Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
Department of Surgery 'P. Valdoni', Sapienza University of Rome, 00161 Rome, Italy.
Molecules. 2020 Sep 25;25(19):4401. doi: 10.3390/molecules25194401.
Inositol and its phosphate metabolites play a pivotal role in several biochemical pathways and gene expression regulation: inositol pyrophosphates (PP-IPs) have been increasingly appreciated as key signaling modulators. Fluctuations in their intracellular levels hugely impact the transfer of phosphates and the phosphorylation status of several target proteins. Pharmacological modulation of the proteins associated with PP-IP activities has proved to be beneficial in various pathological settings. IP has been extensively studied and found to play a key role in pathways associated with PP-IP activities. Three inositol hexakisphosphate kinase (IPK) isoforms regulate IP synthesis in mammals. Genomic deletion or enzymic inhibition of IPK1 has been shown to reduce cell invasiveness and migration capacity, protecting against chemical-induced carcinogenesis. IPK1 could therefore be a useful target in anticancer treatment. Here, we summarize the current understanding that established IPK1 and the other IPK isoforms as possible targets for cancer therapy. However, it will be necessary to determine whether pharmacological inhibition of IPK is safe enough to begin clinical study. The development of safe and selective inhibitors of IPK isoforms is required to minimize undesirable effects.
焦磷酸肌醇（PP-IPs）越来越被认为是关键的信号调节因子。它们在细胞内水平的波动极大地影响了磷酸的转移和几个靶蛋白的磷酸化状态。与 PP-IP 活性相关的蛋白质的药理学调节已被证明在各种病理情况下是有益的。肌醇已被广泛研究，并被发现在与 PP-IP 活性相关的途径中发挥关键作用。三种肌醇六磷酸激酶（IPK）同工酶调节哺乳动物中肌醇的合成。已经表明，IPK1 的基因组缺失或酶抑制可降低细胞侵袭性和迁移能力，从而防止化学诱导的致癌作用。因此，IPK1 可能是癌症治疗的有用靶点。在这里，我们总结了目前的认识，即确立了 IPK1 和其他 IPK 同工酶作为癌症治疗的潜在靶点。然而，有必要确定抑制 IPK 的药理学是否足够安全，可以开始临床研究。需要开发安全且选择性的 IPK 同工酶抑制剂，以最小化不良影响。
