Journal Article

A Lipid‐Sensitive Spider Peptide Toxin Exhibits Selective Anti‐Leukemia Efficacy through Multimodal Mechanisms

Zhang, Peng, Wen, Yuhan, Li, Fengjiao, Luo, Wu, Zhang, Zixin, Nie, Yueqi, Yi, Yan, Wu, Kun, Sang, Longkang, Liu, Zhonghua, Zeng, Youlin, Lv, Mingchong, Wang, Lingxiang, Zhu, Jiaoyue, Ding, Changhao, Ding, Xiaofeng, Liu, Xiaofeng

2024

Overview

Anti‐cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin‐I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin‐I, which can self‐assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin‐I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin‐I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K‐AKT‐mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin‐I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin‐I can provide new insights into the mechanism of ACPs, and Lycosin‐I, which is characterized by high potency and specificity, can be a promising lead for the development of anti‐leukemia drugs. This study demonstrates a multimodal mechanism of spider toxin Lycosin‐I, which exhibits selective and effective treatment of leukemia. Lycosin‐I exhibits membrane lysis, particularly at high concentrations and triggers apoptosis, cell cycle arrest and ferroptosis by suppressing PI3K‐AKT‐mTOR signaling pathway. These findings deepen the understanding of the inhibitory mechanisms of anticancer peptides and Lycosin‐I can be a promising lead for leukemia therapy.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Animals / anticancer peptide / Antimicrobial Cationic Peptides / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Cancer therapies / Cell cycle / cell cycle arrest / Cell death / Cell growth / Cell Line, Tumor / Chemotherapy / Disease Models, Animal / Drug resistance / Ferroptosis / Humans / K562 Cells / Leukemia / Leukemia - drug therapy / Lipids / Lymphocytes / Membranes / Mice / Mice, Nude / Microscopy / Morphology / Peptides / Peptides - pharmacology / PI3K‐AKT‐mTOR signaling pathway / Proteins / Signal Transduction - drug effects / Spider Venoms - chemistry / Spider Venoms - pharmacology / Xenograft Model Antitumor Assays