. Another key step in glucose metabolism is the branch point at which glycolysis-derived pyruvate can either be imported into the mitochondria to be oxidized in the TCA cycle, or converted to lactate in the cytosol. The pyruvate dehydrogenase complex, which converts pyruvate to acetyl-CoA in the mitochondria, is responsible for regulating this key junction in pyruvate fate. An important regulator of PDH activity is pyruvate dehydrogenase kinase. PDHK reduces the activity of PDH via inhibitory phosphorylation, resulting in decreased flux of pyruvate into the mitochondria, and increased production of lactate. Several isoforms of PDHK have been shown to be overexpressed in PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19847069 various cancers, and play an important role in maintaining aerobic glycolysis in tumors. Numerous studies have shown that the inhibition of PDHK through RNAi or a small molecule inhibitor, dichloroacetate, caused cancer cell death in vitro and improved outcome in in vivo models of disease. DCA was shown to alter the energetic balance of cancer cells, promoting the oxidation of glucose and consequent production of ROS. DCA has been utilized clinically for the treatment of lactic acidosis, and several clinical trials have explored DCA as an anti-cancer treatment. In a small clinical trial, DCA treatment was associated with radiological regression of glioblastoma multiforme in some patients, along with reduced proliferation and increased apoptosis of cancer cells. Targeting PDHK with DCA or other novel small molecule inhibitors may be an effective strategy for the inhibition of aerobic glycolysis. The lactate dehydrogenase complex also plays a key role to regulate the fate of pyruvate in cancer. LDH is responsible for the conversion of pyruvate to lactate in the cytosol of the cell, and has increased expression and activity in a variety of cancer types. There are two isoforms of LDH that form tetramers of mixed composition and increased presence of the LDHa isoform is often implicated in contributing to aerobic Author Manuscript Author Manuscript Author Manuscript Author Manuscript Cancer J. Author manuscript; available in PMC 2016 March 01. Kishton and Rathmell Page 5 glycolysis in cancer cells. Of the isoforms of LDH, LDHa has the highest affinity for pyruvate, along with the highest Vmax for enzymatic activity. Thus, LDHa is able to rapidly convert pyruvate into lactate, completing aerobic glycolysis. There are several hypothesized reasons for cancer cells to overexpress LDHa and to convert pyruvate to lactate. The reaction catalyzed by LDHa results in the production of NAD+, which is critical for maintaining the activity of other proteins in the glycolytic pathway such as GAPDH. Also, studies have shown that LDHa activity is critical for keeping a favorable redox environment in cancer cells. Several research groups have shown that the inhibition of LDHa by small molecule inhibitors or genetic approaches results in slowed cancer cell growth and increased cell death in a variety of types of cancer settings, including hepatocellular carcinoma and breast cancer. There have b.