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Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment.

Ruggieri V, Agriesti F, Scrima R, Laurenzana I, Perrone D, Tataranni T, Mazzoccoli C, Lo Muzio L, Capitanio N, Piccoli C - Oncotarget (2015)

Bottom Line: In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15.DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro-apoptotic/cytostatic effect on HSC-2 and HSC-3.This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS, CROB, Rionero in Vulture, Potenza, Italy.

ABSTRACT
Reprogramming of metabolism is a well-established property of cancer cells that is receiving growing attention as potential therapeutic target. Oral squamous cell carcinomas (OSCC) are aggressive and drugs-resistant human tumours displaying wide metabolic heterogeneity depending on their malignant genotype and stage of development. Dichloroacetate (DCA) is a specific inhibitor of the PDH-regulator PDK proved to foster mitochondrial oxidation of pyruvate. In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15. Characterization of the three cell lines unveiled for HSC-2 and HSC-3 a glycolysis-reliant metabolism whereas PE15 accomplished an efficient mitochondrial oxidative phosphorylation. DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro-apoptotic/cytostatic effect on HSC-2 and HSC-3. This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species. The data here presented indicate that the therapeutic efficacy of DCA may depend on the specific metabolic profile adopted by the cancer cells with those exhibiting a deficient mitochondrial oxidative phosphorylation resulting more sensitive to the drug treatment.

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Proposed mechanism of the differential effect of DCA on OSCC-derived cell linesThe proposed model schematically illustrates how the metabolic profile can affect the cellular response to DCA and determine its cytotoxic potential on OSCC cells. HSC-2 and HSC-3 cell lines, adapted to a relatively low oxidative metabolism and high glycolysis displayed a DCA-sensitive respiratory activity. This metabolic feature may predispose cells to a major sensitivity to DCA-induced apoptosis, associated to oxidative stress and mitochondrial fragmentation. On the contrary, PE15 cell line, in which the more efficient respiratory activity resulted to be DCA-insensitive, displays an intrinsic resistance to the detrimental DCA-induced effects.
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Figure 6: Proposed mechanism of the differential effect of DCA on OSCC-derived cell linesThe proposed model schematically illustrates how the metabolic profile can affect the cellular response to DCA and determine its cytotoxic potential on OSCC cells. HSC-2 and HSC-3 cell lines, adapted to a relatively low oxidative metabolism and high glycolysis displayed a DCA-sensitive respiratory activity. This metabolic feature may predispose cells to a major sensitivity to DCA-induced apoptosis, associated to oxidative stress and mitochondrial fragmentation. On the contrary, PE15 cell line, in which the more efficient respiratory activity resulted to be DCA-insensitive, displays an intrinsic resistance to the detrimental DCA-induced effects.

Mentions: It is tempting to speculate that unlike PE15, HSC-2 and HSC-3 being adapted or programmed to a low-regimen oxidative metabolism are not suited to cope with an enhanced O2 metabolism. This might depend on subtle dysfunctions in mitochondria, which, if tolerated under conditions of low cell activity, become detrimental once the cell is forced to rely on them for the bioenergetic demand (see the schematic picture in Fig. 6).


Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment.

Ruggieri V, Agriesti F, Scrima R, Laurenzana I, Perrone D, Tataranni T, Mazzoccoli C, Lo Muzio L, Capitanio N, Piccoli C - Oncotarget (2015)

Proposed mechanism of the differential effect of DCA on OSCC-derived cell linesThe proposed model schematically illustrates how the metabolic profile can affect the cellular response to DCA and determine its cytotoxic potential on OSCC cells. HSC-2 and HSC-3 cell lines, adapted to a relatively low oxidative metabolism and high glycolysis displayed a DCA-sensitive respiratory activity. This metabolic feature may predispose cells to a major sensitivity to DCA-induced apoptosis, associated to oxidative stress and mitochondrial fragmentation. On the contrary, PE15 cell line, in which the more efficient respiratory activity resulted to be DCA-insensitive, displays an intrinsic resistance to the detrimental DCA-induced effects.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359228&req=5

Figure 6: Proposed mechanism of the differential effect of DCA on OSCC-derived cell linesThe proposed model schematically illustrates how the metabolic profile can affect the cellular response to DCA and determine its cytotoxic potential on OSCC cells. HSC-2 and HSC-3 cell lines, adapted to a relatively low oxidative metabolism and high glycolysis displayed a DCA-sensitive respiratory activity. This metabolic feature may predispose cells to a major sensitivity to DCA-induced apoptosis, associated to oxidative stress and mitochondrial fragmentation. On the contrary, PE15 cell line, in which the more efficient respiratory activity resulted to be DCA-insensitive, displays an intrinsic resistance to the detrimental DCA-induced effects.
Mentions: It is tempting to speculate that unlike PE15, HSC-2 and HSC-3 being adapted or programmed to a low-regimen oxidative metabolism are not suited to cope with an enhanced O2 metabolism. This might depend on subtle dysfunctions in mitochondria, which, if tolerated under conditions of low cell activity, become detrimental once the cell is forced to rely on them for the bioenergetic demand (see the schematic picture in Fig. 6).

Bottom Line: In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15.DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro-apoptotic/cytostatic effect on HSC-2 and HSC-3.This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS, CROB, Rionero in Vulture, Potenza, Italy.

ABSTRACT
Reprogramming of metabolism is a well-established property of cancer cells that is receiving growing attention as potential therapeutic target. Oral squamous cell carcinomas (OSCC) are aggressive and drugs-resistant human tumours displaying wide metabolic heterogeneity depending on their malignant genotype and stage of development. Dichloroacetate (DCA) is a specific inhibitor of the PDH-regulator PDK proved to foster mitochondrial oxidation of pyruvate. In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15. Characterization of the three cell lines unveiled for HSC-2 and HSC-3 a glycolysis-reliant metabolism whereas PE15 accomplished an efficient mitochondrial oxidative phosphorylation. DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro-apoptotic/cytostatic effect on HSC-2 and HSC-3. This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species. The data here presented indicate that the therapeutic efficacy of DCA may depend on the specific metabolic profile adopted by the cancer cells with those exhibiting a deficient mitochondrial oxidative phosphorylation resulting more sensitive to the drug treatment.

Show MeSH
Related in: MedlinePlus