Contribution of either YY1 or BclXL-induced inhibition by the NO-donor DETANONOate in the reversal of drug resistance, both in vitro and in vivo. YY1 and BclXL are overexpressed in prostate cancer
Contribution of either YY1 or BclXL-induced inhibition by the NO-donor DETANONOate in the reversal of drug resistance, both in vitro and in vivo. YY1 and BclXL are overexpressed in prostate cancer
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DOI：
10.1016/j.niox.2012.12.001
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发表时间：
2013-02-28
影响因子：
3.9
通讯作者：
Bonavida, Benjamin
中科院分区：
文献类型：
--
作者：
Huerta-Yepez, Sara;Baritaki, Stavroula;Bonavida, Benjamin
一氧化氮（NO）供体已显示激活或抑制癌细胞中组成性激活的存活/抗凋亡途径，如NF-κ B。我们在此报道，用高水平（500-1000 μ M）的NO-供体DETANONOate处理耐药的人前列腺癌细胞系，使耐药肿瘤细胞对CDDP的凋亡敏感，并且该组合是协同的。我们假设DETANONOate抑制先前确定的NF-κ B调节的抵抗因子，如阴阳1（YY 1）和Bcl-2/Bcl（XL）。用DETANONOate处理的肿瘤细胞的裂解物显示YY 1和Bcl（XL）表达的抑制。转染YY 1或Bcl（XL）siRNA均能抑制YY 1和Bcl（XL）的表达，并使细胞对顺铂敏感。携带PC-3肿瘤异种移植物并用DETANONOate和CDDP组合治疗的小鼠导致肿瘤生长的显著抑制;单独用单一药剂治疗对肿瘤生长没有任何影响。对前列腺癌患者TMA组织的分析显示，YY 1和Bcl（XL）的表达均随肿瘤分级而升高，且其水平直接相关。因此，YY 1和Bcl（XL）都是潜在的预后生物标志物。总体而言，上述发现表明地坦酸盐诱导的耐药肿瘤细胞对CDDP的敏感性的一种机制与NF-κ B及其靶点YY 1和Bcl（XL）的抑制相关。NO供体和细胞毒疗法在治疗耐药前列腺癌中的组合的检查可能是必要的。爱思唯尔公司出版
Nitric oxide (NO) donors have been shown to activate or inhibit constitutively-activated survival/antiapoptotic pathways, such as NF-kappa B, in cancer cells. We report here that treatment of drug-resistant human prostate carcinoma cell lines with high levels (500-1000 mu M) of the NO-donor DETANONOate sensitized the resistant tumor cells to apoptosis by CDDP and the combination was synergistic. We hypothesized that DETANONOate inhibits previously identified NF-kappa B-regulated resistant factors such as Yin Yang 1 (YY1) and Bcl-2/Bcl(XL). Lysates from tumor cells treated with DETANONOate showed inhibition of YY1 and Bcl(XL), expressions. Transfection with either YY1 or Bcl(XL) siRNA resulted in the inhibition of both YY1 and Bcl(XL) expressions and sensitized the cells to CDDP apoptosis. Mice bearing PC-3 tumor xenografts and treated with the combination of DETANONOate and CDDP resulted in significant inhibition of tumor growth; treatment with single agent alone did not have any effect on tumor growth. Analysis of patients TMA tissues with prostatic cancer revealed higher expression of both YY1 and Bcl(XL) as a function of tumor grades and their levels were directly correlated. Thus, both YY1 and Bcl(XL), are potential prognostic biomarkers. Overall, the above findings suggest that one mechanism of DETANONOate-induced sensitization of resistant tumor cells to CDDP correlated with the inhibition of NF-kappa B and its targets YY1 and Bcl(XL). The examination of the combination of NO donors and cytotoxic therapy in the treatment of resistant prostate cancer may be warranted. Published by Elsevier Inc.