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Sources of Funding: Pearl River Nova Program of Guangzhou (No. 2013J2200044); and the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. KAKENHI 25861425, 15K20093).

Introduction

Immune checkpoint inhibitors-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development. Lycorine, an alkaloid extracted from plants in the Amaryllidaceae family, which showed a strong anticancer effect by inducing cell lysis of various carcinomas. This study investigated the effectiveness of a combination therapy of lycorine and anti-CTLA-4 in a mouse model of renal cell carcinoma (RCC).

Methods

We investigated the anti-tumor efficacy of lycorine in various RCC cell lines including Caki-1, ACHN, KPK-1 and Renca through XTT proliferation, scratch motility, migration and invasion assays. We also discuss that mechanism underlying this anticancer potential with flow cytometry and western blot. 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 for investigated the combination therapy effect of lycorine and anti-CTLA-4.

Results

We confirmed the anticancer potential of lycorine in vitro as observed time-dependent inhibition in several RCC cell lines. Moreover, lycorine suppressed the migratory and invasive abilities of Renca cells. The possible mechanism underlying this anticancer potential was cell cycle profile arrest. Lycorine and anti-CTLA-4 additively decreased tumor weight, lung metastasis, and luciferin-stained tumor images. Importantly, these effects were dependent on significantly suppressing regulatory T-cells while upregulating effector T-cells.

Conclusions

Herein, as we know, it’s the first report that lycorine in combination with anti-CTLA-4 inhibited orthotopic and metastatic tumors by downregulating Treg, which was accompanied with upregulation of effector T-cells. Our findings suggest and indicate lycorine as a potent candidate for treating RCC and will serve as an excellent aid for developing a better treatment strategy for the use of immune checkpoint inhibitors in RCC.

Funding

Pearl River Nova Program of Guangzhou (No. 2013J2200044); and the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. KAKENHI 25861425, 15K20093).