Novel chloroquine derivative suppresses melanoma cell growth by DNA damage through increasing ROS levels.
Jiaoduan LiJing LongJianglin ZhangNian LiuBei YanLing TangXiang ChenCong PengPublished in: Journal of cellular and molecular medicine (2022)
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.
Keyphrases
- dna damage
- wild type
- oxidative stress
- diabetic rats
- metastatic colorectal cancer
- cell death
- dna repair
- high glucose
- high dose
- flow cytometry
- skin cancer
- drug induced
- signaling pathway
- plasmodium falciparum
- endoplasmic reticulum stress
- cell cycle arrest
- reactive oxygen species
- machine learning
- low dose
- basal cell carcinoma
- squamous cell carcinoma
- young adults
- high throughput
- emergency department
- early stage
- single cell
- squamous cell
- radiation induced
- rectal cancer
- cell proliferation
- adverse drug
- childhood cancer