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

Eleonora Mungo,Loredana Bergandi,Iris Salaroglio,Sophie Doublier

doi:10.3390/ijms19113550

Eleonora Mungo, Loredana Bergandi + Show 2 more

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https://doi.org/10.3390/ijms19113550

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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.

Highlights

Chemotherapy, one of the most efficient therapeutic approaches to solid and hematologic cancers, has led to improved remission and survival in many malignancies
We observed that 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, even though glucose was consumed with avidity by all the cell types (Figure 1A)
The pyruvate level increased in all the cell lines during the incubation time, and we observed that the production of pyruvate was significantly lower in HT29-dx and HMM cells compared to HT29 cells (Figure 1A)

Summary

Introduction

Chemotherapy, one of the most efficient therapeutic approaches to solid and hematologic cancers, has led to improved remission and survival in many malignancies. In a significant number of patients, the tumor is not responsive to the therapeutic agents, the onset of multidrug resistance (MDR), a multiple cross-resistance towards different anticancer drugs, affects about the 40–70% of tumors at diagnosis [3,4]. One of the main mechanisms of MDR is the overexpression of the ATP-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp) and multidrug related proteins (MRPs), that extrude anticancer drugs, leading to a decrease of the accumulation of intracellular chemotherapeutics and of their cytotoxic effects [5]. Cancer cells reprogram their glucose metabolism limiting their energy metabolism largely to increased glycolysis, known as the Warburg effect, which generally facilitates metastasis and inhibits apoptosis [6,7,8,9]

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