Novel Frog Skin-Derived Peptide Dermaseptin-PP for Lung Cancer Treatment: In vitro/vivo Evaluation and Anti-tumor Mechanisms Study.

Ziyi Dong,Lei Li,Xinping Xi,Mei Zhou,Xianglong Yu,Tianbao Chen,Li Tan,Haiyan Hu,Yang Lu,Chengbang Ma,Shouying Du,Lei Wang

doi:10.3389/fchem.2020.00476

Abstract

Lung cancer is the major cause of cancer deaths worldwide, and it has the highest incidence and mortality rate of any cancer among men and women in China. The first-line therapy for lung cancer treatment is platinum-based chemotherapy drugs such as cisplatin. However, the application of present chemotherapies is limited by severe side effects, which stimulates the discovery of new drugs with new anti-tumor mechanisms and fewer side effects. Beneficially, many antimicrobial peptides (AMPs) from frog skin have been reported to exhibit potent anti-cancer activities with low toxicity, high selectivity and a low propensity to induce resistance. In this study, we first reported an AMP named Dermaseptin-PP, from a rarely studied frog species, Phyllomedusa palliata. Dermaseptin-PP exhibited selective cytotoxicity on H157, MCF-7, PC-3, and U251 MG cancer cells instead of normal HMEC-1 cells with low hemolytic effect. Furthermore, on subcutaneous H157 tumor model of nude mice, Dermaseptin-PP was found to display potent in vivo anti-tumor activity in a dose-related manner without obvious hepatopulmonary side effects. It is widely accepted that AMPs usually work through a membrane disruptive mode, and the confocal laser microscope observation confirmed that Dermaseptin-PP could destroy H157 cell membranes. Further investigation of mechanisms by flow cytometry assay and immunohistochemical analysis unraveled that Dermaseptin-PP also exerted its anti-tumor activity by inducing H157 cell apoptosis via both endogenous mitochondrial apoptosis pathway and exogenous death receptor apoptosis pathway. Herein, we emphasize that the membrane disrupting and the apoptosis activation effects of Dermaseptin-PP both depend on its concentration. Overall, a novel frog skin-derived AMP, named Dermaseptin-PP, was identified for the first time. It possesses strong antimicrobial activity and effective anti-tumor activity by distinct mechanisms. This study revealed the possibility of Dermaseptin-PP for lung cancer treatment and provided a new perspective for designing novel AMP-based anti-tumor candidates with low risk of cytotoxicity.

Highlights

Cancer has always been a leading cause of human death, which results from the uncontrolled growth and spread of abnormal cells (Gaspar et al, 2013)
The results suggested that Dermaseptin-PP could serve as an amphipathic αhelical structure under membrane-mimic environments so that it could exhibit the strong antimicrobial and anti-tumor effect via a membrane-disrupting action
The results suggested that compared with the model group, the apoptosis rate of H157 cells of tumor sections treated with low, medium, and high dose Dermaseptin-PP groups (4, 6, 8 mM) and the positive drug group (0.7 mM DDP) all increased, reaching 21.21, 25.64, 71.65, and 28.83%, respectively

Summary

Introduction

Cancer has always been a leading cause of human death, which results from the uncontrolled growth and spread of abnormal cells (Gaspar et al, 2013). Non-small-cell lung cancer (NSCLC) accounts for almost 85% of all lung cancers, and most NSCLC patients are in the advanced stages of treatment (Allingham-Hawkins et al, 2010). The therapeutic efficacy of the existing cancer chemotherapies is limited by narrow therapeutic indexes. Cancer chemotherapies are lethal to both cancer cells and healthy cells undergoing rapid proliferation and may suppress the immune system, causing severe side effects (Arpornsuwan et al, 2014). Drug resistance in cancer and insufficient drug concentration in tumor areas severely limit the efficacy of chemotherapy drugs. New therapeutic anti-tumor drugs with new mechanisms and fewer side effects need to be constantly searched for (Moxley and McMeekin, 2010)

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Conclusion