Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Cancer Lett. 2012 Nov 1;324(1):83-90. doi: 10.1016/j.canlet.2012.05.003. Epub 2012 May 8.
Chronic mTOR inhibition may induce resistance development in renal cell carcinoma (RCC). We analyzed whether long-term exposure of RCC cells to the mTOR-inhibitor RAD001 evokes resistance and whether additional targeting histone deacetylases (HDAC) by valproic acid (VPA) overcomes RAD001 resistance. It is demonstrated that responsiveness to either drug alone is lost over time, evidenced by increased cell growth, proliferation and de-differentiation. However, drug sensitivity was conserved when RAD001 and VPA were applied in concert. Molecular analysis particularly revealed strong re-activation of Akt under chronic RAD001 or diminished histone H3 acetylation under chronic VPA single drug exposure. Combined drug application did not inactivate Akt but rather resulted in H3 acetylation remaining high while RCC cell growth was still reduced. siRNA experiments revealed that histone H3 acetylation is responsible for preserving drug sensitivity in RCCs.
慢性 mTOR 抑制可能会导致肾细胞癌 (RCC) 产生耐药性。我们分析了 RCC 细胞是否会对 mTOR 抑制剂 RAD001 进行长期暴露而产生耐药性，以及是否通过丙戊酸 (VPA) 进一步靶向组蛋白去乙酰化酶 (HDAC) 来克服 RAD001 耐药性。结果表明，随着时间的推移，单独使用任一药物的反应性逐渐丧失，这表现在细胞生长、增殖和去分化的增加。然而，当 RAD001 和 VPA 联合应用时，药物敏感性得以保留。分子分析特别揭示了在慢性 RAD001 或慢性 VPA 单药暴露下 Akt 的强烈再激活或组蛋白 H3 乙酰化的减弱。联合用药并未使 Akt 失活，而是导致 H3 乙酰化仍然保持高水平，同时 RCC 细胞生长仍被抑制。siRNA 实验表明，组蛋白 H3 乙酰化是维持 RCC 药物敏感性的原因。
