title: Antiproliferative and uncoupling effects of delocalized, lipophilic, cationic gallic acid derivatives on cancer cell lines. Validation in vivo in singenic mice.
abstract: Tumor cells principally exhibit increased mitochondrial transmembrane potential (ΔΨ(m)) and altered metabolic pathways. The therapeutic targeting and delivery of anticancer drugs to the mitochondria might improve treatment efficacy. Gallic acid exhibits a variety of biological activities, and its ester derivatives can induce mitochondrial dysfunction. Four alkyl gallate triphenylphosphonium lipophilic cations were synthesized, each differing in the size of the linker chain at the cationic moiety. These derivatives were selectively cytotoxic toward tumor cells. The better compound (TPP(+)C10) contained 10 carbon atoms within the linker chain and exhibited an IC50 value of approximately 0.4-1.6 μM for tumor cells and a selectivity index of approximately 17-fold for tumor compared with normal cells. Consequently, its antiproliferative effect was also assessed in vivo. The oxygen consumption rate and NAD(P)H oxidation levels increased in the tumor cell lines (uncoupling effect), resulting in a ΔΨ(m) decrease and a consequent decrease in intracellular ATP levels. Moreover, TPP(+)C10 significantly inhibited the growth of TA3/Ha tumors in mice. According to these results, the antineoplastic activity and safety of TPP(+)C10 warrant further comprehensive evaluation.
authors.affiliation: Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile , Independencia 1027, Santiago 8380453, Chile.
authors.forename: José A
authors.initials: JA
authors.lastname: Jara
authors.forename: Vicente
authors.initials: V
authors.lastname: Castro-Castillo
authors.forename: Jorge
authors.initials: J
authors.lastname: Saavedra-Olavarría
authors.forename: Liliana
authors.initials: L
authors.lastname: Peredo
authors.forename: Mario
authors.initials: M
authors.lastname: Pavanni
authors.forename: Fabián
authors.initials: F
authors.lastname: Jaña
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Letelier
authors.forename: Eduardo
authors.initials: E
authors.lastname: Parra
authors.forename: María Inés
authors.initials: MI
authors.lastname: Becker
authors.forename: Antonio
authors.initials: A
authors.lastname: Morello
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kemmerling
authors.forename: Juan Diego
authors.initials: JD
authors.lastname: Maya
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000187:drug effects; D061945:Caspase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D002412:Cations / Q000737:chemistry; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008933:Mitochondrial Swelling / Q000187:drug effects; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D015203:Reproducibility of Results; D014475:Uncoupling Agents / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D002412:Cations; D014475:Uncoupling Agents; D009249:NADP; D005707:Gallic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3