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Inhibition of AIDS-Kaposi's Sarcoma Cell Proliferation following Retinoic Acid Receptor Activation¹

Department of Pathology, University of Montreal, C. P. 6128, Succursale, Centreville, Montreal, Quebec, Canada H3C 3J7 [W-X. G., T. A.], and Norris Cancer Center, University of Southern California, Los Angeles, California 90033 [P. S. G.]

Retinoids, a group of natural and synthetic vitamin A analogues the receptors of which belong to the superfamily of steroid receptors, can exert profound effects on growth and/or differentiation of embryonic and neoplastic cells. Kaposi's sarcoma (KS), previously a rare multicentric neoplasm, has become epidemic with HIV infection, although the etiology of KS remains obscure. In the present study, the effects of two potent retinoids, all-trans-retinoic acid (RA) and 13-cis-RA, on the expression of retinoic acid receptor and the growth of AIDS-related KS (AIDS-KS) cells were examined. The proliferation of AIDS-KS cells was significantly inhibited by RA and 13-cis-RA in a dose-dependent manner with 50% inhibitory concentration of 1.4 x 10^-10 M and 4.7 x 10^-9 M, respectively, which correlate with their potency. Growth inhibition was time dependent with maximal inhibition of 90% after 3 days of treatment with 10^-8 M RA. Growth inhibition by RA was further potentiated by forskolin (1 µM), an intracellular cyclic AMP-inducing agent. Moreover, RA treatment blocked the proliferative effect of oncostatin M and tumor necrosis factor , two major KS autocrine growth factors. The effects of RA were accompanied by a dramatic increase in nuclear staining for retinoic acid receptor and in the relative number of strongly positive retinoic acid receptor nuclei. Finally, RA induced morphological changes as KS cells became more flattened, better spread, and more adhesive to the substrate. These results suggest that retinoids inhibit proliferation of AIDS-KS cells and further support their utility as therapeutic agents in AIDS-KS.

¹ This work was supported by National Cancer Institute of Canada Grant 2196 and in part by Medical Research Council of Canada Grant MA 7959. W-X. G. is currently a recipient of a National Health Ph.D. Fellowship from Health Canada and an earlier Ph.D. studentship from the Fonds pour la formation de Chercheurs et l'Aide à la Recherche, Quebec, Canada.

² To whom requests for reprints should be addressed.

Received 8/ 9/94. Accepted 12/16/94.

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