Topic
Pyruvate dehydrogenase kinase
About: Pyruvate dehydrogenase kinase is a research topic. Over the lifetime, 4224 publications have been published within this topic receiving 161052 citations. The topic is also known as: [pyruvate dehydrogenase (lipoamide)] kinase & pyruvate dehydrogenase (lipoamide) kinase.
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TL;DR: Dichloroacetate appears to be safe to give to humans at doses that are required for pyruvate dehydrogenase inhibition, and can be added to a growing group of metabolic modulators that may prove useful in cancer therapy.
Abstract: Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.
673 citations
TL;DR: It is shown that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors and support the notion that small molecule activation ofPKM2 can interfere with anabolic metabolism.
Abstract: Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.
634 citations
TL;DR: The study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression and suggests that PKM2 dimer is an active protein kinase, while the tetramer is anactive pyruvate kinase.
609 citations
TL;DR: The generic drug dichloroacetate is an orally available small molecule that reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo.
Abstract: The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.
608 citations
TL;DR: The discovery that the activity of the multienzyme pyruvate dehydrogenase complex from beef kidney mitochondria is regulated by a phosphorylation-dephosphorylation reaction sequence is reported.
Abstract: This paper reports the discovery that the activity of the multienzyme pyruvate dehydrogenase complex from beef kidney mitochondria is regulated by a phosphorylation-dephosphorylation reaction sequence. The site of this regulation is the pyruvate dehydrogenase component of the complex. Phosphorylation and concomitant inactivation of pyruvate dehydrogenase are catalyzed by an ATP-specific kinase (i.e., a pyruvate dehydrogenase kinase), and dephosphorylation and concomitant reactivation are catalyzed by a phosphatase (i.e., a pyruvate dehydrogenase phosphatase). The kinase and the phosphatase appear to be regulatory subunits of the pyruvate dehydrogenase complex.
594 citations