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

Our plain-English summary of Pyruvate Treatment Restores the Effectiveness of Chemotherapeutic Agents in Human Colon Adenocarcinoma and Pleural Mesothelioma Cells, by E. Mungo, L. Bergandi, I.C. Salaroglio, et al (International Journal of Molecular Sciences, 2018).

The study

• Authors: E. Mungo, L. Bergandi, I.C. Salaroglio, S. Doublier
• Journal: International Journal of Molecular Sciences
• Published: 2018;19(11)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study of human cancer cells grown in culture, not of patients. The authors used a colon cancer cell line (HT29), a drug-resistant version of it made in their laboratory (HT29-dx), and a malignant mesothelioma cell line (HMM) established from the pleural effusion of patients with malignant mesothelioma. Asbestos exposure was not studied. Compared with HT29, the HT29-dx and HMM cells made significantly less pyruvate and more lactate. The drug-resistant HT29-dx cells also accumulated significantly less of the cancer drug doxorubicin than HT29 cells. When 25 mM pyruvate was added, the resistant HT29-dx and HMM cells accumulated more doxorubicin. Doxorubicin, 5-fluorouracil or oxaliplatin alone had no effect on the survival of these cells, but each lowered their survival when combined with pyruvate. Pyruvate also restored mitochondrial respiratory activity and ATP production in the resistant cells. The authors concluded that pyruvate restores respiratory chain function and lowers the activity of MRP1, a drug-pumping protein, improving the drugs' effectiveness in these resistant cells. They stated that they lack a mechanistic explanation for the reduced MRP1 activity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on human cancer cell lines
• Who was studied: Three cell lines: human colon adenocarcinoma cells (HT29), a doxorubicin-resistant version made in the authors' laboratory (HT29-dx), and a human malignant mesothelioma cell line (HMM) established from the pleural effusion of patients with malignant mesothelioma, obtained from the Biologic Bank of Malignant Mesothelioma, Alessandria, Italy. The number of patients is not given.
• Exposure: Cells were treated with pyruvate (25 mM) with or without the chemotherapy drugs doxorubicin (5 µM), 5-fluorouracil (150 µM) and oxaliplatin. Inhibitors (oxamate, UK5099, mitochondrial respiration inhibitors) were also used. No asbestos fibers were tested; asbestos is mentioned only in the introduction.
• Main results:
  • Pyruvate production was significantly lower in HT29-dx and HMM cells than in HT29 cells.
  • Lactate made from the labeled glucose represented about 31.7% of consumed glucose in HT29, 35.9% in HT29-dx and 83.3% in HMM cells.
  • After 24 hours with 5 µM doxorubicin, HT29-dx cells accumulated significantly less doxorubicin than HT29 cells.
  • In HT29-dx cells, doxorubicin accumulation increased significantly from 12.5 mM pyruvate, with a clearer effect from 25 mM. Similar results were seen in HMM cells.
  • Rhodamine 123 retention, used as an index of drug-pump (Pgp plus MRP1) activity, was lower in HT29-dx and HMM cells than in HT29 cells, and higher in HT29-dx and HMM cells treated with pyruvate.
  • In HT29-dx cells, MRP1 gene expression did not change with pyruvate.
  • Doxorubicin, 5-fluorouracil and oxaliplatin alone had no effect on HT29-dx and HMM cells. With pyruvate added, each drug lowered the viability of these cells.
  • Pyruvate restored respiratory activity and ATP synthesis in HT29-dx and HMM cells to the level of HT29 cells.
  • Blocking pyruvate entry into mitochondria with 20 µM UK5099 significantly reduced the pyruvate-induced doxorubicin accumulation in HT29-dx and HMM cells.
  • In HMM cells, mitochondrial respiration inhibitors and an uncoupler did not change doxorubicin accumulation.
• The authors' conclusion: The authors concluded that pyruvate treatment restores respiratory chain function and lowers MRP1 activity, improving the effectiveness of chemotherapy drugs in these resistant cancer cells.
• Limitations the authors state:
  • The authors stated that they lack a mechanistic explanation for the reduced MRP1 activity after pyruvate treatment, since MRP1 gene and protein levels did not change.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Colon cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Adenocarcinoma, Pleural Mesothelioma, Mesothelioma, Doxorubicin.

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