Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 6, pp 1025–1033 | Cite as

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



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


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.


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.


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.


Multikinase inhibitor Sorafenib Skin toxicities Pathology Pathogenesis Animal model 



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.


  1. 1.
    Chanprapaph K, Rutnin S, Vachiramon V (2016) Multikinase inhibitor-induced hand-foot skin reaction: a review of clinical presentation, pathogenesis, and management. Am J Clin Dermatol 17:387–402CrossRefPubMedGoogle Scholar
  2. 2.
    Yasui H, Imai K (2008) Novel molecular-targeted therapeutics for the treatment of cancer. Anticancer Agents Med Chem 8:470–480CrossRefPubMedGoogle Scholar
  3. 3.
    Massey PR, Okman JS, Wilkerson J, Cowen EW (2015) Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature. Support Care Cancer 23:1827–1835CrossRefPubMedGoogle Scholar
  4. 4.
    Abdel-Rahman O, Lamarca A (2017) Development of sorafenib-related side effects in patients diagnosed with advanced hepatocellular carcinoma treated with sorafenib: a systematic-review and meta-analysis of the impact on survival. Expert Rev Gastroenterol Hepatol 11:75–83CrossRefPubMedGoogle Scholar
  5. 5.
    Kontzias A, Laurence A, Gadina M, O’Shea JJ (2012) Kinase inhibitors in the treatment of immune-mediated disease. F1000 Med Rep 4:5CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Robert C, Sibaud V, Mateus C, Cherpelis BS (2012) Advances in the management of cutaneous toxicities of targeted therapies. Semin Oncol 39:227–240CrossRefPubMedGoogle Scholar
  7. 7.
    Dy GK, Adjei AA (2013) Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin 63:249–279CrossRefPubMedGoogle Scholar
  8. 8.
    Ulrich J, Hartmann JT, Dorr W, Ugurel S (2008) Skin toxicity of anti-cancer therapy. J Dtsch Dermatol Ges 6:959–977CrossRefPubMedGoogle Scholar
  9. 9.
    Lacouture ME, Wu S, Robert C et al (2008) Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 13:1001–1011CrossRefPubMedGoogle Scholar
  10. 10.
    Yang CH, Lin WC, Chuang CK, Chang YC, Pang ST, Lin YC (2008) Hand-foot skin reaction in patients treated with sorafenib:a clinicopathological study ofcutaneous manifestations dueto multitargeted kinase inhibitor therapy. Br J Dermatol 158:592–596CrossRefPubMedGoogle Scholar
  11. 11.
    Lipworth AD, Robert C, Zhu AX (2009) Hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia): focus on sorafenib and sunitinib. Oncology 77:257–271CrossRefPubMedGoogle Scholar
  12. 12.
    Ikeda M, Fujita T, Mii S, Tanabe K, Tabata K, Matsumoto K, Satoh T, Iwamura M (2012) Erythema multiforme induced by sorafenib for metastatic renal cell carcinoma. Jpn J Clin Oncol 42:820–824CrossRefPubMedGoogle Scholar
  13. 13.
    Autier J, Escudier B, Wechsler J, Spatz A, Robert C (2008) Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol 144:886–892CrossRefPubMedGoogle Scholar
  14. 14.
    Gutzmer R, Wollenberg A, Ugurel S, Homey B, Ganser A, Kapp A (2012) Cutaneous side effects of new antitumor drugs: clinical features and management. Dtsch Arztebl Int 109:133–140PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kuczynski EA, Lee CR, Man S, Chen E, Kerbel RS (2015) Effects of sorafenib dose on acquired reversible resistance and toxicity in hepatocellular carcinoma. Cancer Res 75:2510–2519CrossRefPubMedGoogle Scholar
  16. 16.
    Xia JX, Mei XL, Zhu WJ, Li X, Jin XH, Mou Y, Yu K, Wang YY, Li FQ (2014) Effect of FGF10 monoclonal antibody on psoriasis-like model in guinea pigs. Int J Clin Exp Pathol 7:2219–2228PubMedPubMedCentralGoogle Scholar
  17. 17.
    Baker BS, Brent L, Valdimarsson H, Powles AV, al-Imara L, Walker M, Fry L (1992) Is epidermal cell proliferation in psoriatic skin grafts on nude mice driven by T-cell derived cytokines? Br J Dermatol 126:105–110CrossRefPubMedGoogle Scholar
  18. 18.
    Sparidans RW, Vlaming ML, Lagas JS, Schinkel AH, Schellens JH, Beijnen JH (2009) Liquid chromatography-tandem mass spectrometric assay for sorafenib and sorafenib-glucuronide in mouse plasma and liver homogenate and identification of the glucuronide metabolite. J Chromatogr B Anal Technol Biomed Life Sci 877:269–276CrossRefGoogle Scholar
  19. 19.
    Gilbert RW, Vickaryous MK, Viloria-Petit AM (2016) Signalling by transforming growth factor beta isoforms in wound healing and tissue regeneration. J Dev Biol 4:21CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Lai SE, Kuzel T, Lacouture ME (2007) Hand-foot and stump syndrome to sorafenib. J Clin Oncol 25:341–343CrossRefPubMedGoogle Scholar
  21. 21.
    Yamamoto K, Mizumoto A, Nishimura K et al (2014) Association of toxicity of sorafenib and sunitinib for human keratinocytes with inhibition of signal transduction and activator of transcription 3 (STAT3). PLoS One 9:e102110CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Shichiri H, Yamamoto K, Tokura M et al (2017) Prostaglandin E1 reduces the keratinocyte toxicity of sorafenib by maintaining signal transducer and activator of transcription 3 (STAT3) activity and enhancing the cAMP response element binding protein (CREB) activity. Biochem Biophys Res Commun 485:227–233CrossRefPubMedGoogle Scholar

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

Personalised recommendations