Mitochondria as targets in angiogenesis inhibition

Park, Danielle; Dilda, Pierre J.

doi:10.1016/j.mam.2009.12.005

Cited by 27 publications

(21 citation statements)

References 155 publications

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“…With regard to a-TOS, we already documented that it not only eliminates cancer cells but also proliferating ECs and inhibits angiogenesis (10,33). We now show that the mitochondrial targeting of MitoVES by the TPP + group greatly enhances the effectivity of the parental, nontargeted compound and results in efficient killing of proliferating ECs already at concentrations as low as 2 lM, while discriminating between proliferating and arrested ECs.…”

Section: Discussionmentioning

confidence: 60%

“…Several agents have been reported to possess such activity, including an analog of arsenite oxide (5) and a-TOS (10), consistent with the notion that targeting mitochondria of proliferating ECs is also an efficient way to suppress angiogenesis. Moreover, these results suggest that agents such as arsenites or a-TOS will efficiently kill angiogenic ECs of tumorigenic blood vessels while being nontoxic to the arrested ECs of normal blood vessels (33).…”

Section: Innovationmentioning

confidence: 87%

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Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Rohlena

Dong

Kľučková

et al. 2011

Antioxidants & Redox Signaling

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Aims: A plausible strategy to reduce tumor progress is the inhibition of angiogenesis. Therefore, agents that efficiently suppress angiogenesis can be used for tumor suppression. We tested the antiangiogenic potential of a mitochondrially targeted analog of a-tocopheryl succinate (MitoVES), a compound with high propensity to induce apoptosis. Results: MitoVES was found to efficiently kill proliferating endothelial cells (ECs) but not contact-arrested ECs or ECs deficient in mitochondrial DNA, and suppressed angiogenesis in vitro by inducing accumulation of reactive oxygen species and induction of apoptosis in proliferating/angiogenic ECs. Resistance of arrested ECs was ascribed, at least in part, to the lower mitochondrial inner transmembrane potential compared with the proliferating ECs, thus resulting in the lower level of mitochondrial uptake of MitoVES. Shorterchain homologs of MitoVES were less efficient in angiogenesis inhibition, thus suggesting a molecular mechanism of its activity. Finally, MitoVES was found to suppress HER2-positive breast carcinomas in a transgenic mouse as well as inhibit tumor angiogenesis. The antiangiogenic efficacy of MitoVES was corroborated by its inhibitory activity on wound healing in vivo. Innovation and Conclusion: We conclude that MitoVES, a mitochondrially targeted analog of a-tocopheryl succinate, is an efficient antiangiogenic agent of potential clinical relevance, exerting considerably higher activity than its untargeted counterpart. MitoVES may be helpful against cancer but may compromise wound healing. Antioxid. Redox Signal. 15, 2923Signal. 15, -2935

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Section: Discussionmentioning

confidence: 60%

Section: Innovationmentioning

confidence: 87%

Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Rohlena

Dong

Kľučková

et al. 2011

Antioxidants & Redox Signaling

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“…GSAO (4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid) is a tripeptide trivalent arsenical (136,137). It is a pro-drug that is activated by γ-glutamyl transpeptidase at the cell surface to produce GCAO ((4-(N-(S-cysteinylglycylacetyl)amino) phenylarsonous acid)) (138).…”

Section: Mitochondrial Atp Transport Inhibitorsmentioning

confidence: 99%

Mitochondrial Metabolism Inhibitors for Cancer Therapy

2011

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Cancer cells catabolise nutrients in a different way than healthy cells. Healthy cells mainly rely on oxidative phosphorylation, while cancer cells employ aerobic glycolysis. Glucose is the main nutrient catabolised by healthy cells, while cancer cells often depend on catabolism of both glucose and glutamine. A key organelle involved in this altered metabolism is mitochondria. Mitochondria coordinate the catabolism of glucose and glutamine across the cancer cell. Targeting mitochondrial metabolism in cancer cells has potential for the treatment of this disease. Perhaps the most promising target is the hexokinase-voltage dependent anion channel-adenine nucleotide translocase complex that spans the outer- and inner-mitochondrial membranes. This complex links glycolysis, oxidative phosphorylation and mitochondrial-mediated apoptosis in cancer cells. This review discusses cancer cell mitochondrial metabolism and the small molecule inhibitors of this metabolism that are in pre-clinical or clinical development.

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“…This observation is consistent with a previous report indicating that mitochondria of endothelial cells are an important target for inhibition of angiogenesis. 26) Since modification of the A-ring, such as derivatization to APDOEGCG, did not change the mode of EGCG action, the distribution of EGCG-TG may reflect the actual EGCG localization: APDOEGCG suppressed motility and invasion of HUVECs and induced morphological changes similar to EGCG, although the concentration required was lower than that of EGCG. However, an alternative possibility that the fluorescence in mitochondria or in other cytoplasmic regions was derived from some degradation product(s) of EGCG-TG cannot be excluded at present.…”

Section: Fig 4 Morphological Changes In Huvecs By Egcg Derivativesmentioning

confidence: 99%

Anti-angiogenic Activity and Intracellular Distribution of Epigallocatechin-3-gallate Analogs

Piyaviriyakul

Shimizu

Asakawa

et al. 2011

Biological & Pharmaceutical Bulletin

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Tumor angiogenesis, a process of new blood vessel formation from pre-existing vessels, is crucial for the growth and development of tumors. It requires multiple interactions among endothelial cells, surrounding pericytes, and smooth muscle cells, extracellular matrix, and angiogenic cytokines/growth factors. [1][2][3] Since effective inhibition of tumor angiogenesis promises to provide crucial suppression of not only tumor growth but also tumor metastasis, the development of agents inhibiting angiogenic processes has become a matter of focus. (Ϫ)-Epigallocatechin-3-O-gallate (EGCG) is known as a major component of green tea extracts and to exhibit various biological activities including anti-viral, anti-microbial, and anti-oxidative ones. [4][5][6][7][8] Especially, the relationship between EGCG and anti-cancer activity is now the most notable, since cancer is the leading cause of human death in various countries. Previous studies demonstrated that EGCG suppresses tumor growth through the inhibition of tumor angiogenesis, and mechanistic studies on this anti-angiogenic effect of EGCG is now ongoing. Tang et al. demonstrated that EGCG inhibits vascular endothelial growth factor (VEGF)-induced Akt activation and VE-cadherin phosphorylation 9) ; and Rodriguez et al., that green tea catechin disrupts VEGF/VEGF receptor (VEGFR) complexes and subsequent signal transduction. 10) Also, Tachibana et al. directly identified the target molecule of EGCG as a 67-kDa laminin receptor by using surface plasmon resonance (SPR) assay, and they observed the suppression of tumor angiogenesis through the inhibition of the receptor-mediated signal transduction. 11,12) Our previous studies also demonstrated that EGCG suppresses tumor angiogenesis through the inhibition of membrane-type1 matrix metalloproteinase (MT1-MMP). 13,14) These findings indicate that EGCG, as a functional component of green tea, will become useful for cancer therapy and chemoprevention.Previous study demonstrated that 5,7-deoxyepigallocatechin gallate (DOEGCG), a synthetic EGCG derivative, possesses more potent anti-influenza infection activity than the original EGCG, suggesting that the phenolic hydroxyl groups on the A-ring in the flavan structure are not involved in the biological activity and that modification of A-ring of the EGCG structure does not abolish but rather enhances the functional ability of EGCG.15) Based on this and other structure-relationship studies, 16,17) we synthesized (Ϯ)-6-(5-aminopentyl)-5,7-deoxyepigallocatechin gallate (cis-APDOEGCG) and (Ϯ)-6-(5-aminopentyl)-5,7-deoxygallocatechin gallate (trans-APDOEGCG) as EGCG derivatives containing linkers and reactive amino groups added to the EGCG structure, as shown in Fig. 1. We compared their antiangiogenic activity with that of EGCG by examining the inhibitory effect on proliferation, migration, invasion, and tube formation by HUVECs. Then, we synthesized fluorescencelabeled EGCG by conjugating the fluorescent reagent TokyoGreen (TG) to (Ϯ)-cis-APDOEGCG (EGCG-TG) and examined the intracel...

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Mitochondria as targets in angiogenesis inhibition

Cited by 27 publications

References 155 publications

Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Mitochondrial Metabolism Inhibitors for Cancer Therapy

Anti-angiogenic Activity and Intracellular Distribution of Epigallocatechin-3-gallate Analogs

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