title: PDK1 inhibition is a novel therapeutic target in multiple myeloma.
abstract: BACKGROUND
  Cancer cells utilise the glycolytic pathway even when adequate oxygen is present, a phenomenon known as the Warburg effect. We examined whether this system is operative in multiple myeloma (MM) cells and whether glycolysis inhibition is a potential therapeutic modality.
  
  
  METHODS
  The MM cells were purified from 59 patients using CD138-immunomagnetic beads. The expression levels of genes associated with glycolysis, c-MYC, GLUT1, LDHA, HIF1A and pyruvate dehydrogenase kinase-1 (PDK1) were determined by real-time PCR. Glucose consumption and lactate production by MM cell lines were analysed. Oxamate, an LDH inhibitor, and dichloroacetate (DCA), a PDK1 inhibitor, were employed. Inhibition of PDK1 expression was achieved using a siRNA.
  
  
  RESULTS
  High LDHA expression was found to be an indicator of poor prognosis. It was also positively correlated with the expression of PDK1, c-MYC and GLUT1. Greater glucose consumption and lactate production in MM cells was associated with higher LDHA expression. All the glycolysis inhibitors (oxamate, DCA and PDK1 siRNA) induced apoptosis in MM cells. DCA combined with bortezomib showed additive cytotoxic effects.
  
  
  CONCLUSIONS
  The present data suggest that the Warburg effect is operative in MM cells. As PDK1 is not overexpressed in normal tissues, PDK1 inhibition could serve as a novel therapeutic approach.
authors: Department of Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors: S
authors: S
authors: Fujiwara
authors: Y
authors: Y
authors: Kawano
authors: H
authors: H
authors: Yuki
authors: Y
authors: Y
authors: Okuno
authors: K
authors: K
authors: Nosaka
authors: H
authors: H
authors: Mitsuya
authors: H
authors: H
authors: Hata
mesh_terms: D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D045022:Lactate Dehydrogenases; D019344:Lactic Acid / Q000096:biosynthesis; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; C000631429:PDK1 protein, human; D011719:Pyrazines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; D019344:Lactic Acid; D000069286:Bortezomib; D003999:Dichloroacetic Acid; D045022:Lactate Dehydrogenases; C071195:D-lactate dehydrogenase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose