R115777 (Zarnestra®)/Zoledronic acid (Zometa®) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation
R115777 (Zarnestra®)/Zoledronic acid (Zometa®) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation
复制标题
DOI：
10.1002/jcp.20960
复制
发表时间：
2007-05-01
影响因子：
5.6
通讯作者：
Abbruzzese, Alberto
中科院分区：
文献类型：
--
作者：
Caraglia, Michele;Marra, Monica;Abbruzzese, Alberto
唑来膦酸(ZOL)通过抑制甲氧戊酸途径和细胞内蛋白质的预烯基化，证实了其在前列腺癌骨转移中的活性。我们已经报道了ZOL与R-115777法呢基转移酶抑制剂(FTI，Zarnestra)在诱导表皮样癌细胞凋亡和抑制其生长方面具有协同作用。在这里，我们研究了这些药物在前列腺癌模型中的联合作用，特别是对雄激素非依赖性(PC3和DU 145)和依赖性(LNCaP)前列腺癌细胞株的影响。我们发现ZOL和R 115777在诱导前列腺癌细胞生长抑制和凋亡方面具有协同作用。这些影响与Ras->；Erk和Akt生存通路的中断平行，从而导致线粒体bcl2和BAD蛋白的磷酸化降低，以及caspase的激活。最后，ZCL/R11S777联合诱导的体内协同作用对前列腺癌裸鼠移植瘤的生长也有明显的抑制作用，存活率明显提高。这些作用与ERK和Akt的凋亡增强和失活相平行。总而言之，ZOL和FTI的联合使用可能通过更有效地抑制ras依赖的生存通路和随后的bcl1相关蛋白依赖的凋亡，从而增强了人前列腺癌细胞的抗肿瘤活性。
Zoledronic acid (ZOL) has proved activity in bone metastases from prostate cancer through inhibition of mevalonate pathway and of prenylation of intracellular proteins. We have reported that ZOL synergizes with R 115777 farnesyltransferase inhibitor (FTI, Zarnestra) in inducing apoptosis and growth inhibition on epidermoid cancer cells. Here, we have studied the effects of the combination of these agents in prostate adenocarcinoma models and, specifically, on androgen-independent (PC3 and DU 145) and -dependent (LNCaP) prostate cancer cell lines. We have found that ZOL and R 115777 were synergistic in inducing both growth inhibition and apoptosis in prostate adenocarcinoma cells. These effects were paralleled by disruption of Ras -> Erk and Akt survival pathways, consequent decreased phosphorylation of both mitochondrial bcl-2 and bad proteins, and caspase activation. Finally, ZCL/R11S777 combination induced cooperative effects also in vivo on tumor growth inhibition of prostate cancer xenografts in nude mice with a significant survival increase. These effects were paralleled by enhanced apoptosis and inactivation of both Erk and Akt. In conclusions, the combination between ZOL and FTI leads to enhanced anti-tumor activity in human prostate adenocarcinorna cells likely through a more efficacious inhibition of ras-dependent survival pathways and consequent bcl-related proteins-dependent apoptosis.