Int J Biol Sci 2019; 15(5):919-928. doi:10.7150/ijbs.32259

Research Paper

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

Naijin Xu1*, Linglong Huang2, Xiezhao Li1,3*, Masami Watanabe1,4, Chaoming Li1,2, Abai Xu2, Chunxiao Liu2, Qiang Li5, Motoo Araki1, Koichiro Wada1, Yasutomo Nasu1,4,6, Peng Huang 1,2,6 ✉

1. Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
2. Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou; China
3. Department of Urology, The 5 th Hospital of Guangzhou Medical University, Guangzhou; China
4. Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
5. Jiangsu Asieris Pharmaceuticals Co., Ltd., Taizhou, Jiangsu 225300, P.R. China
6. Okayama Medical Innovation Center, Okayama University, Okayama, Japan
*These authors contributed to the work equally and should be regarded as co-first authors.

Abstract

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 in vitro 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.

Keywords: prostate cancer, immunotherapy, chemotherapy, preclinical model, combination therapy

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How to cite this article:
Xu N, Huang L, Li X, Watanabe M, Li C, Xu A, Liu C, Li Q, Araki M, Wada K, Nasu Y, Huang P. The Novel Combination of Nitroxoline and PD-1 Blockade, Exerts a Potent Antitumor Effect in a Mouse Model of Prostate Cancer. Int J Biol Sci 2019; 15(5):919-928. doi:10.7150/ijbs.32259. Available from http://www.ijbs.com/v15p0919.htm