title: Inhibitory effect of nordihydroguaiaretic acid and its tetra-acetylated derivative on respiration and growth of adenocarcinoma TA3 and its multiresistant variant TA3MTX-R.
abstract: The effects of nordihydroguaiaretic acid (NDGA) and its tetraacetylated derivative (NDGATA) on the growth, oxygen consumption, adenosine 5'-triphosphate (ATP) level and viability of mouse mammary adenocarcinoma TA3 and its multiresistant variant TA3-MTX-R cell lines were determined. NDGA inhibited mitochondrial carbonyl cyanide m-chlorophenylhydrazone (CCCP)-stimulated oxygen consumption in mouse liver and tumor cells when glutamate plus malate or succinate was added as substrate. The effects were considerably weaker when respiration was supported by duroquinol, indicating that NDGA inhibited primarily mitochondrial electron flow located at some point before ubiquinone. Although NDGATA only inhibited the electron flow through complex I, it was more efficient and selective than NDGA because mouse liver mitochondria were significantly less sensitive to it than both tumor cell lines tested. NDGA and NDGATA inhibited mitochondrial ATP synthesis and, consequently, cell viability and growth rate were also decreased. NDGA and NDGATA inhibited the growth of intramuscularly implanted tumor cells, indicating that NDGATA was also antineoplastic in vivo. In conclusion, NDGATA is cytotoxic to tumor cells, provoking selective induction of mitochondrial dysfunctions, which could be interesting as potential antitumoral agent.
authors.affiliation: Programa de Farmacología Molecular y Clínica, ICBM, Universidad de Chile, Santiago.
authors.forename: Claudio
authors.initials: C
authors.lastname: Plaza
authors.forename: Mario
authors.initials: M
authors.lastname: Pavani
authors.forename: Mario
authors.initials: M
authors.lastname: Faundez
authors.forename: Juan Diego
authors.initials: JD
authors.lastname: Maya
authors.forename: Antonio
authors.initials: A
authors.lastname: Morello
authors.forename: Maria Inés
authors.initials: MI
authors.lastname: Becker
authors.forename: Alfredo
authors.initials: A
authors.lastname: De Ioannes
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Cumsille
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D000107:Acetylation; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D009637:Masoprocol / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000378:metabolism; D015996:Survival Rate
chemical_list: D009637:Masoprocol; D010100:Oxygen