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Cancer Chemotherapy and Pharmacology (2018) 81:1025–1033
https://doi.org/10.1007/s00280-018-3575-y
ORIGINAL ARTICLE
Multikinase inhibitor sorafenib induces skin toxicities in tumor-
bearing mice
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
Received: 6 March 2018 / Accepted: 26 March 2018 / Published online: 9 April 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
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 proliferat-
ing 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
Introduction
Multiple kinase inhibitors (MKIs) inhibit multiple cell sur-
face receptor tyrosine kinases and cytoplasmic kinases,
many of which are drivers for tumor initiation, growth,
and metastasis [1, 2]. The FDA-approved MKIs include
sorafenib, regorafenib, sunitinib, cabozantinib, and
pazopanib, which are indicated for various cancers, includ-
ing gastrointestinal stromal tumor, hepatocellular carci-
noma (HCC), metastatic colorectal cancer, medullary thy-
roid carcinoma, metastatic renal cell carcinoma (mRCC),
pancreatic neuroendocrine tumor, and soft-tissue sarcoma
[1, 3, 4], and recently also indicated for autoimmune dis-
eases [5]. However, MKIs commonly cause severe skin
* Li Feng
Fengli8535@163.com
* Yungchi Cheng
yccheng@yale.edu
1
Department of Traditional Chinese Medicine, National
Cancer Center/Cancer Hospital, Chinese Academy
of Medical Sciences and Peking Union Medical College,
Beijing 100021, China
2
Department of Pathology, National Cancer Center/Cancer
Hospital, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing 100021, China
3
Beijing Researh Insititute of Chinese Medicine, Beijing
University of Chinese Medicine, Beijing 100029, China
4
Department of Cancer Epidemiology, National Cancer
Center/Cancer Hospital, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100021,
China
5
Department of Pharmacology, Yale University School
of Medicine, New Haven, CT 06510, USA
6
Key Laboratory of Traditional Chinese Medicine Resource
and Compound Prescription, Ministry of Education, Hubei
University of Chinese Medicine, Wuhan 430065, China
@Phil_Robichaud
@deepthiw
@JoseServera