title: Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition.
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.
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong. Electronic address: anfernee@hkbu.edu.hk.
authors.forename: Anfernee Kai-Wing
authors.initials: AK
authors.lastname: Tse
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Xiu-Qiong
authors.initials: XQ
authors.lastname: Fu
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Pei-Li
authors.initials: PL
authors.lastname: Zhu
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Hiu-Yee
authors.initials: HY
authors.lastname: Kwan
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Brian Chi-Yan
authors.initials: BC
authors.lastname: Cheng
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Cao
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Sally Kin-Wah
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Wang-Fun
authors.initials: WF
authors.lastname: Fong
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong. Electronic address: zlyu@hkbu.edu.hk.
authors.forename: Zhi-Ling
authors.initials: ZL
authors.lastname: Yu
mesh_terms: D000477:Alkylating Agents / Q000008:administration & dosage; D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009607:Nitrosourea Compounds / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects*; D013876:Thiophenes / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000477:Alkylating Agents; D009607:Nitrosourea Compounds; C477523:SC 514; D013876:Thiophenes; D051550:I-kappa B Kinase
keywords: IKKβ; Melanoma; Nitrosourea; Reactive oxygen species