Development of mitochondria-targeted derivatives of resveratrol

Biasutto, Lucia; Mattarei, Andrea; Marotta, Ester; Bradaschia, Alice; Sassi, Nicola; Garbisa, Spiridione; Zoratti, Mario; Paradisi, Cristina

doi:10.1016/j.bmcl.2008.08.100

Cited by 98 publications

(75 citation statements)

References 25 publications

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“…Conjugation with lipophilic cations, such as triphenylphosphonium (TPP), causes accumulation of the resulting polyphenol derivatives in mitochondria [11,12,58,[63][64][65]. The TPP cation was demonstrated to direct a wide variety of antioxidants, probes, and bioactive molecules to mitochondria in cells, animal models, and patients after intravenous, oral, or intraperitoneal administration [66].…”

Section: Class VI Mitocans: Lipophilic Cations Targeting the Mitochonmentioning

confidence: 99%

Polyphenols as mitochondria-targeted anticancer drugs

2015

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Section: Class VI Mitocans: Lipophilic Cations Targeting the Mitochonmentioning

confidence: 99%

Polyphenols as mitochondria-targeted anticancer drugs

2015

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“…Resveratrol also inhibits the action of many antiapoptotic proteins in vitro, including Bcl-x L (109), and has anti-tumor and chemo-preventative actions in skin and neuroblastoma cancer models (106,110). Derivatives of resveratrol bound to the membrane-permeable lipophilic triphenylphosphonium cation were developed and found to enhance resveratrol accumulation in mitochondria and improve selectivity for C-26 mouse colon cancer cells (111). Resveratrol has been studied in both healthy volunteers and colorectal cancer patients to determine suitable dosing levels for its chemo-preventative action (112,113) (Table I).…”

Section: Oxidative Phosphorylation 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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“…[4] To curb oxidative stress, vitamin E, ubiquinol, lipoic acid (LipAc) and polyphenols, as well as mimetics of A C H T U N G T R E N N U N G superoxide dismutase and glutathione peroxidase, have been conjugated to TPP and successfully targeted towards mitochondria. [5][6][7][8][9][10] In each of these compounds, the antioxidant is firmly bound to the TPP tag and exhibits properties-including antioxidant activity, intra-mitochondrial distribution and metabolism-that are different from those of the original, naturally occurring molecule. As one example, a covalently bound TPP-conjugated a-lipoyl derivative has been successfully introduced into mitochondria, but failed to reduce oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Small‐Molecule Targeting of the Mitochondrial Compartment with an Endogenously Cleaved Reversible Tag

et al. 2009

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Targeted accumulation of chemically unaltered compounds within the mitochondrial compartment has not yet been achieved. Here we describe a reversible tag that is endogenously cleaved after mitochondrial accumulation has occurred. Specifically, we have reversibly tagged alpha-lipoic acid with a triphenylphosphonium moiety that is cleaved by the physiologically contained mitochondrial aldehyde dehydrogenase (ALDH-2). This reversibly tagged compound activates the lipoic acid-sensitive pyruvate dehydrogenase complex, and this results in increased glucose oxidation. We observed a reduction in ROS accumulation after preincubation with the reversibly tagged compound, whereas untagged or irreversibly tagged compounds either had no effect on ROS formation or rather caused increased oxidative stress, respectively. Lastly, the cytotoxicity of the reversibly tagged compound is less than that of the irreversibly tagged compound. Overall, reversible tagging combines decreased tag-related cytotoxicity with increased bioactivity, and this potentially provides a novel concept in mitochondrial pharmacology.

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Development of mitochondria-targeted derivatives of resveratrol

Cited by 98 publications

References 25 publications

Polyphenols as mitochondria-targeted anticancer drugs

Polyphenols as mitochondria-targeted anticancer drugs

Mitochondrial Metabolism Inhibitors for Cancer Therapy

Small‐Molecule Targeting of the Mitochondrial Compartment with an Endogenously Cleaved Reversible Tag

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