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首页> 外文期刊>Cell cycle >In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells.
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In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells.

机译：Saquinavir-NO（一种新的蛋白酶抑制剂沙奎那韦的一氧化氮衍生物）对激素抵抗性前列腺癌细胞的体外和体内抗癌作用。

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The NO-derivative of the HIV protease inhibitor saquinavir (Saq-NO) is a nontoxic variant of the parental drug with enhanced anticancer activity on several cell lines. However, it is still unclear whether the p53 status of the target cell might influence the sensitivity to Saq-NO. In this study we evaluated the in vitro and in vivo activity of Saq-NO on the p53-deficient hormone resistant prostate cancer PC-3 cells. We demonstrate that the absence of functional p53 is not essential for the capacity of Saq-NO to reduce prostate cancer cell growth. In contrast to its previously described cytostatic action in B16 and C6 cell lines, Saq-NO exerted cytotoxic effects in PC-3 cells leading to dominant induction of apoptosis and enhanced production of proapoptotic Bim. In addition, differently from saquinavir, Saq-NO restored TRAIL sensitivity that was correlated with increased expression of DR5 independent from ROS/RNS production and YY1 repression. NF-kappaB activation may be responsible of the Saq-NO induced DR5 expression. Moreover, Saq-NO but not saquinavir, exerted synergistic activity with conventional cytostatic therapy. In agreement with these in vitro studies, Saq-NO inhibited the in vivo growth of PC-3 cells xenotransplants to a greater extent than the parental compound. Taken together, these data indicate that Saq-NO possesses powerful and suitable in vitro and in vivo chemotherapeutic potential to be further studied as a novel drug for the treatment of prostate cancer in the clinical setting.
机译：HIV蛋白酶抑制剂沙奎那韦（Saq-NO）的NO衍生物是母体药物的无毒变体，在几种细胞系中具有增强的抗癌活性。但是，尚不清楚靶细胞的p53状态是否会影响对Saq-NO的敏感性。在这项研究中，我们评估了Saq-NO对p53缺乏激素抵抗性前列腺癌PC-3细胞的体外和体内活性。我们证明功能性p53的缺乏对于Saq-NO减少前列腺癌细胞生长的能力不是必需的。与先前描述的在B16和C6细胞系中的细胞抑制作用相反，Saq-NO在PC-3细胞中发挥细胞毒性作用，导致凋亡的显性诱导和促凋亡Bim的产生。另外，与沙奎那韦不同，Saq-NO恢复了TRAIL敏感性，这与DR5的表达增加相关，而DR5的表达独立于ROS / RNS的产生和YY1的抑制。 NF-κB激活可能是Saq-NO诱导的DR5表达的原因。此外，Saq-NO（而非沙奎那韦）与常规细胞抑制疗法具有协同活性。与这些体外研究相一致，Saq-NO抑制PC-3细胞异种移植物的体内生长的程度大于亲本化合物。综上所述，这些数据表明Saq-NO具有强大而合适的体外和体内化学治疗潜力，有待在临床上进一步研究其作为治疗前列腺癌的新药。

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