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

Li, Jiaoduan1,2,3,4; Long, Jing1,2,3,4; Zhang, Jianglin5; Liu, Nian1,2,3,4; Yan, Bei1,2,3,4; Tang, Ling1,2,3,4; Chen, Xiang1,2,3,4; Peng, Cong1,2,3,4

2022-03-01

10.1111/jcmm.17260

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE   影响因子和分区

1582-1838

1582-4934

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.

chloroquine derivative DNA damage G2 M arrest and apoptosis melanoma ROS

SCI

英语

其他

Major Projects of International Cooperation and Exchanges NSFC[81620108024] ; Program of Introducing Talents of Discipline to Universities[B20017] ; National Natural Science Foundation of China[81673065,81772917,81974476,82073018,82073458] ; Science and Technology Innovation Program of Hunan Province[2021RC4013]

Cell Biology ; Research & Experimental Medicine

Cell Biology ; Medicine, Research & Experimental

WOS:000772961000001

WILEY

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Cent South Univ, Xiangya Hosp, Dept Dermatol, Changsha, Hunan, Peoples R China
2.Xiangya Hosp, Hunan Key Lab Skin Canc & Psoriasis, Changsha, Peoples R China
3.Xiangya Hosp, Hunan Engn Res Ctr Skin Hlth & Dis, Changsha, Peoples R China
4.Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha, Peoples R China
5.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1,Dept Dermatol,Clin Med Coll 2, Shenzhen, Peoples R China

Li, Jiaoduan,Long, Jing,Zhang, Jianglin,et al. Novel chloroquine derivative suppresses melanoma cell growth by DNA damage through increasing ROS levels[J]. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,2022.

Li, Jiaoduan.,Long, Jing.,Zhang, Jianglin.,Liu, Nian.,Yan, Bei.,...&Peng, Cong.(2022).Novel chloroquine derivative suppresses melanoma cell growth by DNA damage through increasing ROS levels.JOURNAL OF CELLULAR AND MOLECULAR MEDICINE.

Li, Jiaoduan,et al."Novel chloroquine derivative suppresses melanoma cell growth by DNA damage through increasing ROS levels".JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2022).