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首页> 外文期刊>Journal of Cellular Physiology >Pharmacological inhibition of HSP90 and ras activity as a new strategy in the treatment of HNSCC
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Pharmacological inhibition of HSP90 and ras activity as a new strategy in the treatment of HNSCC

机译：药物抑制以及ras活动作为一种新的治疗策略HNSCC

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Advanced head and neck squamous cell cancer (HNSCC) is currently treated with taxane-based chemotherapy. We have previously shown that docetaxel (DTX) induces a ras-dependent survival signal that can be antagonized by farnesyl transferase inhibitors (FTI) such as tipifarnib (TIP). Here we show that the synergistic TIP/DTX combination determines synergistic apoptotic conditions but, at the same time, it modulates the expression of the components of the multichaperone complex that is, in turn, involved in the regulation of the stability of members of the ras-mediated pathway. Therefore, we have stably transfected HNSCC KB and Hep-2 cells with a plasmid encoding for HSP90. The expression of the protein was increased in both transfected cell lines but its activation status was increased in Hep-2 clones and decreased in KB clones. On the basis of these results, we have treated both parental and HSP90-transfected cells with a HSP90 inhibitor geldanamycin (GA). We have found that the antiproliferative activity of GA is dependent upon the activation status of HSP90 and that it is strongly synergistic when added in combination with TIP but not with DTX in cells overexpressing HSP90 and even more in cells with increased HSP90 activity. These data were paralleled by the decreased expression and activity of the components belonging to the ras→mediated signal transduction pathway. The present results suggest that multichaperone complex activation could be a resistance mechanism to the anti-proliferative and apoptotic effects induced by TIP and that the combination of FTIs such as TIP with GA could be a suitable therapeutic strategy in the treatment of HSP90-overexpressing HNSCC.
机译：先进的头颈部鳞状细胞癌(HNSCC)目前taxane-based处理化疗。多西他赛(DTX)诱发ras-dependent生存引起信号,可以通过tipifarnib等转移酶抑制剂(FTI)(提示)。组合决定了协同凋亡条件,但与此同时,它调节的组件的表达反过来,multichaperone复杂,参与其中的成员的稳定性ras-mediated通路。稳定转染HNSCC KB和Hep-2细胞一半的质粒编码。蛋白质提高转染细胞系,但其激活状态增加在Hep-2克隆和减少在KB克隆。对待父母和HSP90-transfected细胞有一半抑制剂geldanamycin (GA)。发现的抗增殖活动是依赖于一半的激活状态添加时,强烈的协同结合尖端但不是DTX细胞overexpressing一半甚至更多的细胞增加一半的活动。平行的表达和下降属于活动的组件ras→介导的信号转导通路。目前的结果表明,multichaperone复杂的激活可能是阻力anti-proliferative和凋亡的机制提示,结合引起的影响提示与GA等呢可能是合适的治疗的治疗策略HSP90-overexpressing HNSCC。

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