Article

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

BMC Cancer (Impact Factor: 3.32). 01/2013; 13(1). DOI: 10.1186/1471-2407-13-285

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.

0 Bookmarks
 · 
173 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria produce reactive oxygen species (mROS) as a natural by-product of electron transport chain activity. While initial studies focused on the damaging effects of reactive oxygen species, a recent paradigm shift has shown that mROS can act as signaling molecules to activate pro-growth responses. Cancer cells have long been observed to have increased production of ROS relative to normal cells, although the implications of this increase were not always clear. This is especially interesting considering cancer cells often also induce expression of antioxidant proteins. Here, we discuss how cancer-associated mutations and microenvironments can increase production of mROS, which can lead to activation of tumorigenic signaling and metabolic reprogramming. This tumorigenic signaling also increases expression of antioxidant proteins to balance the high production of ROS to maintain redox homeostasis. We also discuss how cancer-specific modifications to ROS and antioxidants may be targeted for therapy.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolism is an important differentiating feature of cancer cells. Lactate dehydrogenases (LDH) A/B are metabolically important proteins and are involved in the critical step of inter-conversion of lactate to pyruvate. Panepoxydone (PP), a natural NF-kB inhibitor, significantly reduces the oxygen consumption and lactate production of MCF-7 and triple negative (MDA-MB-231, MDA-MB-468 and MDA-MB-453) breast cancer cells. We further observed that PP inhibited mitochondrial membrane potential and the ATP synthesis using flow cytometry. PP also up-regulated LDH-B and down-regulated LDH-A expression levels in all breast cancer cells to similar levels observed in HMEC cells. Over-expression of LDH-B in cancer cell lines leads to enhanced apoptosis, mitochondrial damage, and reduced cell migration. Analyzing the patient data set GDS4069 available on the GEO website, we observed 100% of non TNBC and 60% of TNBC patients had less LDH-B expression than LDH-A expression levels. Herein we report a new term called Glycolytic index, a novel method to calculate utilization of oxidative phosphorylation in breast cancer cells through measuring the ratio of the LDH-B to LDH-A. Furthermore, inhibitors of NF-kB could serve as a therapeutic agent for targeting metabolism and for the treatment of triple negative breast cancer.
    Oncotarget 01/2015; · 6.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural small molecule surfactants (lecithin and quillaja saponin) were used to fabricate nanoemulsionbased delivery systems from vitamin E acetate using high pressure homogenization. The effect of oil composition (0–100% vitamin E acetate), surfactant type, and surfactant concentration (0.0005–5%) on the mean particle diameter (d32) and vitamin loading capacity was examined. The mean particle diameter had a minimum value at an intermediate vitamin E-to-orange oil ratio in the oil phase: d32 = 0.13 lm for lecithin and 0.12 lm for quillaja saponin at 50% vitamin E. The mean particle diameter decreased with increasing surfactant concentration for both surfactants, with lower levels of quillaja saponin being required to form small droplets. The effect of pH, ionic strength, and temperature on the physical stability of the nanoemulsions was also investigated. Both surfactants formed unstable nanoemulsions at pH 2, which was attributed to loss of electrostatic repulsion due to a reduction in droplet charge. Emulsion instability was also observed at >100 mM NaCl for lecithin and P400 mM NaCl for quillaja saponin, which was attributed to electrostatic screening. Both systems were stable at temperatures from 30 to 90 �C (pH 7), i.e., no particle growth or creaming was observed. These results provide useful information about the emulsifying and stabilizing capacities of natural surfactants intended for use in the food and other industries.
    Journal of Food Engineering 12/2014; 142:57-63. DOI:10.1016/j.jfoodeng.2014.06.015 · 2.58 Impact Factor

Full-text (3 Sources)

Download
19 Downloads
Available from
May 20, 2014