International Journal of Molecular Sciences

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Dear Colleagues,

The recognition of altered metabolism as a hallmark of cancer has led to much interest in the potential of targeting the metabolic phenotype of cancer cells as a therapeutic approach. An important component of the phenotype is the glycolytic phenotype, or Warburg effect, which can contribute to many other phenotypes of cancer, such as drug resistance and stemness. At this stage, however, agents specifically targeting the glycolytic phenotype are still limited to clinical trials.

Dichloroacetate, which is an inhibitor of pyruvate dehydrogenase kinases, is a good candidate for cancer therapy. With decades of clinical use in congenital lactic acidosis, its use in a small number of early phase clinical trials for cancer therapy has been published. The next steps for clinical trials involve identifying those cancer types most appropriate for DCA treatment, deciding which combination therapies to test, and developing a better understanding of the effects of altering metabolism on cancer cell phenotypes, such as metastatic behavior and drug resistance. This requires a deeper molecular understanding of the actions of DCA, and identification of biomarkers that may predict which cancers will respond.

In this Special Issue of IJMS, we are seeking papers (original, reviews, communications, and new concepts) that can contribute to the molecular and pre-clinical knowledge base around the actions of DCA on cancer cells and cancer microenvironments, to inform the future clinical trials of DCA. Topics of interest include, but are not limited to the following:

Metabolic and gene expression signatures and readouts of anti-cancer activities of DCA
Additional mechanisms and pathways of action of DCA with implications for cancer therapy
Investigations in pre-clinical models of cancer
Activity and molecular mechanisms of DCA in combination with other therapies
Novel formulations of DCA
Investigations of the role and regulation of pyruvate and lactate metabolism in cancer
Investigations of other pyruvate dehydrogenase kinase inhibitors

Dr. Anneke Blackburn
Guest Editor

Manuscript Submission Information

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Keywords

Pyruvate dehydrogenase
Pyruvate dehydrogenase kinase inhibitor
PDK2
Dichloroacetate
Cancer glycolytic phenotype
Warburg effect
Mitochondrial activation
Biomarker

Published Papers (2 papers)

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Research

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17 pages, 3616 KiB

Open AccessArticle

Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities

by Jiske F. Tiersma, Bernard Evers, Barbara M. Bakker, Mathilde Jalving and Steven de Jong

Int. J. Mol. Sci. 2022, 23(7), 3745; https://doi.org/10.3390/ijms23073745 - 29 Mar 2022

Cited by 6 | Viewed by 2973

Abstract

Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC₅₀ values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2- to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3- to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs. Full article

(This article belongs to the Special Issue Dichloroacetate (DCA) and Cancer: Advancing DCA to a Cancer Therapeutic)

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Review

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15 pages, 1273 KiB

Open AccessReview

Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas

by Kristina M. Cook, Han Shen, Kelly J. McKelvey, Harriet E. Gee and Eric Hau

Int. J. Mol. Sci. 2021, 22(14), 7265; https://doi.org/10.3390/ijms22147265 - 6 Jul 2021

Cited by 26 | Viewed by 4747

Abstract

As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA’s pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients. Full article

(This article belongs to the Special Issue Dichloroacetate (DCA) and Cancer: Advancing DCA to a Cancer Therapeutic)

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