title: Ferruginol suppresses survival signaling pathways in androgen-independent human prostate cancer cells.
abstract: Ferruginol, a bioactive compound isolated from a Chilean tree (Podocarpaceae), attracts attention as a consequence of its pharmacological properties, which include anti-fungal, anti-bacterial, cardioprotective, anti-oxidative, anti-plasmodial and anti-ulcerogenic actions. Nevertheless, the molecular basis for these actions remains only partly understood and hence we investigated the effects of ferruginol on androgen-independent human prostate cancer cells (PC3), a known model for solid tumor cells with an exceptional resistance to therapy. The results show that ferruginol induces PC3 cell death via activation of caspases as well as apoptosis-inducing factor (AIF) as confirmed by its translocation into the nucleus. In order to clarify the biochemical mechanism responsible for the anti-tumor activity of ferruginol, we analyzed a set of molecular mediators involved in tumor cell survival, progression and aggressiveness. Ferruginol was able to trigger inhibition/downregulation of Ras/PI3K, STAT 3/5, protein tyrosine phosphatase and protein kinases related to cell cycle regulation. Importantly, the toxic effect of ferruginol was dramatically impeded in a more reducing environment, which indicates that at least in part, the anti-tumoral activity of ferruginol might be related to redox status modulation. This study supports further examination of ferruginol as a potential agent for both the prevention and treatment of prostate cancer.
authors.affiliation: Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Cidade Universitária, Zeferino Vaz, Barão Geraldo, 13083-970 Campinas, SP, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Bispo de Jesus
authors.forename: Willian Fernando
authors.initials: WF
authors.lastname: Zambuzzi
authors.forename: Roberta Regina
authors.initials: RR
authors.lastname: Ruela de Sousa
authors.forename: Carlos
authors.initials: C
authors.lastname: Areche
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Santos de Souza
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoyama
authors.forename: Guillermo
authors.initials: G
authors.lastname: Schmeda-Hirschmann
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Rodríguez
authors.forename: Alba Regina
authors.initials: AR
authors.lastname: Monteiro de Souza Brito
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Hertog
authors.forename: Eneida
authors.initials: E
authors.lastname: de Paula
authors.forename: Carmen Veríssima
authors.initials: CV
authors.lastname: Ferreira
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000633:toxicity*; D000728:Androgens; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D045784:Abietanes; D000728:Androgens; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D011518:Proto-Oncogene Proteins; D050791:STAT Transcription Factors; C431074:ferruginol; D051550:I-kappa B Kinase; C490429:ACP1 protein, human; D017027:Protein Tyrosine Phosphatases; D020169:Caspases