Novel chloroquine derivative suppresses melanoma cell growth by DNA damage through increasing ROS levels.

Abstract

Melanoma is a fatal cancer with a significant feature of resistance to traditional chemotherapeutic drugs and radiotherapy. A mutation in the kinase BRAF is observed in more than 66% of metastatic melanoma cases. Therefore, there is an urgent need to develop new BRAF-mutant melanoma inhibitors. High-dose chloroquine has been reported to have antitumour effects, but it often induces dose-limiting toxicity. In this study, a series of chloroquine derivatives were synthesized, and lj-2-66 had the best activity and was selected for further investigation. Furthermore, the anti-BRAF-mutant melanoma effect and mechanism of this compound were explored. CCK-8 and colony formation assays indicated that lj-2-66 significantly inhibited the proliferation of BRAF-mutant melanoma cells. Flow cytometry revealed that lj-2-66 induced G2/M arrest in melanoma cells and promoted apoptosis. Furthermore, lj-2-66 increased the level of ROS in melanoma cells and induced DNA damage. Interestingly, lj-2-66 also played a similar role in BRAF inhibitor-resistant melanoma cells. In summary, we found a novel chloroquine derivative, lj-2-66, that increased the level of ROS in melanoma cells and induced DNA damage, thus leading to G2/M arrest and apoptosis. These findings indicated that lj-2-66 may become a potential therapeutic drug for melanoma harbouring BRAF mutations.

• Authors: Jiaoduan Li, Jing Long, Jianglin Zhang, Nian Liu, Bei Yan, Ling Tang, Xiang Chen, Cong Peng
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 26 Issue 9 Pg. 2579-2593 (05 2022) ISSN: 1582-4934 [Electronic] England
• PMID: 35332658 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Protein Kinase Inhibitors
• Reactive Oxygen Species
• Chloroquine
• Proto-Oncogene Proteins B-raf

Topics

• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Chloroquine (pharmacology)
• DNA Damage
• Drug Resistance, Neoplasm
• G2 Phase Cell Cycle Checkpoints
• Humans
• Melanoma (drug therapy, genetics, pathology)
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins B-raf (genetics)
• Reactive Oxygen Species