PAK1 抑制剂 IPA-3 减轻转移性前列腺癌诱导的骨重塑。
PAK1 inhibitor IPA-3 mitigates metastatic prostate cancer-induced bone remodeling.
机构信息
Clinical and Experimental Therapeutics, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA, United States.
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia Athens, GA, United States; Interdisciplinary Toxicology Program, University of Georgia, United States.
出版信息
Biochem Pharmacol. 2020 Jul;177:113943. doi: 10.1016/j.bcp.2020.113943. Epub 2020 Mar 30.
Metastatic prostate cancer (PCa) has high mortality and a poor 5-year survival rate primarily due to the lack of effective treatments. Bone is the primary site of PCa metastasis in humans and the development of reliable therapeutic options for bone metastatic PCa will make a huge impact in reducing the mortality among these patients. Although P21 activated kinases (PAKs) have been studied in the past for their role in cancer, the efficacy of targeting PAKs to treat lung and bone metastatic PCa has not been tested yet. In the current study, we report that targeting PAK1 using IPA-3, an allosteric inhibitor of PAK1 kinase activity, significantly inhibits the murine metastatic PCa (RM1) cell proliferation and motility in vitro, and metastasis to the lungs in vivo. More importantly, we demonstrate for the first time that treatment with IPA-3 can blunt metastatic PCa-induced bone remodeling in vivo as analyzed by the 3-dimensional microcomputer tomography analysis. Our study has identified IPA-3 as a potential drug to treat bone metastatic PCa.
转移性前列腺癌（PCa）死亡率高，5 年生存率低，主要原因是缺乏有效治疗方法。骨骼是人前列腺癌转移的主要部位，开发可靠的骨转移性 PCa 治疗方法将对降低这些患者的死亡率产生巨大影响。尽管 P21 激活激酶（PAKs）过去曾因其在癌症中的作用而受到研究，但靶向 PAKs 治疗肺和骨转移性 PCa 的疗效尚未得到验证。在本研究中，我们报告称，使用 IPA-3（PAK1 的别构抑制剂）靶向 PAK1，可显著抑制体外鼠转移性 PCa（RM1）细胞的增殖和迁移，并抑制体内肺转移。更重要的是，我们首次证明，用 IPA-3 治疗可减弱转移性 PCa 诱导的体内骨重塑，这可通过三维微机断层扫描分析进行分析。我们的研究确定 IPA-3 是一种治疗骨转移性 PCa 的潜在药物。
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