Elsevier

Redox Biology

Volume 11, April 2017, Pages 562-576
Redox Biology

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

https://doi.org/10.1016/j.redox.2017.01.010Get rights and content
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Highlights

  • Oxidative stress and IKKβ inhibition together enhance nitrosourea's cytotoxicity.

  • Increase of ROS augments DNA cross-links generated by nitrosoureas.

  • Inhibition of IKKβ leading to increased DNA damage and cancer cell death.

  • ROS-inducing IKKβ Inhibitor is a potential nitrosourea sensitizing agent for melanoma treatment.

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.

Abbreviations

BRAF
serine/threonine-protein kinase B-Raf
ICL
DNA interstrand crosslink
IKKβ
Inhibitor of nuclear factor kappa-B kinase subunit beta
NAC
N-acetyl cysteine
NF-κB
Nuclear factor kappa B
ROS
Reactive oxygen species

Keywords

Melanoma
Reactive oxygen species
IKKβ
Nitrosourea

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1

These authors contributed equally to this work.