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Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death.

Cheng G, Zielonka J, McAllister DM, Mackinnon AC, Joseph J, Dwinell MB, Kalyanaraman B - BMC Cancer (2013)

Bottom Line: Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy.Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed.These effects were significantly augmented by inhibition of glycolysis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Free Radical Research Center and Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.

ABSTRACT

Background: Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells.

Methods: In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed.

Results: Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer.

Conclusions: We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect.

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Effects of Mito-ChM on colony formation in MCF-7, MDA-MB-231 and MCF-10A cells. (A) MCF-7, MDA-MB-231 and MCF-10A cells were treated with Mito-ChM (1–10 μM) for 4 h and the colonies formed were counted. (B) The survival fraction was calculated under the same conditions as in (A). Data shown represent the mean ± SEM. *, P < 0.05, **, P < 0.01 (n = 6) comparing MCF-7 and MDA-MB-231 with MCF-10A under the same treatment conditions.
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Figure 2: Effects of Mito-ChM on colony formation in MCF-7, MDA-MB-231 and MCF-10A cells. (A) MCF-7, MDA-MB-231 and MCF-10A cells were treated with Mito-ChM (1–10 μM) for 4 h and the colonies formed were counted. (B) The survival fraction was calculated under the same conditions as in (A). Data shown represent the mean ± SEM. *, P < 0.05, **, P < 0.01 (n = 6) comparing MCF-7 and MDA-MB-231 with MCF-10A under the same treatment conditions.

Mentions: We used a clonogenic assay to monitor the anti-proliferative effects of Mito-ChM. As shown in Figure 2A, there was a dramatic decrease in colony formation in MCF-7 and MDA-MB-231 cells, as compared to MCF-10A cells, when treated with Mito-ChM (1–10 μM) for 4 h. Figure 2B shows the calculated survival fractions of MCF-7, MDA-MB-231 and MCF-10A cells. Mito-ChM significantly decreased the survival fraction in MCF-7 and MDA-MB-231 cells as compared to MCF-10A cells. Notably, the colony formation data indicate that a 4 h treatment with 3 μM Mito-ChM was sufficient to induce significant anti-proliferative effects in both MCF-7 and MDA-MB-231 cells without noticeable cell death under those conditions (Figure 1A). Taken together, we conclude that a 4 h treatment with 3 μM Mito-ChM was sufficient to inhibit cancer cell growth, without directly causing cell death at this time point.


Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death.

Cheng G, Zielonka J, McAllister DM, Mackinnon AC, Joseph J, Dwinell MB, Kalyanaraman B - BMC Cancer (2013)

Effects of Mito-ChM on colony formation in MCF-7, MDA-MB-231 and MCF-10A cells. (A) MCF-7, MDA-MB-231 and MCF-10A cells were treated with Mito-ChM (1–10 μM) for 4 h and the colonies formed were counted. (B) The survival fraction was calculated under the same conditions as in (A). Data shown represent the mean ± SEM. *, P < 0.05, **, P < 0.01 (n = 6) comparing MCF-7 and MDA-MB-231 with MCF-10A under the same treatment conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3686663&req=5

Figure 2: Effects of Mito-ChM on colony formation in MCF-7, MDA-MB-231 and MCF-10A cells. (A) MCF-7, MDA-MB-231 and MCF-10A cells were treated with Mito-ChM (1–10 μM) for 4 h and the colonies formed were counted. (B) The survival fraction was calculated under the same conditions as in (A). Data shown represent the mean ± SEM. *, P < 0.05, **, P < 0.01 (n = 6) comparing MCF-7 and MDA-MB-231 with MCF-10A under the same treatment conditions.
Mentions: We used a clonogenic assay to monitor the anti-proliferative effects of Mito-ChM. As shown in Figure 2A, there was a dramatic decrease in colony formation in MCF-7 and MDA-MB-231 cells, as compared to MCF-10A cells, when treated with Mito-ChM (1–10 μM) for 4 h. Figure 2B shows the calculated survival fractions of MCF-7, MDA-MB-231 and MCF-10A cells. Mito-ChM significantly decreased the survival fraction in MCF-7 and MDA-MB-231 cells as compared to MCF-10A cells. Notably, the colony formation data indicate that a 4 h treatment with 3 μM Mito-ChM was sufficient to induce significant anti-proliferative effects in both MCF-7 and MDA-MB-231 cells without noticeable cell death under those conditions (Figure 1A). Taken together, we conclude that a 4 h treatment with 3 μM Mito-ChM was sufficient to inhibit cancer cell growth, without directly causing cell death at this time point.

Bottom Line: Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy.Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed.These effects were significantly augmented by inhibition of glycolysis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Free Radical Research Center and Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.

ABSTRACT

Background: Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells.

Methods: In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed.

Results: Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer.

Conclusions: We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect.

Show MeSH
Related in: MedlinePlus