title: Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model.
abstract: It is estimated that approximately 90% of patients with advanced prostate cancer develop bone metastases; an occurrence that results in a substantial reduction in the quality of life and a drastic worsening of prognosis. The development of novel therapeutic strategies that impair the metastatic process and associated skeletal adversities is therefore critical to improving prostate cancer patient survival. Recognition of the importance of Cathepsin L (CTSL) to metastatic dissemination of cancer cells has led to the development of several CTSL inhibition strategies. The present investigation employed intra-cardiac injection of human PC-3ML prostate cancer cells into nude mice to examine tumor cell dissemination in a preclinical bone metastasis model. CTSL knockdown confirmed the validity of targeting this protease and subsequent intervention studies with the small molecule CTSL inhibitor KGP94 resulted in a significant reduction in metastatic tumor burden in the bone and an improvement in overall survival. CTSL inhibition by KGP94 also led to a significant impairment of tumor initiated angiogenesis. Furthermore, KGP94 treatment decreased osteoclast formation and bone resorptive function, thus, perturbing the reciprocal interactions between tumor cells and osteoclasts within the bone microenvironment which typically result in bone loss and aggressive growth of metastases. These functional effects were accompanied by a significant downregulation of NFκB signaling activity and expression of osteoclastogenesis related NFκB target genes. Collectively, these data indicate that the CTSL inhibitor KGP94 has the potential to alleviate metastatic disease progression and associated skeletal morbidities and hence may have utility in the treatment of advanced prostate cancer patients.
authors.affiliation: Department of Radiation Oncology, University of Florida Health Cancer Center, Gainesville, FL.
authors.forename: Dhivya R
authors.initials: DR
authors.lastname: Sudhan
authors.affiliation: Department of Radiation Oncology, University of Florida Health Cancer Center, Gainesville, FL.
authors.forename: Christine
authors.initials: C
authors.lastname: Pampo
authors.affiliation: Department of Radiation Oncology, University of Florida Health Cancer Center, Gainesville, FL.
authors.forename: Lori
authors.initials: L
authors.lastname: Rice
authors.affiliation: Department of Radiation Oncology, University of Florida Health Cancer Center, Gainesville, FL.|Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Siemann
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D013882:Thiosemicarbazones / Q000008:administration & dosage; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C581086:KGP94; D013882:Thiosemicarbazones; D056668:Cathepsin L; D013890:Thiourea
keywords: KGP94; bone resorption; cathepsin L; metastasis; prostate cancer