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The traditional Chinese medical compound Rocaglamide protects nonmalignant primary cells from DNA damage-induced toxicity by inhibition of p53 expression

机译:中药复方罗卡酰胺通过抑制p53表达来保护非恶性原代细胞免受DNA损伤诱导的毒性作用

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摘要

One of the main obstacles of conventional anticancer therapy is the toxicity of chemotherapeutics to normal tissues. So far, clinical approaches that aim to specifically reduce chemotherapy-mediated toxicities are rare. Recently, a number of studies have demonstrated that herbal extracts derived from traditional Chinese medicine (TCM) may reduce chemotherapy-induced side effects. Thus, we screened a panel of published cancer-inhibiting TCM compounds for their chemoprotective potential and identified the phytochemical Rocaglamide (Roc-A) as a candidate. We show that Roc-A significantly reduces apoptotic cell death induced by DNA-damaging anticancer drugs in primary human and murine cells. Investigation of the molecular mechanism of Roc-A-mediated protection revealed that Roc-A specifically blocks DNA damage-induced upregulation of the transcription factor p53 by inhibiting its protein synthesis. The essential role of p53 in Roc-A-mediated protection was confirmed by siRNA knockdown of p53 and by comparison of the effects of Roc-A on chemoprotection of splenocytes isolated from wild-type and p53-deficient mice. Importantly, Roc-A did not protect p53-deficient or -mutated cancer cells. Our data suggest that Roc-A may be used as an adjuvant to reduce the side effects of chemotherapy in patients with p53-deficient or -mutated tumors.
机译:常规抗癌疗法的主要障碍之一是化学疗法对正常组织的毒性。迄今为止,旨在特异性降低化疗介导的毒性的临床方法很少见。最近,许多研究表明,源自中药(TCM)的草药提取物可减少化疗引起的副作用。因此,我们筛选了一组已发表的抑制癌症的中药化合物的化学保护潜力,并确定了植物化学药罗卡酰胺(Roc-A)作为候选药物。我们显示,Roc-A显着降低了原发性人和鼠细胞中DNA破坏性抗癌药物诱导的凋亡细胞死亡。对Roc-A介导的保护作用的分子机制的研究表明,Roc-A通过抑制蛋白质的合成来特异性阻断DNA损伤诱导的转录因子p53的上调。通过p53的siRNA敲除和比较Roc-A对从野生型和p53缺陷型小鼠分离的脾细胞的化学保护作用,证实了p53在Roc-A介导的保护中的重要作用。重要的是,Roc-A不能保护p53缺陷或突变的癌细胞。我们的数据表明,Roc-A可用作佐剂,以减少p53缺乏或突变的肿瘤患者化疗的副作用。

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