Research article summary (published 4 Jun 2009):

Emodin enhances gefitinib-induced cytotoxicity via Rad51 downregulation and ERK1/2 inactivation.

Full Abstract

Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It reportedly exhibits an anticancer effect on lung cancer. Gefitinib (Iressa) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for human non-small cell lung cancer (NSCLC). However, the molecular mechanism of how emodin combined with gefitinib decreases NSCLC cell viability is unclear. The recombinase protein Rad51 is essential for homologous recombination repair, and Rad51 overexpression is resistant to DNA double-strand break-inducing cancer therapies. In this study, we found that emodin enhanced the cytotoxicity induced by gefitinib in two NSCLC cells lines, A549 and H1650. Emodin at low doses of 2-10 microM did not affect ERK1/2 activation, mRNA, and Rad51 protein levels; however, it enhanced a gefitinib-induced decrease in phospho-ERK1/2 and Rad51 protein levels by enhancing Rad51 protein instability. Expression of constitutively active MKK1/2 vectors (MKK1/2-CA) significantly rescued the reduced phospho-ERK1/2 and Rad51 protein levels as well as cell viability on gefitinib and emodin cotreatment. Blocking of ERK1/2 activation by U0126 (an MKK1/2 inhibitor) lowered Rad51 protein levels and cell viability in emodin-treated H1650 and A549 cells. Knockdown of Rad51 expression by transfection with si-Rad51 RNA enhanced emodin cytotoxicity. In contrast, Rad51 overexpression protected the cells from the cytotoxic effects induced by emodin and gefitinib. Consequently, emodin-gefitinib cotreatment may serve as the basis for a novel and better therapeutic modality in the management of advanced lung cancer.

Author information

Author/s: Chen, Ruey-Shyang (RS); Jhan, Jhih-Yuan (JY); Su, Ying-Jhen (YJ); Lee, Wei-Ting (WT); Cheng, Chao-Min (CM); Ciou, Shih-Ci (SC); Lin, Szu-Ting (ST); Chuang, Show-Mei (SM); Ko, Jen-Chung (JC); Lin, Yun-Wei (YW);

Affiliation: Molecular Genetics of Microorganisms Laboratory, Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Experimental cell research (Exp Cell Res), published in United States. (Language: eng)

Reference: 2009-Sep; vol 315 (issue 15) : pp 2658-72

Dates: Created 2009/07/31; Completed 2009/09/28;

PMID: 19505457, status: MEDLINE (last retrieval date: 9/28/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Antineoplastic Agents - metabolism; toxicity Apoptosis - physiology Butadienes - metabolism Cell Line, Tumor Emodin - metabolism Humans MAP Kinase Kinase 1 - antagonists & inhibitors; genetics; metabolism Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; genetics; metabolism

Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; genetics; metabolism Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; genetics; metabolism Nitriles - metabolism Proteasome Endopeptidase Complex - metabolism Protein Kinase Inhibitors - metabolism; toxicity Quinazolines - toxicity RNA, Small Interfering - genetics; metabolism Rad51 Recombinase - genetics; metabolism Signal Transduction - physiology

Associated Chemicals: Antineoplastic Agents (0) ; Butadienes (0) ; Nitriles (0) ; Protein Kinase Inhibitors (0) ; Quinazolines (0) ; RNA, Small Interfering (0) ; U 0126 (0) ; gefitinib (184475-35-2) ; Emodin (518-82-1) ; MAP Kinase Kinase 1 (EC 2.7.1.-) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.1.37) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.1.37) ; Rad51 Recombinase (EC 2.7.7.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATP dependent 26S protease (EC 3.4.99.-)

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