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Carcinogenesis Advance Access published online on September 30, 2005
Carcinogenesis, doi:10.1093/carcin/bgi233
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 28, 2005
Revised September 5, 2005
Accepted September 24, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

N-(4-hydroxyphenyl)retinamide and nitric oxide pro-drugs exhibit apoptotic and anti-invasive effects against bone metastatic breast cancer cells

Ann-Marie Simeone 1*, Stefano Colella 2, Ralf Krahe 2, Marcella M.Johnson 3, Edna Mora 4, and Ana M.Tari 1

1 Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
2 Department of Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
3 Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
4 Puerto Rico Cancer Center and Surgery Division, The University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936

* To whom correspondence should be addressed.
Ann-Marie Simeone, E-mail: amsimeon{at}mdanderson.org


  Abstract

Breast cancer most frequently metastasizes to bone causing decreased quality of life and morbidity. Since current treatments are palliative, strategies to prevent bone metastases in breast cancer patients are needed. There is substantial evidence indicating that high levels of nitric oxide (NO) suppress tumor growth and metastasis in vivo. We hypothesize that agents that produce high concentrations of NO could prevent the spread of breast cancer to bone. We previously demonstrated that the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) produces high levels of NO via the induction of NO synthases. NO pro-drugs are designed to produce large amounts of NO without inducing NO synthases but upon metabolism by their intracellular targets. The objective of this study was to determine the effectiveness of 4-HPR and a NO pro-drug, diethylamineNONOate/AM (NONO-AM), in inhibiting the growth and invasiveness of bone metastatic breast cancer cells. Parental MDA-MB-231 breast cancer cells were resistant to 4-HPR-induced apoptosis at clinically relevant doses, whereas 4-HPR induced apoptosis in a dose-dependent manner in MDA-MB-231/F10 bone metastatic breast cancer cells. Unlike 4-HPR, NONO-AM induced apoptosis in a dose-dependent manner in both parental MDA-MB-231 cells and F10 cells. The bone metastatic F10 cells were more sensitive to the anti-invasive effects of 4-HPR and NONO-AM than were MDA-MB-231 cells. Although suppression of matrix metalloprotease-9 activity may be one mechanism by which 4-HPR decreases the invasion of F10 cells, it does not appear to be the anti-invasion mechanism of NONO-AM. These in vitro results suggest that 4-HPR and NO pro-drugs may be effective chemopreventive agents against bone metastatic breast cancer.


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