The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus  

作　　者：Hao Yin Xi-tong Chen Qiao-na Chi Yan-nan Ma Xing-yan Fu Shan-shan Du Yun-kun Qi Ke-wei Wang 

机构地区：[1]Department of Pharmacology,School of Pharmacy,Qingdao University Medical College,Qingdao University,#1 Ningde Road,Qingdao,266073,China [2]Institute of Innovative Drugs,Qingdao University,38 Dengzhou Road,Qingdao,266021,China [3]Department of Medicinal Chemistry,School of Pharmacy,Qingdao University Medical College,Qingdao University,#1 Ningde Road,Qingdao,266073,China [4]College of Chemical Engineering,Qingdao University of Science and Technology,Qingdao,266042,China

出　　处：《Acta Pharmacologica Sinica》2023年第1期201-210,共10页中国药理学报（英文版）

基　　金：This project was supported by grants from the National Natural Science Foundation of China (81973299,22177058,82003647);the China Postdoctoral Science Foundation (2020T130332,2019M652307);the Qingdao postdoctoral application research project.

摘　　要：The use of oncolytic peptides with activity against a wide range of cancer entities as a new and promising cancer therapeutic strategy has drawn increasing attention.The oncolytic peptide LTX-315 derived from bovine lactoferricin(LfcinB)was found to be highly effective against suspension cancer cells,but not adherent cancer cells.In this study,we tactically fused LTX-315 with rhodamine B through a hybridization strategy to design and synthesize a series of nucleus-targeting hybrid peptides and evaluated their activity against adherent cancer cells.Thus,four hybrid peptides,NTP-212,NTP-217,NTP-223 and NTP-385,were synthesized.These hybrid peptides enhanced the anticancer activity of LTX-315 in a panel of adherent cancer cell lines by 2.4-to 37.5-fold.In model mice bearing B16-F10 melanoma xenografts,injection of NTP-385(0.5 mg per mouse for 3 consecutive days)induced almost complete regression of melanoma,prolonged the median survival time and increased the overall survival.Notably,the administered dose of NTP-385 was only half the effective dose of LTX-315.We further revealed that unlike LTX-315,which targets the mitochondria,NTP-385 disrupted the nuclear membrane and accumulated in the nucleus,resulting in the transfer of a substantial amount of reactive oxygen species(ROS)from the cytoplasm to the nucleus through the fragmented nuclear membrane.This ultimately led to DNA double-strand break(DSB)-mediated intrinsic apoptosis.In conclusion,this study demonstrates that hybrid peptides obtained from the fusion of LTX-315 and rhodamine B enhance anti-adherent cancer cell activity by targeting the nucleus and triggering DNA DSB-mediated intrinsic apoptosis.This study also provides an advantageous reference for nucleus-targeting peptide modification.

关 键 词：oncolytic peptides LTX-315 rhodamine B hybridization strategy MELANOMA ROS DNA double-strand break intrinsic apoptosis nucleus-targetingpeptides 

分 类 号：R73[医药卫生—肿瘤]