PAK1 inhibitor IPA-3 mitigates metastatic prostate cancer-induced bone remodeling

• Published in: Biochemical pharmacology 2020-07, Vol.177, p.113943-113943, Article 113943
• Main Authors: Verma, Arti, Artham, Sandeep, Alwhaibi, Abdulrahman, Adil, Mir S., Cummings, Brian S., Somanath, Payaningal R.
• Format: Article
• Language: English
• Subjects: Animals; Bone remodeling; Bone Remodeling - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Disease Models, Animal; Disulfides - pharmacology; Disulfides - therapeutic use; Humans; IPA-3; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Male; Metastasis; Mice; Mice, Inbred C57BL; Naphthols - pharmacology; Naphthols - therapeutic use; p21-Activated Kinases - antagonists & inhibitors; PAK1; Prostatic Neoplasms - pathology; Tibia - pathology; µCT
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2020.113943

Our study demonstrates that targeting P21 activated kinase-1 (PAK1) using IPA-3, an allosteric inhibitor of its kinase activity, inhibits prostate cancer metastasis to distant tissues and blunts metastatic prostate cancer cell-induced bone remodeling in a mouse model as analyzed by the three-dimensional microcomputer tomography analysis. Our study has identified IPA-3 as a potential drug to treat bone metastatic PCa. [Display omitted] 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.