School of Chinese Medicine
Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKβ inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKβ inhibitor which enhanced the function of nitrosoureas. Elevated ROS level results in increased DNA crosslink efficiency triggered by nitrosoureas and IKKβ inhibition enhances DNA damage signals and sensitizes nitrosourea-induced cell death. Using xenograft mouse model, we confirm that ROS-inducing IKKβ inhibitor cooperates with nitrosourea to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new direction in nitrosourea treatment, and reveal that the combination of ROS-inducing IKKβ inhibitors with nitrosoureas can be potentially exploited for melanoma therapy.
Melanoma, Reactive oxygen species, IKKβ, Nitrosourea
Source Publication Title
© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
This work was partially supported by Food and Health Bureau of Hong Kong (HMRF 11122441), Hong Kong Baptist University (FRG2/13–14/046 and FRG2/14–15/104), National Natural Science Foundation of China (81673649), Science, Technology and Innovation Commission of Shenzhen (JCYJ20140807091945050, JCYJ20150630164505508 and JCYJ20160229210327924); Research Grants Council of Hong Kong (12125116); Guangdong Natural Science Foundation (2016A030313007); and Consun Pharmaceutical Group Limited.
Link to Publisher's Edition
Tse, Anfernee Kai-Wing, Ying-Jie Chen, Xiu-Qiong Fu, Tao Su, Ting Li, Hui Guo, Pei-Li Zhu, Hiu-Yee Kwan, Brian Chi-Yan Cheng, Hui-Hui Cao, Sally Kin-Wah Lee, Wang-Fun Fong, and Zhi-Ling Yu. "Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition." Redox Biology 11 (2017): 562-576.
Additional FilesJA-5007-29370_suppl.docx (1014 kB)
Appendix A. Supplementary material