Nitidine chloride induces S phase cell cycle arrest and mitochondria-dependent apoptosis in HaCaT cells and ameliorates skin lesions in psoriasis-like mouse models.

Abstract

Psoriasis is a common dermatosis causing considerable inconvenience to 4% of the general population. Traditional psoriasis treatments often cause side effects, drug resistance and complications, necessitating development of safer and more effective treatments. In this study, we screened over 600 natural compounds to identify viability inhibitors of human HaCaT keratinocytes cultured in vitro. The results showed that nitidine chloride was a highly effective inhibitor. Further studies revealed that nitidine chloride inhibited HaCaT proliferation and induced S phase cell cycle arrest; these effects were associated with reduced DNA synthesis, decreased Ki67, cyclin A, and cyclin D1 levels, and increased p53 protein expression. Nitidine chloride also significantly downregulated bcl-2 and upregulated bax, cleaved caspase-9 and cleaved caspase-3. Mechanistic studies revealed that nitidine chloride-induced apoptosis involved the c-Jun N-terminal kinase (JNK) pathway. More importantly, in 12-O-tetradecanoyl-phorbol-13-acetate (TPA)- and imiquimod (IMQ)-induced epidermal hyperplasia and inflammation models, nitidine chloride inhibited topical edema in mouse ear and back skin, substantially reducing tissue thickness and weight. In some cases, nitidine chloride also ameliorated conditions caused by TPA and IMQ, such as angiogenesis and infiltration of large numbers of inflammatory cells around blood vessels. Additionally, nitidine chloride inhibited the expression of various proinflammatory cytokines in the two animal models. In conclusion, our results are the first to demonstrate that nitidine chloride inhibits the proliferation of HaCaT cells, induces apoptosis partly via the JNK signaling pathway in vitro and ameliorates skin lesions and inflammation in vivo, making it an appropriate candidate for psoriasis treatment.

• Authors: Xiao-Guang Yang, Bo-Wen Jiang, Qian-Qian Jing, Wen-Juan Li, Li-Ping Tan, Yong-Li Bao, Zhen-Bo Song, Chun-Lei Yu, Lei Liu, Yi-Chun Liu, Yu-Xin Li
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 863 Pg. 172680 (Nov 15 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 31563649 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Benzophenanthridines
• nitidine
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Benzophenanthridines (pharmacology, therapeutic use)
• Cell Line
• Cell Survival (drug effects)
• Disease Models, Animal
• Female
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Keratinocytes (drug effects, pathology)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mice, Inbred BALB C
• Mitochondria (drug effects, pathology)
• Psoriasis (drug therapy, metabolism, pathology)
• S Phase Cell Cycle Checkpoints (drug effects)
• Skin (drug effects, pathology)