Mitochondria-Targeted Antioxidants

Smith, Robin A.J.; Hartley, Richard C.; Murphy, Michael P.

doi:10.1201/b12308-8

Cited by 72 publications

(86 citation statements)

References 91 publications

(143 reference statements)

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“…Recent studies of mitochondrial involvement in cancer have uncovered a plethora of differences in the structure, genome, and function of these organelles, by comparing metastatic mitochondria with those from nontransformed cells. However, there are limited therapeutic strategies selectively targeting cancer cell mitochondria (42,43).…”

Section: Discussionmentioning

confidence: 99%

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

et al. 2015

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Mitochondria are the powerhouses of cells. Mitochondrial CRaf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its Nterminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf S338 ) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK S308 ), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF C-RafÀ/À or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity.In the presence of pDAPK S308 , this drug-target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf S338 and pDAPK S308 translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK S308 to DAPK. PP2A then dissociated from the C-Raf-DAPK complex and induced profound cancer cell death. Increased pDAPK S308 modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK S308 may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation. Cancer Res; 75(17); 3568-82. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

et al. 2015

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“…Mitochondria-targeted antioxidants have also been employed in in vivo studies (Table 1). In the case of MitoQ, the role it plays in in vitro settings of mitochondrial oxidative stress has been shown to be beneficial in many conditions; moreover, its protective actions have also been observed in animal models of cardiometabolic diseases, including ischemia/reperfusion, diabetes, and sepsis, and also in patients (297). Notably, it has been demonstrated that MitoQ is uptaken rapidly from the blood into cells (246).…”

Section: Skq1 Skqr1mentioning

confidence: 99%

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

Apostolova

Víctor

2015

Antioxidants & Redox Signaling

235

147

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Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid-and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686-729.

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“…Due to their functionality and participation in these multiple roles, any mitochondrial dysfunction contributes to a series of events that generate a wide range of pathologies [13,14]. Among these mitochondrial disorders Alzheimer, ischemia-reperfusion injury, inflammation, and cancer are well known; however, chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), or Pearson syndrome are other 'rare' diseases associate to mitochondrial abnormalities that are poorly treated [13,15].…”

Section: Influence Of Triphenylphosphonium (Tpp) Cation Hydrophobizatmentioning

confidence: 99%

Influence of Triphenylphosphonium (TPP) Cation Hydrophobization with Phospholipids on Cellular Toxicity and Mitochondrial Selectivity

Villanueva¹

2015

SOJPPS

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Mitochondria-Targeted Antioxidants

Cited by 72 publications

References 91 publications

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

Influence of Triphenylphosphonium (TPP) Cation Hydrophobization with Phospholipids on Cellular Toxicity and Mitochondrial Selectivity

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