Cepharanthine as a Potential Novel Tumor-Regional Therapy in Treating Cutaneous Melanoma: Altering the Expression of Cathepsin B, Tumor Suppressor Genes and Autophagy-Related Proteins.

Wei Lai,Yang Xie,Yue Zheng,Mengran Peng,Yufang Liu,Qingfang Xu,Yunfen Huang,Yao Lin

doi:10.3389/fbioe.2020.601969

Abstract

The incidence of primary cutaneous melanoma continues to increase annually and is one of the most aggressive malignancies in humans and need to develop more novel non-surgical therapies. Autophagy and cathepsin B targeted therapy was reported to improve melanoma treatment. Cepharanthine (CEP), a natural alkaloid extracted from the genus Cephalophyllum has been reported to have the function of inhibiting cancers. We found that CEP inhibited human primary cutaneous melanoma cells viability and proliferation in 24 h in vitro, and topical application or intra-tumoral injection of CEP decreased the growth of cutaneous melanoma in mice within 4 weeks. CEP preparations below 50% concentration did not induce skin irritation and allergy reaction on human skin in vivo. Primary cutaneous melanoma cells incubated with CEP, the expression of cathepsin B was decreased and the LC3-I and LC3-II expression changed in a dose-dependent manner, while p53, p21Cip1p, and p16Inka gene expression was up-regulated. We demonstrated the effects of CEP as a novel tumor-regional therapy for cutaneous melanoma and provided a preliminary research basis for future clinical treatment researches and the exploration of integrated treatments with systemic therapy, radiotherapy, and surgery for human primary cutaneous melanoma.

Highlights

The incidence of primary cutaneous melanoma continues to increase annually and is one of the most aggressive malignancies in humans
Cepharanthine was purchased from Shiji-Aoke (Beijing, China), cell counting kit-8 was bought from APExBio (Houston, TX, United States), DMEM, penicillin, streptomycin, fetal bovine serum (FBS) and PBS were obtained from Gibco Life Technologies (Grand Island, NY, United States)
Melanoma cells incubated with 200 ug/L cathepsin B for 24 h, the total apoptotic value of melanoma cells was decreased from 3.82 ± 0.12 to 3.45 ± 0.09% (P = 0.03) (Figure 2A)

Summary

Introduction

The incidence of primary cutaneous melanoma continues to increase annually and is one of the most aggressive malignancies in humans. Primary cutaneous melanomas arise from melanocytes and are insensitive to conventional radiotherapy and systemic chemotherapy. The treatment of primary cutaneous melanoma included surgical excision (such as Mohs micrographic surgery) and non-surgical treatments (such as topical imiquimod and radiation therapy). The most appropriate treatment time for PD-1/PD-L1 or MAPK inhibition is unclear, and Cepharanthine Inhibit Primary Cutaneous Melanoma its chronic cutaneous and systemic toxicity may receive more attention (Swetter et al, 2019). More novel non-surgical therapies need to be developed. There is a need to investigate and develop more effective and less side-effect therapies and formulations for primary cutaneous melanoma treatment

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Conclusion