PDF(Pubmed)
Abstract：
Proteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found to mediate therapy resistance in GBM. The use of combinations of chemotherapeutic agents is considered a promising direction in cancer therapy. The present work aimed to evaluate the efficacy of the combination of proteasome and RNR inhibitors in yeast and GBM cell models. We have shown that impaired proteasome function results in increased levels of RNR subunits and increased enzyme activity in yeast. Co-administration of the proteasome inhibitor bortezomib and the RNR inhibitor hydroxyurea was found to significantly reduce the growth rate of S. cerevisiae yeast. Accordingly, the combination of bortezomib and another RNR inhibitor gemcitabine reduced the survival of DBTRG-05MG compared to the HEK293 cell line. Thus, yeast can be used as a simple model to evaluate the efficacy of combinations of proteasome and RNR inhibitors.
摘要：
蛋白酶体抑制剂用于治疗几种癌症，并且正在进行用于治疗胶质母细胞瘤（GBM）的临床试验。然而,GBM对化疗的抗性相对较快。最近,发现核糖核苷酸还原酶（RNR）基因的过表达介导GBM的治疗抗性。化学治疗剂的组合的使用被认为是癌症治疗中的有希望的方向。本工作旨在评估蛋白酶体和RNR抑制剂组合在酵母和GBM细胞模型中的功效。我们已经表明，蛋白酶体功能受损导致酵母中RNR亚基水平增加和酶活性增加。发现蛋白酶体抑制剂硼替佐米和RNR抑制剂羟基脲的共同施用显著降低酿酒酵母的生长速率。因此，与HEK293细胞系相比,硼替佐米和另一种RNR抑制剂吉西他滨的组合降低了DBTRG-05MG的存活率.因此，酵母可以用作评估蛋白酶体和RNR抑制剂组合的功效的简单模型。
