Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma

Xiezhao Li, Peng Xu, Chongshan Wang, Naijin Xu, Abai Xu, Yawen Xu, Takuya Sadahira, Motoo Araki, Koichiro Wada, Eiji Matsuura, Masami Watanabe, Junxia Zheng, Pinghua Sun, Peng Huang, Yasutomo Nasu, Chunxiao Liu

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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, luciferaseexpressing 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.

Original languageEnglish
Pages (from-to)21177-21186
Number of pages10
JournalOncotarget
Volume8
Issue number13
DOIs
Publication statusPublished - 2017

Fingerprint

Growth Inhibitors
Cytotoxic T-Lymphocytes
Renal Cell Carcinoma
Proteins
Regulatory T-Lymphocytes
Neoplasms
T-Lymphocytes
Lung
Therapeutics
Cell Cycle Checkpoints
Tumor Burden
Alkaloids
lycorine
Clinical Trials
Staining and Labeling
Neoplasm Metastasis
Kidney
Cell Line
Control Groups
Thomsen-Friedenreich antibodies

Keywords

  • Anti-CTLA-4
  • Immunotherapy
  • Lycorine
  • Preclinical model
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Oncology

Cite this

Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma. / Li, Xiezhao; Xu, Peng; Wang, Chongshan; Xu, Naijin; Xu, Abai; Xu, Yawen; Sadahira, Takuya; Araki, Motoo; Wada, Koichiro; Matsuura, Eiji; Watanabe, Masami; Zheng, Junxia; Sun, Pinghua; Huang, Peng; Nasu, Yasutomo; Liu, Chunxiao.

In: Oncotarget, Vol. 8, No. 13, 2017, p. 21177-21186.

Research output: Contribution to journalArticle

Li, Xiezhao ; Xu, Peng ; Wang, Chongshan ; Xu, Naijin ; Xu, Abai ; Xu, Yawen ; Sadahira, Takuya ; Araki, Motoo ; Wada, Koichiro ; Matsuura, Eiji ; Watanabe, Masami ; Zheng, Junxia ; Sun, Pinghua ; Huang, Peng ; Nasu, Yasutomo ; Liu, Chunxiao. / Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma. In: Oncotarget. 2017 ; Vol. 8, No. 13. pp. 21177-21186.
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abstract = "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, luciferaseexpressing 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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AU - Xu, Naijin

AU - Xu, Abai

AU - Xu, Yawen

AU - Sadahira, Takuya

AU - Araki, Motoo

AU - Wada, Koichiro

AU - Matsuura, Eiji

AU - Watanabe, Masami

AU - Zheng, Junxia

AU - Sun, Pinghua

AU - Huang, Peng

AU - Nasu, Yasutomo

AU - Liu, Chunxiao

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AB - 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, luciferaseexpressing 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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