This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shishodia, S. Articles by Aggarwal, B. B. Search for Related Content PubMed PubMed Citation Articles by Shishodia, S. Articles by Aggarwal, B. B. Related Collections Preclinical Intervention Preclinical Intervention: In Vitro: Drugs, Mechanisms

N-(4-Hydroxyphenyl)Retinamide Inhibits Invasion, Suppresses Osteoclastogenesis, and Potentiates Apoptosis through Down-regulation of IB Kinase and Nuclear Factor-B–Regulated Gene Products

¹ Cytokine Research Laboratory, Department of Experimental Therapeutics and ² Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Bharat B. Aggarwal, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston, TX 77030. Phone: 713-794-1817; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

N-(4-hydroxyphenyl) retinamide [4-HPR], a synthetic retinoid, has been shown to inhibit tumor cell growth, invasion, and metastasis by a mechanism that is not fully understood. Because the nuclear factor-B (NF-B) has also been shown to regulate proliferation, invasion, and metastasis of tumor cells, we postulated that 4-HPR modulates the activity of NF-B. To test this postulate, we examined the effect of this retinoid on NF-B and NF-B–regulated gene products. We found that 4-HPR potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, suppressed TNF-induced invasion, and inhibited RANKL-induced osteoclastogenesis, all of which are known to require NF-B activation. We found that 4-HPR suppressed both inducible and constitutive NF-B activation without interfering with the direct DNA binding of NF-B. 4-HPR was found to be synergistic with Velcade, a proteasome inhibitor. Further studies showed that 4-HPR blocked the phosphorylation and degradation of IB through the inhibition of activation of IB kinase (IKK), and this led to suppression of the phosphorylation and nuclear translocation of p65. 4-HPR also inhibited TNF-induced Akt activation linked with IKK activation. NF-B–dependent reporter gene expression was also suppressed by 4-HPR, as was NF-B reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKK but not that induced by p65 transfection. The expression of NF-B–regulated gene products involved in antiapoptosis (IAP1, Bfl-1/A1, Bcl-2, cFLIP, and TRAF1), proliferation (cyclin D1 and c-Myc), and angiogenesis (vascular endothelial growth factor, cyclooxygenase-2, and matrix metalloproteinase-9) were also down-regulated by 4-HPR. This correlated with potentiation of apoptosis induced by TNF and chemotherapeutic agents.

This article has been cited by other articles:

				R. Piva, B. Ruggeri, M. Williams, G. Costa, I. Tamagno, D. Ferrero, V. Giai, M. Coscia, S. Peola, M. Massaia, et al. CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib Blood, March 1, 2008; 111(5): 2765 - 2775. [Abstract] [Full Text] [PDF]

				A. S. Nair, S. Shishodia, K. S. Ahn, A. B. Kunnumakkara, G. Sethi, and B. B. Aggarwal Deguelin, an Akt Inhibitor, Suppresses I{kappa}B{alpha} Kinase Activation Leading to Suppression of NF-{kappa}B-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion J. Immunol., October 15, 2006; 177(8): 5612 - 5622. [Abstract] [Full Text] [PDF]

				G. Sethi, K. S. Ahn, S. K. Sandur, X. Lin, M. M. Chaturvedi, and B. B. Aggarwal Indirubin Enhances Tumor Necrosis Factor-induced Apoptosis through Modulation of Nuclear Factor-{kappa}B Signaling Pathway J. Biol. Chem., August 18, 2006; 281(33): 23425 - 23435. [Abstract] [Full Text] [PDF]

				S. M. Lippman, J. J. Lee, J. W. Martin, A. K. El-Naggar, X. Xu, D. M. Shin, M. Thomas, L. Mao, H. A. Fritsche Jr., X. Zhou, et al. Fenretinide Activity in Retinoid-Resistant Oral Leukoplakia. Clin. Cancer Res., May 15, 2006; 12(10): 3109 - 3114. [Abstract] [Full Text] [PDF]