Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma
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Xiezhao Li1,2,*, Peng Xu1,2,*, Chongshan Wang1, Naijin Xu2,*, Abai Xu1, Yawen Xu1, Takuya Sadahira2, Motoo Araki2, Koichiro Wada2, Eiji Matsuura3, Masami Watanabe2,4, Junxia Zheng5, Pinghua Sun6, Peng Huang1,2,3, Yasutomo Nasu2,3,4, Chunxiao Liu1
1Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
2Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
3Okayama Medical Innovation Center, Okayama University, Okayama, Japan
4Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
5Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, China
6Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
*These authors contributed equally to this work and share co-first authorship
Peng Huang, email: [email protected]
Keywords: renal cell carcinoma, anti-CTLA-4, lycorine, immunotherapy, preclinical model
Received: December 21, 2016 Accepted: February 08, 2017 Published: February 19, 2017
Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.
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