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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Print ISSN: 2073-4409 (Print) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Apoptosis/*drug effects ; Carcinoma, Pancreatic Ductal/*metabolism ; Cell Movement/*drug effects ; Cell Proliferation/*drug effects ; Dichloroacetic Acid/*pharmacology ; Mitochondria/*drug effects ; Pancreatic Neoplasms/*metabolism; Animals ; Carcinoma, Pancreatic Ductal/drug therapy ; Cell Line, Tumor ; DNA, Mitochondrial/metabolism ; Dichloroacetic Acid/therapeutic use ; Glycolysis/drug effects ; Humans ; Mice ; Mice, Nude ; Microtubule-Associated Proteins/metabolism ; Mitophagy/drug effects ; Oxidative Phosphorylation/drug effects ; Pancreatic Neoplasms/drug therapy ; Pyruvate Dehydrogenase (Lipoamide)/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays

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.
Competing Interests: The authors declare no conflict of interest.

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Keywords: cancer stem cells; metabolism; mitochondria

0 (DNA, Mitochondrial)
0 (Map1lc3b protein, mouse)
0 (Microtubule-Associated Proteins)
0 (Reactive Oxygen Species)
9LSH52S3LQ (Dichloroacetic Acid)
EC 1.2.4.1 (Pyruvate Dehydrogenase (Lipoamide))
EC 1.2.4.1 (pyruvate dehydrogenase E1alpha subunit)

Date Created: 20190522 Date Completed: 20200106 Latest Revision: 20201230

20221213

PMC6562462

10.3390/cells8050478

31109089