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

Abstract

BackgroundRecent 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.MethodsIn 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.ResultsBoth 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.ConclusionsWe 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.

Inhibition of the Warburg effect with a natural compound reveals a novel measurement for determining the metastatic potential of breast cancers

“…Previous studies also reported decreased ATP level in the mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and mitochondrial ErBB2 over-expressing cells. Decreased ATP level in MCF-7 and MDA-MB-231 cells identified to be effective in inhibiting energy metabolism in breast cancer cells and in mice xenografts [29, 30]. Thus, PP induces nonproductive mitochondrial respiration, as reported previously for cells with knockout LDH-A and for cells treated with FX-11 (LDH-A inhibitor) [14, 27].…”

Reversal of doxorubicin resistance in breast cancer by mitochondria-targeted pH-responsive micelles

“…The evidence accumulated to date indicates that mitochondria-associated apoptosis and energy metabolism could play important roles in cancer chemotherapy since the mitochondrion is also a crucial regulator of cell death [14][15][16][17]. Furthermore, recent studies conducted by several groups, including ours, have demonstrated that the mitochondria could be an alternative target to surmount multidrug resistance by suppressing the mitochondria's function of producing ATP and subsequently inhibiting the drug efflux function of P-gp protein [18,19].…”

Targeting Warburg Effect in Cancers with PEGylated Glucose

“…[20][21][22][23] In particular, recent studies that target the glucose transporters have yielded a promising approach. Several analogs of glucose have been used in an attempt to reduce the glucose metabolism in cancer cells.…”