Document Detail


A water soluble parthenolide analog suppresses in vivo tumor growth of two tobacco-associated cancers, lung and bladder cancer, by targeting NF-κB and generating reactive oxygen species.
MedLine Citation:
PMID:  20669221     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Dimethylaminoparthenolide (DMAPT) is a water soluble parthenolide analog with preclinical activity in hematologic malignancies. Using non-small lung cancer (NSCLC) cell lines (A549 and H522) and an immortalized human bronchial epithelial cell line (BEAS2B) and TCC cell lines (UMUC-3, HT-1197 and HT-1376) and a bladder papilloma (RT-4), we aimed to characterize DMAPT's anticancer activity in tobacco-associated neoplasms. Flow cytometric, electrophoretic mobility gel shift assays (EMSA), and Western blot studies measured generation of reactive oxygen species (ROS), inhibition of NFκB DNA binding, and changes in cell cycle distribution and apoptotic proteins. DMAPT generated ROS with subsequent JNK activation and also decreased NFκB DNA binding and antiapoptotic proteins, TRAF-2 and XIAP. DMAPT-induced apoptotic cell death and altered cell cycle distribution with upregulation of p21 and p73 levels in a cell type-dependent manner. DMAPT suppressed cyclin D1 in BEAS2B. DMAPT retained NFκB and cell cycle inhibitory activity in the presence of the tobacco carcinogen nitrosamine ketone, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Using a BrdU accumulation assay, 5-20 μM of DMAPT was shown to inhibit cellular proliferation of all cell lines by more than 95%. Oral dosing of DMAPT suppressed in vivo A549 and UMUC-3 subcutaneous xenograft growth by 54% (p = 0.015) and 63% (p < 0.01), respectively, and A549 lung metastatic volume by 28% (p = 0.043). In total, this data demonstrates DMAPT's novel anticancer properties in both early and late stage tobacco-associated neoplasms as well as its significant in vivo activity. The data provides support for the conduct of clinical trials in TCC and NSCLC.
Authors:
Rajasubramaniam Shanmugam; Praveen Kusumanchi; Hitesh Appaiah; Liang Cheng; Peter Crooks; Sundar Neelakantan; Tyler Peat; James Klaunig; William Matthews; Harikrishna Nakshatri; Christopher J Sweeney
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  128     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-03-28     Completed Date:  2011-05-26     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2481-94     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 UICC.
Affiliation:
Department of Medicine, Indiana University, Indianapolis, IN, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Carcinogens / toxicity
Cell Cycle / drug effects
Cell Division / drug effects*
DNA Primers
Electrophoretic Mobility Shift Assay
Flow Cytometry
Lung Neoplasms / etiology,  metabolism,  pathology*
Male
Mice
Mice, Nude
NF-kappa B / metabolism*
Nitrosamines / toxicity
RNA, Small Interfering
Reactive Oxygen Species / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Sesquiterpenes / chemistry,  pharmacology*
Tobacco* / chemistry
Urinary Bladder Neoplasms / etiology,  metabolism,  pathology*
Grant Support
ID/Acronym/Agency:
R03 CA137796/CA/NCI NIH HHS; R03 CA137796-01/CA/NCI NIH HHS; R03 CA137796-02/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Carcinogens; 0/DNA Primers; 0/NF-kappa B; 0/Nitrosamines; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 0/Sesquiterpenes; 2RDB26I5ZB/parthenolide; 64091-91-4/4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
Comments/Corrections

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