B-Raf inhibitor vemurafenib counteracts sulfur mustard-induced epidermal impairment through MAPK/ERK signaling

Abstract

The chemical warfare agent sulfur mustard (SM) causes severe cutaneous lesions characterized by epidermal cell death, apoptosis, and inflammation. At present, the molecular mechanisms underlying SM-induced injury are not well understood, and there is no standard treatment protocol for SM-exposed patients. Here, we conducted a high-content screening of the Food and Drug Administration (FDA)-approved drug library of 1018 compounds against SM injury on an immortal human keratinocyte HaCaT cell line, focusing on cell survival. We found that the B-Raf inhibitor vemurafenib had an apparent therapeutic effect on HaCaT cells and resisted SM toxicity. Other tested B-Raf inhibitors, both type-I (dabrafenib and encorafenib) and type-II (RAF265 and AZ628), also exhibited potent therapeutic effects on SM-exposed HaCaT cells. Both SM and vemurafenib triggered extracellular signal-related kinase (ERK) activation. The therapeutic effect of vemurafenib in HaCaT cells during SM injury was ERK-dependent, indicating a specific role of ERK in keratinocyte regulatory mechanisms. Furthermore, vemurafenib partially improved cutaneous damage in a mouse ear vesicant model. Collectively, our results provide evidence that the B-Raf inhibitor vemurafenib is a potential therapeutic agent against SM injury, and oncogenic B-Raf might be an exciting new therapeutic target following exposure to mustard vesicating agents.

Keywords:

• Vemurafenib
• B-Raf
• sulfur mustard
• ERK
• MAPK
• skin injury

Acknowledgements

The authors thank Zhang Xiaorui (Beijing Institute of Pharmacology & Toxicology) for the technical assistance.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All experiments were conducted according to the NHI Guide for the Care and Use of Laboratory Animals and approved by the Bioethics Committee of the Beijing Institute of Pharmacology and Toxicology (no. 80-23). The study does not involve any experiments with human participants.

Authors contributions

Zhiyong Xiao: conceptualization, methodology, visualization, writing-original draft. Feng Liu: investigation, resources. Junping Cheng: investigation. Ying Wang: investigation. Wenxia Zhou: supervision, validation, funding acquisition. Yongxiang Zhang: supervision, funding acquisition.

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

This work was supported by the Ministry of Science and Technology of China [Grant Nos. 2013ZX09J13103-01B, 2016ZX09J16104-001, and 2019ZX09J19101].