Preclinical ReportsAnti-prostate cancer activity of a nanoformulation of the spleen tyrosine kinase (SYK) inhibitor C61Sahin, Taha Koraya; Aktepe, Oktay Halitb; Uckun, Fatih Mehmetc,,d; Yalcin, SuayibbAuthor Information aDepartment of Internal Medicine, Faculty of Medicine, Hacettepe University bDepartment of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey cChildren’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles dDepartment of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California, USA Received 16 October 2019 Revised form accepted 31 December 2019 Correspondence to Taha Koray Sahin, MD, Department of Internal Medicine, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey, Tel: +905368525350; fax: +90312310 05 80 e-mail: email@example.com Anti-Cancer Drugs: July 2020 - Volume 31 - Issue 6 - p 609-616 doi: 10.1097/CAD.0000000000000910 Buy Metrics Abstract Patients with advanced or metastatic castration-resistant prostate cancer have a dismal prognosis and are therefore in urgent need for therapeutic innovations. Spleen tyrosine kinase has emerged as a new molecular target for castration-resistant prostate cancer. This study was done to test the cytotoxicity of the lead nanoformulation of a potent spleen tyrosine kinase inhibitor, C61-LNP, against the human prostatic carcinoma cell line, PC-3. PC-3 cells were treated with various concentrations of C61-LNP either alone or in combination with cisplatin (CDDP) for 24, 48 and 72 hours. The cell viability was evaluated by MTS assay. Cellular expression levels of various regulatory proteins in treated PC-3 cells were evaluated by Western blot analyses. C61-LNP exhibited dose-dependent cytotoxicity against PC-3 cells. C61-LNP, as well as C61-LNP + CDDP treatments, caused pro-apoptotic proteomic changes including an increase in cleaved fragments of caspases-3 and -9 consistent with caspase activation as well as an improvement in the anti-apoptotic Bcl2 and Bax levels. The combination of C61-LNP and CDDP changed in alterations of the cell cycle regulatory proteins p53, p21, p27, cyclin D1 and cyclin E levels. C61-LNP exhibited cytotoxicity against the castration-resistant prostate cancer cell line PC3. It also caused alterations in expression levels of regulatory proteins involved in apoptosis and cell cycle regulation and these effects were not abrogated by the standard chemotherapy drug CDDP. We are planning to further develop C61-LNP as a selective spleen tyrosine kinase inhibitor as part of a multi-modality treatment strategy for advanced/metastatic castration-resistant prostate cancer. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.