JPET xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 6, 2004; DOI: 10.1124/jpet.104.072496

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.104.072496v1
312/1/339    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Moreb, J.
Right arrow Articles by Mohuczy, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Moreb, J.
Right arrow Articles by Mohuczy, D.


Received for publication June 11, 2004.
Revised October 5, 2004.
Accepted for publication October 5, 2004.

Retinoic acid downregulates aldehyde dehydrogenase and increases cytotoxicity of 4-hydroperoxycyclophosphamide and acetaldehyde

Jan Moreb 1*, Amir Gabr 1, Govind R. Vartikar 1, Santosh Gowda 1, James R. Zucali 1, Dagmara Mohuczy 1

1 University of Florida

* Address correspondence to: E-mail: morebjs{at}medicine.ufl.edu

Abstract

Multiple prior studies have identified aldehyde dehydrogenases (ALDH) able to oxidize retinal to retinoic acid. In this study, we test the hypothesis that the accumulation of intracellular retinoic acid may lead to the suppression of ALDH expression and thus increase cytotoxicity to 4-hydroperoxycyclophosphamide (4-HC) in vitro. Mainly A549, but also other lung cancer cell lines, were used in our experiments with the former having high levels of two ALDH isozymes expressed. Dose response and time course were performed incubating the cells with all-trans retinoic acid (ATRA) as well as other commercially available retinoids. The results show that incubation of A549 cells with any of the retinoids at pharmacologic doses for ≥48 hr results in significant decrease in ALDH-1A1 and ALDH-3A1 enzyme activity and protein levels, but not the corresponding mRNAs. Such decrease in ALDH activity was seen in all cell lines tested and results in a significant increase in toxicity of 4-HC and acetaldehyde, both are substrates for the enzymes. Prior incubation with ATRA also results in increased cytotoxicity, although to a lesser degree, of phenylketophosphamide (PKP) and melphalan, neither is substrate for ALDH. These results suggest a posttranslational mechanism through which retinoids decrease both ALDH expression, which results in increased cytotoxicity of 4-HC and acetaldehyde, although other previously described effects of these retinoids may be contributing to the slight increase in cytotoxicity seen with other chemotherapy agents. These results may have clinical implications in regards to the use of retinoids in lung cancer prevention and treatment.


Key words: 4-HC, ALDH, Acetaldehyde, Cytotoxicity, lung cancer, retinoic acid


This article has been cited by other articles:


Home page
 Hum ReprodHome page
M. Zaitseva, B. J. Vollenhoven, and P. A.W. Rogers
Retinoids regulate genes involved in retinoic acid synthesis and transport in human myometrial and fibroid smooth muscle cells
Hum. Reprod., May 1, 2008; 23(5): 1076 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Visus, D. Ito, A. Amoscato, M. Maciejewska-Franczak, A. Abdelsalem, R. Dhir, D. M. Shin, V. S. Donnenberg, T. L. Whiteside, and A. B. DeLeo
Identification of Human Aldehyde Dehydrogenase 1 Family Member A1 as a Novel CD8+ T-Cell Defined Tumor Antigen in Squamous Cell Carcinoma of the Head and Neck
Cancer Res., November 1, 2007; 67(21): 10538 - 10545.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
M. Yoon, M. C. Madden, and H. A. Barton
Developmental Expression of Aldehyde Dehydrogenase in Rat: a Comparison of Liver and Lung Development
Toxicol. Sci., February 1, 2006; 89(2): 386 - 398.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics.