Bispo de Jesus Marcelo, Zambuzzi Willian Fernando, Ruela de Sousa Roberta Regina, Areche Carlos, Santos de Souza Ana Carolina, Aoyama Hiroshi, Schmeda-Hirschmann Guillermo, Rodríguez Jaime A, Monteiro de Souza Brito Alba Regina, Peppelenbosch Maikel P, den Hertog Jeroen, de Paula Eneida, Ferreira Carmen Veríssima
Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Cidade Universitária, Zeferino Vaz, Barão Geraldo, 13083-970 Campinas, SP, Brazil.
Biochimie. 2008 Jun;90(6):843-54. doi: 10.1016/j.biochi.2008.01.011. Epub 2008 Feb 3.
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.
铁杉醇是一种从智利树木（罗汉松科）中分离出的生物活性化合物，因其药理特性而备受关注，这些特性包括抗真菌、抗菌、心脏保护、抗氧化、抗疟原虫和抗溃疡作用。然而，这些作用的分子基础仍仅部分为人所知，因此我们研究了铁杉醇对雄激素非依赖性人前列腺癌细胞（PC3）的影响，PC3是一种已知的实体瘤细胞模型，对治疗具有特殊抗性。结果表明，铁杉醇通过激活半胱天冬酶以及凋亡诱导因子（AIF）诱导PC3细胞死亡，这一点通过其转位至细胞核得到证实。为了阐明铁杉醇抗肿瘤活性的生化机制，我们分析了一组参与肿瘤细胞存活、进展和侵袭性的分子介质。铁杉醇能够引发Ras/PI3K、STAT 3/5、蛋白酪氨酸磷酸酶以及与细胞周期调控相关的蛋白激酶的抑制/下调。重要的是，在还原性更强的环境中，铁杉醇的毒性作用受到显著阻碍，这表明铁杉醇的抗肿瘤活性至少部分可能与氧化还原状态调节有关。本研究支持进一步研究铁杉醇作为预防和治疗前列腺癌的潜在药物。
