New designed pH-responsive histidine-rich peptides with antitumor activity

Autor:	Yun Zhang, Jingman Ni, Hui Liu, Chao Zhong, Sanhu Gou, Hexin Bao, Linlin Chang, Jia Yao
Rok vydání:	2021
Předmět:	Cell cycle checkpoint Pharmaceutical Science Antineoplastic Agents Peptide 02 engineering and technology KB Cells 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Neoplasms Humans Histidine chemistry.chemical_classification L-Lactate Dehydrogenase Chemistry Cell Cycle Checkpoints Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology In vitro Amino acid Biochemistry Apoptosis 030220 oncology & carcinogenesis MCF-7 Cells Leucine Peptides 0210 nano-technology Intracellular HeLa Cells
Zdroj:	Journal of Drug Targeting. 29:651-659
ISSN:	1029-2330 1061-186X
DOI:	10.1080/1061186x.2021.1873351
Popis:	Anticancer peptides have received widespread attention as alternative antitumor therapeutics due to their unique action mode. However, the systemic toxicity hampers their successful utilisation in tumour therapy. Here, the tumour acidic environment was used as a trigger to design a series of histidine-rich peptides by optimising the distribution of histidine and leucine based on the amphiphilic peptide LK, in hoping to achieve desirable acid-activate anticancer peptides. Among all the obtained peptides, L9H5-1 showed enhanced antitumor activity at acidic pH concomitant with low toxicity at normal pH, exhibiting excellent pH-response. At acidic pH, protonated L9H5-1 could rapidly kill tumour cells by efficient membrane disruption as evidenced by in vitro experiments, including increasing intracellular PI uptake and LDH release, dramatic membrane damage and increase of later apoptotic/necrotic cells. Moreover, no cell cycle arrest was observed after treated with L9H5-1. Interestingly, this study found that the new peptides with the same number of histidines and leucines displayed different pH-dependent antitumor activity, indicating that the position of amino acid alteration is extremely important for the design of acid-activated histidine-rich peptides. In short, our work provides a new avenue to develop new acid-activated anticancer peptides as promising antitumor drugs with high efficiency and good selectivity.
Databáze:	OpenAIRE
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