The Novel Combination of Nitroxoline and PD-1 Blockade, Exerts a Potent Antitumor Effect in a Mouse Model of Prostate Cancer

• Published in: International journal of biological sciences 2019-01, Vol.15 (5), p.919-928
• Main Authors: Xu, Naijin, Huang, Linglong, Li, Xiezhao, Watanabe, Masami, Li, Chaoming, Xu, Abai, Liu, Chunxiao, Li, Qiang, Araki, Motoo, Wada, Koichiro, Nasu, Yasutomo, Huang, Peng
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Anticancer properties; Antigens; Antitumor activity; Apoptosis; Bcl-2 protein; Bcl-x protein; Bioluminescence; CD44 antigen; CD8 antigen; Cell Cycle - drug effects; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Disease Models, Animal; Drug Synergism; Flow Cytometry; Fluorescence; Humans; Immunity; Immunohistochemistry; Immunological memory; Immunotherapy; Kinases; L-selectin; Lymphocytes; Lymphocytes T; Male; Memory cells; Mice; Mice, Inbred C57BL; Nitroquinolines - therapeutic use; PD-1 protein; PD-L1 protein; Peripheral blood; Prostate cancer; Prostate-specific antigen; Prostatic Neoplasms - drug therapy; Research Paper; Strategy; Tumors; Viability
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.32259

Programmed cell death protein 1 (PD-1) blockade is a promising therapeutic strategy against prostate cancer. Nitroxoline has been found to have effective anticancer properties in several cancer types. We investigated the efficacy of a combination therapy involving nitroxoline and PD-1 blockade in a prostate cancer mouse model. In our analysis we found that nitroxoline inhibited the viability and proliferation of the mouse prostate cancer cell line RM9-Luc-PSA. Additionally, nitroxoline downregulated the expressions of phospho-PI3 kinase, phospho-Akt (Thr308), phospho-Akt (Ser473), phospho-GSK-3β, Bcl-2, and Bcl-xL. Nitroxoline also downregulated programmed death-ligand 1 (PD-L1) expression levels in prostate cancer cell line and tumor tissue. In our murine prostate cancer orthotopic model, nitroxoline plus PD-1 blockade synergistically suppressed tumor growth when compared with nitroxoline or PD-1 blockade alone, leading to reductions in tumor weight, bioluminescence tumor signals, and serum prostate-specific antigen levels. Furthermore, fluorescence-activated cell sorting analysis showed that the combination strategy significantly enhanced antitumor immunity by increasing CD44 CD62L CD8 memory T cell numbers and reducing myeloid-derived suppressor cell numbers in peripheral blood. In conclusion, our findings suggest that nitroxoline plus PD-1 blockade may be a promising treatment strategy in patients with prostate cancer.