title: Modulation of mitochondrial functions by the indirect antioxidant sulforaphane: a seemingly contradictory dual role and an integrative hypothesis.
abstract: The chemotherapeutic isothiocyanate sulforaphane (SFN) was early linked to anticarcinogenic and antiproliferative activities. Soon after, this compound, derived from cruciferous vegetables, became an excellent and useful trial for anti-cancer research in experimental models including growth tumor, metastasis, and angiogenesis. Many subsequent reports showed modifications in mitochondrial signaling, functionality, and integrity induced by SFN. When cytoprotective effects were found in toxic and ischemic insult models, seemingly contradictory behaviors of SFN were discovered: SFN was inducing deleterious changes in cancer cell mitochondria that eventually would carry the cell to death via apoptosis and also was protecting noncancer cell mitochondria against oxidative challenge, which prevented cell death. In both cases, SFN exhibited effects on mitochondrial redox balance and phase II enzyme expression, mitochondrial membrane potential, expression of the family of B cell lymphoma 2 homologs, regulation of proapoptotic proteins released from mitochondria, activation/inactivation of caspases, mitochondrial respiratory complex activities, oxygen consumption and bioenergetics, mitochondrial permeability transition pore opening, and modulation of some kinase pathways. With the ultimate findings related to the induction of mitochondrial biogenesis by SFN, it could be considered that SFN has effects on mitochondrial dynamics that explain some divergent points. In this review, we list the reports involving effects on mitochondrial modulation by SFN in anti-cancer models as well as in cytoprotective models against oxidative damage. We also attempt to integrate the data into a mechanism explaining the various effects of SFN on mitochondrial function in only one concept, taking into account mitochondrial biogenesis and dynamics and making a comparison with the theory of reactive oxygen species threshold of cell death. Our interest is to achieve a complete view of cancer and protective therapies based on SFN that can be extended to other chemotherapeutic compounds with similar characteristics. The work needed to test this hypothesis is quite extensive.
authors.affiliation: Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510 Mexico City, DF, Mexico.
authors.forename: Mario
authors.initials: M
authors.lastname: Negrette-Guzmán
authors.affiliation: Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, Mexico City, DF, Mexico.
authors.forename: Sara
authors.initials: S
authors.lastname: Huerta-Yepez
authors.affiliation: Laboratorio de Patología Renal, Departamento de Nefrología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, DF, Mexico.
authors.forename: Edilia
authors.initials: E
authors.lastname: Tapia
authors.affiliation: Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510 Mexico City, DF, Mexico. Electronic address: pedraza@unam.mx.
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverri
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D063269:Mitochondrial Turnover / Q000187:drug effects; D009369:Neoplasms / Q000378:metabolism; D018384:Oxidative Stress; D013454:Sulfoxides
chemical_list: D000975:Antioxidants; D017879:Isothiocyanates; D013454:Sulfoxides; C016766:sulforaphane
keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 4-HNE; 4-hydroxynonenal; ARE; B cell lymphoma 2; B cell lymphoma–extra large; Bcl-2; Bcl-x(L); Cancer cells; Cul3; Cyt c; Cytoprotection; Drp1; ERK; Free radicals; GSH; GST; HIF-1; IRL; JNK; K(ATP); Keap1; Kelch-like ECH-associated protein 1; MPT; MTT; Mitochondria; Mitochondria-dependent apoptosis; Mitochondrial biogenesis; Mitochondrial dynamics; Mn-SOD; Mn-dependent superoxide dismutase (mitochondrial SOD); NAD(P)H:quinone oxidoreductase; NF-κB; NQO-1; NRF-1; Nrf2; OMM; PGC-1; PI3K; PKC; RC; RL; ROS; ROS level; Reactive oxygen species; SFN; Sulforaphane; antioxidant-response element; c-Jun NH(2)-terminal kinase; cullin 3; cytochrome c; dynamin-related protein 1; extracellular signal-regulated kinase; glutathione; glutathione S-transferase; hypoxia-inducible factor-1; inherent ROS level; mitochondrial ATP-sensitive potassium channel; mitochondrial membrane potential; mitochondrial permeability transition; nuclear factor E2-related factor 2; nuclear factor κB; nuclear respiratory factor-1; outer mitochondrial membrane; peroxisome proliferator-activated receptor γ coactivator-1; phosphoinositide 3-kinase; protein kinase C; reactive oxygen species; respiratory control; sulforaphane; Δψ(m)