Antiproliferative and Uncoupling Effects of Delocalized, Lipophilic, Cationic Gallic Acid Derivatives on Cancer Cell Lines. Validation in Vivo in Singenic Mice

Jara, JA; Castro-Castillo; Saavedra-Olavarria, J; Peredo, L; Pavanni M.; Jaña F; Letelier, ME; Parra E.; Becker, MI; Morello A.; Kemmerling U.; Maya, Juan Diego.; Ferreira J.

Abstract

Tumor cells principally exhibit increased mitochondrial transmembrane potential (Delta Psi(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 mu M 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 Delta Psi(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.

Más información

Título según WOS: Antiproliferative and Uncoupling Effects of Delocalized, Lipophilic, Cationic Gallic Acid Derivatives on Cancer Cell Lines. Validation in Vivo in Singenic Mice
Título según SCOPUS: Antiproliferative and uncoupling effects of delocalized, lipophilic, cationic gallic acid derivatives on cancer cell lines. Validation in vivo in singenic mice
Título de la Revista: JOURNAL OF MEDICINAL CHEMISTRY
Volumen: 57
Número: 6
Editorial: AMER CHEMICAL SOC
Fecha de publicación: 2014
Página de inicio: 2440
Página final: 2454
Idioma: English
DOI:

10.1021/jm500174v

Notas: ISI, SCOPUS - ISI