title: Evaluation of the genotoxicity of piplartine, an alkamide of Piper tuberculatum, in yeast and mammalian V79 cells.
abstract: The genus Piper belongs to the Piperaceae family, and includes species of commercial and medicinal importance. Chemical studies on Piper species resulted in the isolation of several biologically active molecules, including alkaloid amides, such as piplartine. This molecule, isolated from Piper tuberculatum, has significant cytotoxic activity against tumor cell lines, and presents antifungal, anti-platelet aggregation, anxiolytic, and antidepressant effects. In order to understand the biological properties of piplartine, this study investigated the genotoxicity and the induction of apoptosis by piplartine in V79 cells and its mutagenic and recombinogenic potential in Saccharomyces cerevisiae. Piplartine induced dose-dependent cytotoxicity in S. cerevisiae cultures in either stationary -- or exponential growth phase. In addition, piplartine was not mutagenic when cells were treated during exponential-growth phase and kept in buffer solution, but it increased the frequencies of point, frameshift, and forward mutations when cells were treated in medium during growth. Piplartine treatment induced DNA strand breaks in V79 cells, as detected by neutral and alkaline comet assay. In cell cycle analysis, piplartine induced G2/M cell cycle arrest, probably as a consequence of the DNA damage induced and repair. Moreover, piplartine treatment induced apoptosis in a dose-dependent manner, as observed by a decrease in mitochondrial membrane potential and an increase in internucleosomal DNA fragmentation. These data suggest that the DNA damage caused by piplartine induces G2/M cell cycle arrest, followed by apoptosis. Moreover, we suggest that cells surviving piplartine-induced DNA damage can accumulate mutations, since this alkaloid was mutagenic and recombinogenic in S. cerevisiae assays.
authors: Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil.
authors: Daniel Pereira
authors: DP
authors: Bezerra
authors: Dinara Jaqueline
authors: DJ
authors: Moura
authors: Renato Moreira
authors: RM
authors: Rosa
authors: Marne Carvalho
authors: MC
authors: de Vasconcellos
authors: Ana Catarina Romano
authors: AC
authors: e Silva
authors: Manoel Odorico
authors: MO
authors: de Moraes
authors: Edilberto Rocha
authors: ER
authors: Silveira
authors: Mary Anne Sousa
authors: MA
authors: Lima
authors: João Antonio Pegas
authors: JA
authors: Henriques
authors: Letícia Veras
authors: LV
authors: Costa-Lotufo
authors: Jenifer
authors: J
authors: Saffi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D020552:Comet Assay; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009152:Mutagenicity Tests / Q000379:methods*; D031701:Piper / Q000737:chemistry*; D010881:Piperidones / Q000633:toxicity*; D012441:Saccharomyces cerevisiae / Q000187:drug effects
chemical_list: D010881:Piperidones; C498077:piperlongumine