Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death
BMC Cancer
Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death
Gang Cheng 0
Jacek Zielonka 0
Donna M McAllister 0
A Craig Mackinnon Jr 2
Joy Joseph 0
Michael B Dwinell 1
Balaraman Kalyanaraman 0
0 Free Radical Research Center and Department of Biophysics, Medical College of Wisconsin , Milwaukee, WI , USA
1 Department of Microbiology and Molecular Genetics, Medical College of Wisconsin , Milwaukee, WI , USA
2 Department of Pathology, Medical College of Wisconsin , Milwaukee, WI , USA
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.
Breast cancer metabolism; Mitochondria; Bioenergetics; Tocopherol; Antiglycolytics; Mitochondria-targeted drugs; Triphenylphosphonium cations
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Background
Emerging research in cancer therapy is focused on
exploiting the biochemical differences between cancer cell
and normal cell metabolism [1,2]. A major metabolic
reprogramming change that occurs in most malignant
cancer cells is the shift in energy metabolism from oxidative
phosphorylation to aerobic glycolysis (the Warburg effect)
[3]. Strategies to selectively deplete ATP levels in tumor
cells include mitochondrial targeting of lipophilic,
delocalized cationic drugs [4]. Enhanced accumulation of
cationic drugs in tumor mitochondria has been attributed
to a higher (more negative inside) mitochondrial
transmembrane potential as compared to normal cells [5].
The current chemotherapies are often associated with
significant morbidity and enhanced toxic side effects.
Many of the chemotherapeutic drugs are potently
cytotoxic to neoplastic and normal cells, although newer
targeted therapies developed against specific cancer
phenotypes may potentially increase efficacy and decrease
toxic side effects [6]. A major objective in cancer
chemotherapy is to enhance tumor cell cytotoxicity without
exerting undue cytotoxicity in normal cells. Ongoing
efforts in our and other laboratories include development
of cationic drugs containing triphenylphosphonium cation
(TPP+) moiety or TPP+ conjugated to a naturally
occurring compound (e.g., Mito-Q wherein TPP+ is conjugated
to Co-Q) that preferentially target tumor cell
mitochondria [4,7,8].
Chromanols are a family of phenolic compounds
containing a chromanol ring system and an aliphatic
sidechain. Tocopherols (T) and tocotrienols (TT), a group of
structurally related isomeric compounds (-, -, - and
-T and TT) consist of a chromanol ring and a 16-carbon
side chain. A few of these compounds (-T or Vit-E, -T
and -TT) are present in the human diet. Isomers of T
and TT exhibit cancer preventive, anti-proliferative and
pro-apoptotic antitumor activity differently in xenograft
tumor models [9-11]. The exact mechanisms by which
these agents inhibit tumorigenesis and tumor progression
remain unknown; however, various models have been
put forth, ranging from their antioxidant and
antiinflammatory effects to altered redox-signaling [12,13].
Mito-chromanol (Mito-ChM) and Mito-chromanol
acetate (Mito-ChMAc) are synthetic compounds containing a
naturally occurring chromanol ring system conjugated to
an alkyl TPP+ via a side chain carbon-carbon linker
sequence (Additional file 1: Figure S1). Mito-chromanol
(Mito-ChM) was prepared by hydrolyzing
Mitochromanol acetate (Mito-ChMAc) (Additional file 1:
Figure S1).
R (...truncated)