Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis

Sayed, Salah Mohamed El; Baghdadi, Hussam; Ahmed, Nagwa S.; Almaramhy, Hamdi H.; Mahmoud, Ahmed A.; El-Sawy, Samer A.; Ayat, Mongi; Elshazley, Momen; Abdel-Aziz, Wafaa; Abdel-Latif, Haitham Mahmoud; Ibrahim, Walaa; Aboonq, Moutasem Salih

doi:10.1016/j.mehy.2018.11.012

Cited by 8 publications

(8 citation statements)

References 21 publications

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“…It must be taken into account that DCA can target other cellular pathways in addition to PDK. Indeed, it has been reported that DCA affects the CoA biosynthetic pathway [42], activates the AMPK signaling pathway [43], antagonizes with acetate [44], and disturbs the tyrosine catabolism [45]. Moreover, comparison of the metabolite profiles in cells treated with DCA or more selective novel inhibitors of PDK resulted in different outcomes [46].…”

Section: Discussionmentioning

confidence: 99%

Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines

Tataranni

Agriesti

Pacelli

et al. 2019

Cells

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Targeting metabolism represents a possible successful approach to treat cancer. Dichloroacetate (DCA) is a drug known to divert metabolism from anaerobic glycolysis to mitochondrial oxidative phosphorylation by stimulation of PDH. In this study, we investigated the response of two pancreatic cancer cell lines to DCA, in two-dimensional and three-dimension cell cultures, as well as in a mouse model. PANC-1 and BXPC-3 treated with DCA showed a marked decrease in cell proliferation and migration which did not correlate with enhanced apoptosis indicating a cytostatic rather than a cytotoxic effect. Despite PDH activation, DCA treatment resulted in reduced mitochondrial oxygen consumption without affecting glycolysis. Moreover, DCA caused enhancement of ROS production, mtDNA, and of the mitophagy-marker LC3B-II in both cell lines but reduced mitochondrial fusion markers only in BXPC-3. Notably, DCA downregulated the expression of the cancer stem cells markers CD24/CD44/EPCAM only in PANC-1 but inhibited spheroid formation/viability in both cell lines. In a xenograft pancreatic cancer mouse-model DCA treatment resulted in retarding cancer progression. Collectively, our results clearly indicate that the efficacy of DCA in inhibiting cancer growth mechanistically depends on the cell phenotype and on multiple off-target pathways. In this context, the novelty that DCA might affect the cancer stem cell compartment is therapeutically relevant.

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Section: Discussionmentioning

confidence: 99%

Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines

Tataranni

Agriesti

Pacelli

et al. 2019

Cells

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“…Hence, due to the metabolic adaptability of CSCs, targeting a single metabolic pathway is likely insufficient for tumor eradication. For example, glycolytic inhibitors such as dichloroacetate and phloretin are proposed novel anti-cancer drugs that rely upon the metabolic reprogramming of cancer cells (73)(74)(75). However, the results of a recent phase I/II clinical trial reported modest responses when patients with tumors with altered metabolic activity were treated with targeted pentose phosphate pathway, glycolysis, and amino acid depleting inhibitors (76).…”

Section: Discussionmentioning

confidence: 99%

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

et al. 2019

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Within heterogeneous tumors, cancer stem cell (CSC) populations exhibit the greatest tumor initiation potential, promote metastasis, and contribute to therapy resistance. For breast cancer specifically, CSCs are identified by CD44 high CD24 low cell surface marker expression and increased aldehyde dehydrogenase activity. In general, bulk breast tumor cells possess altered energetics characterized by aerobic glycolysis. In contrast, breast CSCs appear to have adaptive metabolic plasticity that allows these tumor-initiating cells to switch between glycolysis and oxidative phosphorylation, depending on factors present in the tumor microenvironment (e.g., hypoxia, reactive oxygen species, availability of glucose). In this article, we review the regulatory molecules that may facilitate the metabolic plasticity of breast CSCs. These regulatory factors include epigenetic chromatin modifiers, non-coding RNAs, transcriptional repressors, transcription factors, energy and stress sensors, and metabolic enzymes. Furthermore, breast cancer cells acquire CSC-like characteristics and altered energetics by undergoing epithelial-mesenchymal transition (EMT). This energy costly process is paired with reprogrammed glucose metabolism by epigenetic modifiers that regulate expression of both EMT and other metabolism-regulating genes. The survival advantage imparted to breast CSCs by metabolic plasticity suggests that targeting the factors that mediate the energetic switch should hinder tumorigenesis and lead to improved patient outcomes.

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“…Since high concentrations of CoA resulted to be toxic for cells, this metabolic effect could be responsible of cancer cell toxicity mediated by DCA [88]. A very recent work by El Sayed et al introduced a novel evidence-based hypothesis, suggesting that DCA efficiency against cancer may derive from its ability to antagonize acetate [89], known to be an energetic substrate for glioblastoma and brain metastases, able to enhance DNA, RNA, and protein synthesis and posttranslational modifications, thus favouring cell proliferation and cancer progression. Moreover, high acetate levels are associated to anticancer drug resistance [90].…”

Section: Other Proposed Mechanisms Of Action Of Dcamentioning

confidence: 99%

“…It has been shown that DCA is able to revert metabolic alterations induced by acetate by restoring physiological serum levels of lactate and free fatty acid and potassium and phosphorus concentration. According to the authors, thanks to a structural similarity to acetate, DCA could inhibit metabolic effects driven by acetate, responsible for cancer cell growth and chemoresistance [89]. Another possible additional effect of DCA could be pH modulation.…”

Section: Other Proposed Mechanisms Of Action Of Dcamentioning

confidence: 99%

Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

Tataranni

Piccoli

2019

Oxidative Medicine and Cellular Longevity

163

137

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An extensive body of literature describes anticancer property of dichloroacetate (DCA), but its effective clinical administration in cancer therapy is still limited to clinical trials. The occurrence of side effects such as neurotoxicity as well as the suspicion of DCA carcinogenicity still restricts the clinical use of DCA. However, in the last years, the number of reports supporting DCA employment against cancer increased also because of the great interest in targeting metabolism of tumour cells. Dissecting DCA mechanism of action helped to understand the bases of its selective efficacy against cancer cells. A successful coadministration of DCA with conventional chemotherapy, radiotherapy, other drugs, or natural compounds has been tested in several cancer models. New drug delivery systems and multiaction compounds containing DCA and other drugs seem to ameliorate bioavailability and appear more efficient thanks to a synergistic action of multiple agents. The spread of reports supporting the efficiency of DCA in cancer therapy has prompted additional studies that let to find other potential molecular targets of DCA. Interestingly, DCA could significantly affect cancer stem cell fraction and contribute to cancer eradication. Collectively, these findings provide a strong rationale towards novel clinical translational studies of DCA in cancer therapy.

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Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis

Cited by 8 publications

References 21 publications

Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines

Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

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