Molecular mechanisms of lung-specific toxicity induced by epidermal growth factor receptor tyrosine kinase inhibitors

Sakao, Seiichiro

doi:10.3892/ol.2012.872

Cited by 13 publications

(12 citation statements)

References 29 publications

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“…Such signal fades away after normal organogenesis and tissue injury/repair to maintain homeostasis [ 37 ]. Unlike honokiol, EGFR tyrosine kinase inhibitors erlotinib and gefitinib impair the regeneration of normal pulmonary epithelial cells [ 38 – 41 ] through the blockade of EGFR-dependent phosphorylation, and therefore this group of drugs is commonly incriminated as etiologies of interstitial lung disease, a lung-specific toxicity arising in NSCLC patients receiving these drugs.…”

Section: Discussionmentioning

confidence: 99%

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors

et al. 2016

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Since epidermal growth factor receptor (EGFR) is commonly deregulated in pre-malignant lung epithelium, targeting EGFR may arrest the development of lung cancer. Here, we showed that honokiol (2.5–7.5 μM), a bioactive compound of Magnolia officinalis, differentially suppressed proliferation (up to 93%) and induced apoptosis (up to 61%) of EGFR overexpressing tumorigenic bronchial cells and these effects were paralleled by downregulation of phospho-EGFR, phospho-Akt, phospho-STAT3 and cell cycle-related proteins as early as 6–12 h post-treatment. Autocrine secretion of EGF sensitized 1170 cells to the effects of honokiol. Molecular docking studies indicated that honokiol binds to the tyrosine kinase domain of EGFR although it was less efficient than erlotinib. However, the anti-proliferative and pro-apoptotic activities of honokiol were stronger than those of erlotinib. Upon combinatory treatment, honokiol sensitized bronchial cells and erlotinib resistant H1650 and H1975 cells to erlotinib. Furthermore, in a mouse lung tumor bioassay, intranasal instillation of liposomal honokiol (5 mg/kg) for 14 weeks reduced the size and multiplicity (49%) of lung tumors and the level of total- and phospho-EGFR, phospho-Akt and phospho-STAT3. Overall, our results indicate that honokiol is a promising candidate to suppress the development and even progression of lung tumors driven by EGFR deregulation.

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Section: Discussionmentioning

confidence: 99%

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors

et al. 2016

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“…Development processes were found in the main process classification of T2DM, CML, and PCa. In cancer development process, TKIs also have been demonstrated to play a role through receptor tyrosine kinases (RTKs) signaling pathways . Recent studies on molecular therapies have indicated that TKIs may involve cell growth, migration, invasion, development, adhesion, proliferation, apoptosis, and angiogenesis via Nuclear factor‐kB (NF‐κB), Focal adhesion kinase (FAK), Janus kinase1/2 (JAK1/2), ETK, C‐Jun N‐terminal kinase (JNK), Mitogen activated kinase‐like protein (MAPK), Extracellular regulated MAP kinase (ERK), Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha‐Serine/threonine kinase 1 (PI3K‐Akt), and other cancer‐related signaling pathways (Figure B) …”

Section: Discussionmentioning

confidence: 99%

Deciphering the scalene association among type‐2 diabetes mellitus, prostate cancer, and chronic myeloid leukemia via enrichment analysis of disease‐gene network

et al. 2019

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The potential biological relationship between type‐2 diabetes mellitus (T2DM) has been focused in numerous studies. To investigate the molecular associations among T2DM, prostate cancer (PCa), and chronic myeloid leukemia (CML), using a biomolecular network enrichment analysis. We obtained a list of disease‐related genes and constructed disease networks. Then, GO enrichment analysis was performed to identify the significant functions and pathways of overlapping modules in the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. More than 75% of these overlapping genes were found to be consistent with the findings of previous studies. In the three diseases, we found that Sarcoglycan delta (SGCD) and Rho family GTPase 3 (RND3) were the overlapping genes and identified negative regulation of apoptotic process and negative regulation of transcription from RNA polymerase II promoter RNA as the two overlapping biological functions. CML and PCa were the most closely related, with 34 overlapping genes, five overlapping modules, 27 overlapping biological functions, and nine overlapping pathways. There were 13 overlapping genes, one overlapping modules, four overlapping biological functions and one overlapping pathway (FoxO signaling pathway) were found in T2DM and CML.And T2DM and PCa were the least related pair in our study, with only six overlapping genes, five overlapping modules, and one overlapping biological function. SGCD and RND3 were the main gene‐to‐gene relationship among T2DM, CML, and PCa; apoptosis, development, and transcription from RNA polymerase II promote processes were the main functional connections among T2DM, CML, and PCa by network enrichment analysis. There is a “scalene” relationship among T2DM, CML, and PCa at gene, pathway, biological process, and module levels: CML and PCa were the most closely related, the second were T2DM and PCa, and T2DM and PCa were the least related pair in our study. Our study provides a new avenue for further studies on T2DM and cancers, which may promote the discovery and development of novel therapeutic and can be used to treat multiple diseases.

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“… 7 Gefitinib and erlotinib are the 2 most widely used receptor TKIs’ which selectively inhibit the EGFR tyrosine kinase domain. 8 In May of 2013, erlotinib was approved by Food and Drug administration as first line treatment of patients with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. 2 Skin rash is one of the most common AE’s noted in the clinical trials, where its’ appearance has been associated with better overall survival.…”

Section: Discussionmentioning

confidence: 99%

Erlotinib Induced Fatal Interstitial Lung Disease in a Patient with Metastatic Non-Small Cell Lung Cancer: Case Report and Review of Literature

et al. 2016

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Erlotinib is one of the most widely used tyrosine kinase inhibitor targeting human epidermal growth factor receptor. Since its introduction, it has revolutionized the treatment of advanced non-small cell lung cancer. Skin rashes and diarrhea are the most often reported side effects of erlotinib however it is also associated with interstitial pneumonitis or interstitial lung disease, which often turns out to be fatal complication of using this medicine. Though reported scarcely in the western world, the association of interstitial lung disease with epidermal growth factor receptor has attracted a lot of attention in the recent times. Various researches working with murine models of bleomycin-induced pulmonary fibrosis have found a pro and con role of the receptor in development of the interstitial lung disease. We present the case of a patient diagnosed with stage IV adenocarcinoma of the lung with metastasis to brain. He was found to be positive for the human epidermal growth factor mutation and was hence started on erlotinib. Within a few weeks of starting the medicine the patient was admitted with diarrhea. During the course of this admission he developed acute shortness of breath diagnosed as interstitial pneumonitis. The purpose of this case report is to review the literature associated with erlotinib induced interstitial pneumonitis and make the practicing oncologists aware of this rare yet fatal complication of erlotinib. Here we will also review literature, pertaining to the role of epidermal growth factor receptor in development of interstitial lung disease.

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Molecular mechanisms of lung-specific toxicity induced by epidermal growth factor receptor tyrosine kinase inhibitors

Cited by 13 publications

References 29 publications

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors

Deciphering the scalene association among type‐2 diabetes mellitus, prostate cancer, and chronic myeloid leukemia via enrichment analysis of disease‐gene network

Erlotinib Induced Fatal Interstitial Lung Disease in a Patient with Metastatic Non-Small Cell Lung Cancer: Case Report and Review of Literature

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