Pyruvate Treatment Restores the Effectiveness of Chemotherapeutic Agents in Human Colon Adenocarcinoma and Pleural Mesothelioma Cells

Int J Mol Sci. 2018 Nov 10;19(11):3550. doi: 10.3390/ijms19113550.

Abstract

Emerging evidence supports the idea that a dysfunction in cell metabolism could sustain a resistant phenotype in cancer cells. As the success of chemotherapeutic agents is often questioned by the occurrence of multidrug resistance (MDR), a multiple cross-resistance towards different anti-cancer drugs represent a major obstacle to cancer treatment. The present study has clarified the involvement of the carbon metabolites in a more aggressive tumor colon adenocarcinoma phenotype and in a chemoresistant mesothelioma, and the role of pyruvate treatment in the reversion of the potentially related resistance. For the first time, we have shown that human colon adenocarcinoma cells (HT29) and its chemoresistant counterpart (HT29-dx) displayed different carbon metabolism: HT29-dx cells had a higher glucose consumption compared to HT29 cells, whereas human malignant mesothelioma (HMM) cells showed a lower glucose consumption compared to HT29 cells, accompanied by a lower pyruvate production and, consequently, a higher production of lactate. When treated with pyruvate, both HT29-dx and HMM cells exhibited a re-established accumulation of doxorubicin and a lower survival ability, a decreased activity of multidrug resistance protein 1 (MRP1) and a restored mitochondrial respiratory chain function, improving the effectiveness of the chemotherapeutic agents in these resistant cancer cells.

Keywords: carbon metabolism; chemoresistance; human colon adenocarcinoma cells; human pleural mesothelioma cells; mitochondria respiratory chain; pyruvate.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Acrylates / pharmacology
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology
  • Adenosine Triphosphate / biosynthesis
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carbon Isotopes / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Respiration / drug effects
  • Cell Survival / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology
  • Doxorubicin / pharmacology
  • Electron Transport / drug effects
  • Gluconeogenesis
  • Glycolysis
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • Mesothelioma / drug therapy*
  • Mesothelioma / pathology
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Phenotype
  • Phosphoenolpyruvate Carboxykinase (ATP) / genetics
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Pleural Neoplasms / drug therapy*
  • Pleural Neoplasms / pathology
  • Pyruvic Acid / pharmacology
  • Pyruvic Acid / therapeutic use*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Treatment Outcome

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Acrylates
  • Antineoplastic Agents
  • Carbon Isotopes
  • Isoenzymes
  • RNA, Messenger
  • Reactive Oxygen Species
  • 2-cyano-3-(1-phenylindol-3-yl)acrylate
  • Doxorubicin
  • Pyruvic Acid
  • Adenosine Triphosphate
  • L-Lactate Dehydrogenase
  • PCK2 protein, human
  • Phosphoenolpyruvate Carboxykinase (ATP)