Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition
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 a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-04-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323171630372X |
| _version_ | 1828417320984248320 |
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| author | Anfernee Kai-Wing Tse 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 Zhi-Ling Yu |
| author_facet | Anfernee Kai-Wing Tse 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 Zhi-Ling Yu |
| author_sort | Anfernee Kai-Wing Tse |
| collection | DOAJ |
| description | 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. Keywords: Melanoma, Reactive oxygen species, IKKβ, Nitrosourea |
| first_indexed | 2024-12-10T14:18:23Z |
| format | Article |
| id | doaj.art-dfaacdd1929340358f005403dd74bf86 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-10T14:18:23Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-dfaacdd1929340358f005403dd74bf862022-12-22T01:45:17ZengElsevierRedox Biology2213-23172017-04-0111562576Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibitionAnfernee Kai-Wing Tse0Ying-Jie Chen1Xiu-Qiong Fu2Tao Su3Ting Li4Hui Guo5Pei-Li Zhu6Hiu-Yee Kwan7Brian Chi-Yan Cheng8Hui-Hui Cao9Sally Kin-Wah Lee10Wang-Fun Fong11Zhi-Ling Yu12Corresponding authors.; Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCenter for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongCorresponding authors.; Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong KongNitrosourea 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. Keywords: Melanoma, Reactive oxygen species, IKKβ, Nitrosoureahttp://www.sciencedirect.com/science/article/pii/S221323171630372X |
| spellingShingle | Anfernee Kai-Wing Tse 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 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 |
| title | Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition |
| title_full | Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition |
| title_fullStr | Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition |
| title_full_unstemmed | Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition |
| title_short | Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition |
| title_sort | sensitization of melanoma cells to alkylating agent induced dna damage and cell death via orchestrating oxidative stress and ikkβ inhibition |
| url | http://www.sciencedirect.com/science/article/pii/S221323171630372X |
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