Multikinase inhibitor sorafenib induces skin toxicities in tumor-bearing mice

  • Aiping Tian
  • Haizhen Lu
  • Jingxuan Zhang
  • Shilan Fu
  • Zaoli Jiang
  • Wing Lam
  • Fulan Guan
  • Linlin Chen
  • Li Feng
  • Yungchi Cheng
Original Article
  • 12 Downloads

Abstract

Objectives

To investigate the pathologic changes and pathogenesis of multikinase inhibitor (MKI)-induced skin lesions in an animal model.

Methods

Tumor-bearing nude mice and BDF1 mice were treated with different doses (30–240 mg/kg, Bid) of sorafenib. The pathology and severity of the skin lesions was assessed and evaluated. The concentration of sorafenib in the skin was also determined.

Results

Sorafenib transiently induced skin rash at high doses (120–240 mg/kg). The induced skin lesions had pathological manifestations resembling the observations in human patients. The skin of mice treated with sorafenib had significantly increased pathological scores and thickness of the stratum spinosum compared with the control, and induced more severe cutaneous lesions in nude mice than in BDF1 mice. The severity of skin lesions was correlated with the local concentration of sorafenib in the skin, which was significantly higher in nude mice than in BDF1 mice. Sorafenib treatment significantly increased the expression of F4-80, Ly6G, tumor growth factor (TGF)-1β, Smad2/3, α-smooth-muscle actin, and proliferating cell nuclear antigen.

Conclusions

The severity of skin lesions was positively correlated with the concentration of sorafenib in the skin. Our results suggested the involvement of the TGF-β1/Smads signaling pathway in the skin reaction induced by MKIs.

Keywords

Multikinase inhibitor Sorafenib Skin toxicities Pathology Pathogenesis Animal model 

Notes

Acknowledgements

This study was funded by the Ten Diseases/Ten Drugs Research and Development Program, sponsored by the Beijing Municipal Science and Technology Commission (Project# Z171100001717019).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Aiping Tian
    • 1
  • Haizhen Lu
    • 2
  • Jingxuan Zhang
    • 3
  • Shilan Fu
    • 4
  • Zaoli Jiang
    • 5
  • Wing Lam
    • 5
  • Fulan Guan
    • 5
  • Linlin Chen
    • 6
  • Li Feng
    • 1
  • Yungchi Cheng
    • 5
  1. 1.Department of Traditional Chinese Medicine, National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  2. 2.Department of Pathology, National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  3. 3.Beijing Researh Insititute of Chinese MedicineBeijing University of Chinese MedicineBeijingChina
  4. 4.Department of Cancer Epidemiology, National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  5. 5.Department of PharmacologyYale University School of MedicineNew HavenUSA
  6. 6.Key Laboratory of Traditional Chinese Medicine Resource and Compound Prescription, Ministry of EducationHubei University of Chinese MedicineWuhanChina

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