Low doses of niclosamide and quinacrine combination yields synergistic effect in melanoma via activating autophagy-mediated p53-dependent apoptosis

Xuan Zheng; Jianyun Zhang; Shuangting Li; Xiaolei Gao; Yixin Zhang; Meng Wang; Liying Dong; Liangjie Sun; Na Zhao; Zeyun Ma; Chong Ding; Yixiang Wang

doi:10.1016/j.tranon.2022.101425

Low doses of niclosamide and quinacrine combination yields synergistic effect in melanoma via activating autophagy-mediated p53-dependent apoptosis

Transl Oncol. 2022 Jul:21:101425. doi: 10.1016/j.tranon.2022.101425. Epub 2022 Apr 20.

Authors

Xuan Zheng¹, Jianyun Zhang², Shuangting Li³, Xiaolei Gao¹, Yixin Zhang¹, Meng Wang⁴, Liying Dong¹, Liangjie Sun¹, Na Zhao⁵, Zeyun Ma⁶, Chong Ding⁷, Yixiang Wang⁸

Affiliations

¹ Central Laboratory, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China; Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
² Department of Oral Pathology, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
³ Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan 030001, China.
⁴ Central Laboratory, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China.
⁵ Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USA; Shanghai Stomatological Hospital, Fudan University, No.356, Beijing Road East, Shanghai, China.
⁶ Department of VIP Service, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China. Electronic address: kqmzy101@sina.com.
⁷ Central Laboratory, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China. Electronic address: idtbbsb@163.com.
⁸ Central Laboratory, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China; Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China. Electronic address: kqwangyx@bjmu.edu.cn.

Abstract

Malignant melanoma is a highly aggressive, malignant, and drug-resistant tumor. It lacks an efficient treatment approach. In this study, we developed a novel anti-melanoma strategy by using anti-tapeworm drug niclosamide and anti-malarial drug quinacrine, and investigated the molecular mechanism by in vitro and in vivo assays. Meanwhile, other types of tumor cells, immortalized epithelial cells and bone marrow mesenchymal stem cells were used to evaluate the universal role of anti-cancer and safety of the strategy. The results showed, briefly, an exposure to niclosamide and quinacrine led to an increased apoptosis-related protein p53, cleaved caspase-3 and cleaved PARP and autophagy-related protein LC3B expression, and a decreased expression of autophagy-related protein p62, finally leading to cell apoptosis and autophage. After inhibiting autophagy by Baf-A1, flow cytometry and western blot showed that the expression of apoptosis-related proteins was down-regulated and the number of apoptotic cells decreased. Subsequently, in the siRNA-mediated p53 knockdown cells, the expression of apoptosis-related proteins and the number of apoptotic cells were also reduced, while the expression of autophagy-related proteins including LC3B, p62 did not change significantly. To sum up, we developed a new, safe strategy for melanoma treatment by using low doses of niclosamide and quinacrine to treat melanoma; and found a novel mechanism by which the combination application of low doses of niclosamide and quinacrine exerts an efficient anti-melanoma effect through activation of autophagy-mediated p53-dependent apoptosis. The novel strategy was verified to exert a universal anti-cancer role in other types of cancer.

Keywords: Apoptosis; Autophagy; Melanoma; Niclosamide; Quinacrine.