Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells.

High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase alpha (PDHalpha) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDHalpha phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1alpha expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.

Increased lactate levels and reduced pH in postmortem brains of schizophrenics: medication confounds.

A number of postmortem studies have found decreased pH in brains of patients with schizophrenia. Insofar as lower pH has been associated with decreased mRNA expression in postmortem human brain, decreased pH in schizophrenia may represent an important potential confound in comparisons between patients and controls. We hypothesized that decreased pH may be related to increased concentration of lactic acid. However, in contrast to the previous notion that an increase in lactic acid represents evidence for primary metabolic abnormalities in schizophrenia, we hypothesized that this increase is secondary to prior antipsychotic treatment. We have tested this by first demonstrating that lactate levels in the cerebellum of patients with schizophrenia (n=35) are increased relative to control subjects (n=42) by 28%, p=0.001. Second, we have shown that there is an excellent correlation between lactate levels in the cerebellum and pH, and that this correlation is particularly strong in patients (r=-0.78, p=3E-6). Third, we have shown in rats that chronic haloperidol (0.8mg/kg/day) and clozapine (5mg/kg/day) increase lactic acid concentration in the frontal cortex relative to vehicle (by 31% and 22% respectively, p<0.01). These data suggest that lactate increases in postmortem human brain of patients with schizophrenia are associated with decreased pH and that these changes are possibly related to antipsychotic treatment rather than a primary metabolic abnormality in the prefrontal cortex of patients with schizophrenia.

Comparison of clarithromycin and ciprofloxacin therapy for Bacillus anthracis Sterne infection in mice with or without (60)Co gamma-photon irradiation.

Biological agents and ionizing radiation lead to more severe clinical outcomes than either insult alone. This study investigated the survival of non-irradiated and (60)Co-gamma-irradiated mice given therapy for inhalation anthrax with ciprofloxacin (CIP) or a clinically relevant mixture of clarithromycin (CLR) and its major human microbiologically important metabolite 14-hydroxy clarithromycin (14-OH CLR). All B6D2F1/J 10-week-old female mice were inoculated intratracheally with 3 x 10(8) c.f.u. of Bacillus anthracis Sterne spores 4 days after the non-lethal 7 Gy dose of (60)Co gamma radiation. Twenty-one days of treatment with CLR/14-OH CLR, 150 mg kg(-1) twice daily, or CIP, 16.5 mg kg(-1) twice daily, began 24 h after inoculation. Pharmacokinetics indicate that the area under the curve (AUC) for 14-OH CLR on the concentration-versus-time graph was slightly higher in gamma-irradiated than non-irradiated animals. Neither drug was able to increase survival in gamma-irradiated animals. CIP and CLR/14-OH CLR therapies in non-irradiated animals increased survival from 49 % (17/35 mice) in buffer-treated animals to 94 % (33/35) and 100 %, respectively (P < 0.001). B. anthracis Sterne only was isolated from 25-50 % of treated mice with or without irradiation. Mixed infections with B. anthracis Sterne were present in 50-71 % of gamma-irradiated mice but only in 5-10 % of mice without irradiation.