Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition

Anfernee K W TSE*, Ying Jie Chen, Xiuqiong FU, Tao Su, Ting Li, Hui Guo, Pei Li Zhu, Hiu Yee KWAN, Brian Chi Yan Cheng, Hui Hui Cao, Sally Kin Wah Lee, David W F FONG, Zhiling YU

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)
1 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)562-576
Number of pages15
JournalRedox Biology
Volume11
DOIs
Publication statusPublished - 1 Apr 2017

Scopus Subject Areas

  • Organic Chemistry
  • Clinical Biochemistry

User-Defined Keywords

  • IKKβ
  • Melanoma
  • Nitrosourea
  • Reactive oxygen species

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