title: Anacardic Acid, Salicylic Acid, and Oleic Acid Differentially Alter Cellular Bioenergetic Function in Breast Cancer Cells.
abstract: Anacardic acid is a dietary and medicinal phytochemical that inhibits breast cancer cell proliferation and uncouples oxidative phosphorylation (OXPHOS) in isolated rat liver mitochondria. Since mitochondrial-targeted anticancer therapy (mitocans) may be useful in breast cancer, we examined the effect of anacardic acid on cellular bioenergetics and OXPHOS pathway proteins in breast cancer cells modeling progression to endocrine-independence: MCF-7 estrogen receptor α (ERα)+ endocrine-sensitive; LCC9 and LY2 ERα+, endocrine-resistant, and MDA-MB-231 triple negative breast cancer (TNBC) cells. At concentrations similar to cell proliferation IC50 s, anacardic acid reduced ATP-linked oxygen consumption rate (OCR), mitochondrial reserve capacity, and coupling efficiency while increasing proton leak, reflecting mitochondrial toxicity which was greater in MCF-7 compared to endocrine-resistant and TNBC cells. These results suggest tolerance in endocrine-resistant and TNBC cells to mitochondrial stress induced by anacardic acid. Since anacardic acid is an alkylated 2-hydroxybenzoic acid, the effects of salicylic acid (SA, 2-hydroxybenzoic acid moiety) and oleic acid (OA, monounsaturated alkyl moiety) were tested. SA inhibited whereas OA stimulated cell viability. In contrast to stimulation of basal OCR by anacardic acid (uncoupling effect), neither SA nor OA altered basal OCR- except OA inhibited basal and ATP-linked OCR, and increased ECAR, in MDA-MB-231 cells. Changes in OXPHOS proteins correlated with changes in OCR. Overall, neither the 2-hydroxybenzoic acid moiety nor the monounsaturated alky moiety of anacardic acid is solely responsible for the observed mitochondria-targeted anticancer activity in breast cancer cells and hence both moieties are required in the same molecule for the observed effects. J. Cell. Biochem. 117: 2521-2532, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, University of Louisville, Louisville, Kentucky 40292.
authors.forename: Brandie N
authors.initials: BN
authors.lastname: Radde
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, University of Louisville, Louisville, Kentucky 40292.
authors.forename: Negin
authors.initials: N
authors.lastname: Alizadeh-Rad
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, University of Louisville, Louisville, Kentucky 40292.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Price
authors.affiliation: Department of Biology, University of Louisville, Louisville, Kentucky 40292.
authors.forename: David J
authors.initials: DJ
authors.lastname: Schultz
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, University of Louisville, Louisville, Kentucky 40292. carolyn.klinge@louisville.edu.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
mesh_terms: D048729:Anacardic Acids / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D064688:Metabolic Flux Analysis; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D020156:Salicylic Acid / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D048729:Anacardic Acids; D000890:Anti-Infective Agents; C088115:anacardic acid; D019301:Oleic Acid; D020156:Salicylic Acid
keywords: ANACARDIC ACID; BREAST CANCER; ENDOCRINE RESISTANCE; MITOCHONDRIAL BIOENERGETICS; OLEIC ACID; OXYGEN CONSUMPTION RATE; SALICYLIC ACID