| The phosphatase inhibitor menadione (Vitamin K3) protects cells from EGFR inhibition by erlotinib and cetuximab. | |
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MedLine Citation:
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PMID: 21914790 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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PURPOSE: Skin toxicity is the main side effect of EGFR inhibitors often leading to dose reduction or discontinuation. We hypothesized that phosphatase inhibition in the skin keratinocytes may prevent receptor dephosphorylation caused by EGFR inhibitors and be used as a new potential strategy for the prevention or treatment of this side effect. EXPERIMENTAL DESIGN: Menadione (Vitamin K3) was used as the prototype compound to test our hypothesis. HaCat skin keratinocyte cells and A431 squamous carcinoma cells were used. EGFR inhibition was measured by western blotting and immunofluorescence. Phosphatase inhibition and reactive oxygen species (ROS) generation were measured by standard ELISA and fluorescence assays. RESULTS: Menadione caused significant and reversible EGFR activation in a dose dependent manner starting at non-toxic concentrations. EGFR activation by menadione was associated with reversible protein tyrosine phosphatase inhibition, which appeared to be mediated by ROS generation as exposure to antioxidants prevented both menadione-induced ROS generation and phosphatase inhibition. Short-term co-incubation of cells with non-toxic concentrations of menadione and the EGFR inhibitors erlotinib or cetuximab prevented EGFR dephosphorylation. Seventy two-hour co-incubation of cells with the highest non-toxic concentration of menadione and erlotinib provided of a 4-fold cell growth inhibitory protection in HaCat human keratinocyte cells. CONCLUSIONS: Menadione at non-toxic concentrations causes EGFR activation and prevents EGFR dephosphorylation by erlotinib and cetuximab. This effect appears to be mediated by ROS generation and secondary phosphatase inhibition. Mild oxidative stress in skin keratinocytes by topical menadione may protect the skin from the toxicity secondary to EGFR inhibitors without causing cytotoxicity. |
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Authors:
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Roman Perez-Soler; Yiyu Zou; Tianhong Li; Yi-He Ling |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-13 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: - ISSN: 1078-0432 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Dept of Oncology, Montefiore Medical Center. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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