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 Puduvalli, V. K. Articles by Kyritsis, A. P. Search for Related Content PubMed PubMed Citation Articles by Puduvalli, V. K. Articles by Kyritsis, A. P.

Fenretinide Activates Caspases and Induces Apoptosis in Gliomas

Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The synthetic retinoid fenretinide (N-[4-hydroxyphenyl] retinamide or 4HPR) has been shown to not only inhibit cell growth but also to induce apoptosis in a variety of malignant cell lines. It is being tested presently for its potential as a chemopreventive agent against several cancers. A related retinoid, 13-cis-retinoic acid (cRA), has been shown to have activity against gliomas in vitro as well as in a recent clinical study. The present study aimed at assessing the activity of fenretinide against glioma cells in vitro and comparing it with that of cRA at pharmacologically relevant doses. We hypothesized that the ability of fenretinide to induce apoptosis would make it more potent against gliomas than cRA. Four glioma cell lines (D54, U251, U87MG, and EFC-2) were treated with fenretinide (1–100 µM) and showed dose- and time-dependent induction of cell death. At pharmacologically relevant doses, fenretinide was more active against glioma cells than cRA because of its ability to induce apoptosis. Flow cytometric studies using D54 cells demonstrated no significant changes in the cell cycle distribution compared with untreated control, but a sub-G₁ fraction consistent with apoptosis was detected. Terminal deoxynucleotidyl transferase-mediated nick end labeling assay indicated that the apoptotic fraction was cell cycle nonspecific. Fenretinide treatment resulted in cleavage of poly ADP-ribose polymerase, indicating an activation of the caspase 3. Immunofluorescence studies using the nu-clear stain 4',6-diamidine-2'-phenylindole dihydrochloride showed nuclear condensation and an apoptotic morphology. Hence, this study demonstrates that, at clinically relevant doses, fenretinide is a potent inducer of apoptosis in gliomas acting via the caspase pathway. We also show that at clinically achievable doses, fenretinide has more activity against gliomas than comparable doses of cRA. The favorable side effect profile seen in previous clinical studies and the in vitro activity against gliomas demonstrated in this study suggest that fenretinide could be a promising therapeutic agent against gliomas.

This article has been cited by other articles:

				C. Guilbault, J. B. De Sanctis, G. Wojewodka, Z. Saeed, C. Lachance, T. A. A. Skinner, R. M. Vilela, S. Kubow, L. C. Lands, M. Hajduch, et al. Fenretinide Corrects Newly Found Ceramide Deficiency in Cystic Fibrosis Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 47 - 56. [Abstract] [Full Text] [PDF]

				M. Tiwari, A. Kumar, R. A. Sinha, A. Shrivastava, A. K. Balapure, R. Sharma, V. K. Bajpai, K. Mitra, S. Babu, and M. M. Godbole Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress Carcinogenesis, October 1, 2006; 27(10): 2047 - 2058. [Abstract] [Full Text] [PDF]

				Y. Rong, F. Hu, R. Huang, N. Mackman, J. M. Horowitz, R. L. Jensen, D. L. Durden, E. G. Van Meir, and D. J. Brat Early Growth Response Gene-1 Regulates Hypoxia-Induced Expression of Tissue Factor in Glioblastoma Multiforme through Hypoxia-Inducible Factor-1-Independent Mechanisms. Cancer Res., July 15, 2006; 66(14): 7067 - 7074. [Abstract] [Full Text] [PDF]

				S. Shishodia, A. M. Gutierrez, R. Lotan, and B. B. Aggarwal N-(4-Hydroxyphenyl)Retinamide Inhibits Invasion, Suppresses Osteoclastogenesis, and Potentiates Apoptosis through Down-regulation of I{kappa}B{alpha} Kinase and Nuclear Factor-{kappa}B-Regulated Gene Products Cancer Res., October 15, 2005; 65(20): 9555 - 9565. [Abstract] [Full Text] [PDF]

				V. K. Puduvalli, W.K. A. Yung, K. R. Hess, J. G. Kuhn, M. D. Groves, V. A. Levin, J. Zwiebel, S. M. Chang, T. F. Cloughesy, L. Junck, et al. Phase II Study of Fenretinide (NSC 374551) in Adults With Recurrent Malignant Gliomas: A North American Brain Tumor Consortium Study J. Clin. Oncol., November 1, 2004; 22(21): 4282 - 4289. [Abstract] [Full Text] [PDF]

				K. R. Kalli, K. E. Devine, M. C. Cabot, C. R. Arnt, M. P. Heldebrant, P. A. Svingen, C. Erlichman, L. C. Hartmann, C. A. Conover, and S. H. Kaufmann Heterogeneous Role of Caspase-8 in Fenretinide-Induced Apoptosis in Epithelial Ovarian Carcinoma Cell Lines Mol. Pharmacol., December 1, 2003; 64(6): 1434 - 1443. [Abstract] [Full Text] [PDF]

				A. Erdreich-Epstein, L. B. Tran, N. N. Bowman, H. Wang, M. C. Cabot, D. L. Durden, J. Vlckova, C. P. Reynolds, M. F. Stins, S. Groshen, et al. Ceramide Signaling in Fenretinide-induced Endothelial Cell Apoptosis J. Biol. Chem., December 13, 2002; 277(51): 49531 - 49537. [Abstract] [Full Text] [PDF]