Oxidative stress induces EGFR inhibition-related skin cell death

Cutaneous side effects are often observed in patients treated with chemotherapeutic agents, including those treated with epidermal growth factor receptor (EGFR) inhibitors. These side effects are not fatal but often require dose reduction of chemotherapies. The mechanisms of epidermal growth factor...

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Bibliographic Details
Published in:Journal of Clinical Biochemistry and Nutrition 2021/05/01, Vol.68(3), pp.235-242
Main Authors: Morita, Midori, Iizuka-Ohashi, Mahiro, Watanabe, Motoki, Narita, Takumi, Kato, Chikage, Kakibuchi, Daichi, Kitano, Fuyuki, Ouchi, Yoshimi, Sakaguchi, Koichi, Taguchi, Tetsuya
Format: Article
Language:English
Subjects:
Apoptosis
Cell death
Chemotherapy
cutaneous side effect
Cytotoxicity
EGFR inhibitor
Epidermal growth factor
Epidermal growth factor receptors
Glutathione
Glycolysis
Growth factors
Liquid chromatography
Mass spectrometry
Mass spectroscopy
Metabolism
Metabolites
metabolomics
Original
Oxidative stress
Polyamines
Reactive oxygen species
Receptors
Side effects
Supplements
Toxicity
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Summary:Cutaneous side effects are often observed in patients treated with chemotherapeutic agents, including those treated with epidermal growth factor receptor (EGFR) inhibitors. These side effects are not fatal but often require dose reduction of chemotherapies. The mechanisms of epidermal growth factor receptor inhibition-related dermatologic toxicities are unclear, and prophylactic approaches are not well-established. To explore the mechanisms of the cutaneous side effects induced by epidermal growth factor receptor inhibition, we analyzed the metabolome using human keratinocyte cells. We first demonstrated that afatinib and lapatinib induced apoptosis in HaCaT cells. Using liquid chromatography-mass spectrometry, we detected 676 and 482 metabolites and compounds in the cells and media, respectively. We observed diverse metabolic alterations, including glycolysis, TCA metabolism, and polyamine metabolism, and also found a change in glutathione metabolites after epidermal growth factor receptor inhibition, which led to the accumulation of reactive oxygen species. Supplementation of N-acetyl cysteine partly rescued the afatinib-induced apoptosis, suggesting that reactive oxygen species are involved in the cytotoxicity of skin cells. We observed epidermal growth factor receptor inhibitor-associated comprehensive metabolic changes in human keratinocyte cells, suggesting that oxidative stress evokes cutaneous side effects induced by EGFR inhibition.
ISSN:0912-0009
1880-5086
DOI:10.3164/jcbn.20-112