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Antitumor Activity of the Retinoid-Related Molecules (E)-3-(4'-Hydroxy-3'-adamantylbiphenyl-4-yl)acrylic Acid (ST1926) and 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene Carboxylic Acid (CD437) in F9 Teratocarcinoma: Role of Retinoic Acid Receptor and Retinoid-Independent Pathways

Laboratory of Molecular Biology, Centro Catullo e Daniela Borgomainerio (M.G., M.F., M.M.B., I.R., L.D., M.K., M.Te., E.G.) and Department of Oncology (M.Ta.), Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy; Sigma-Tau Industrie Farmaceutiche Riunite, Pomezia, Italy (C.P., P.C.); Dipartimento di Scienze Molecolari Agroalimentari, Università degli Studi di Milano, Milano, Italy (L.M., S.D.); and Institut de Genetique et Biologie Moleculaire, Illkirch, France (C.R.-E., E.P.)

The retinoid-related molecules (RRMs) ST1926 [(E)-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid] and CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) are promising anticancer agents. We compared the retinoic acid receptor (RAR) trans-activating properties of the two RRMs and all-trans-retinoic acid (ATRA). ST1926 and CD437 are better RAR agonists than ATRA. We used three teratocarcinoma cell lines to evaluate the significance of RAR in the activity of RRMs: F9-wild type (WT); F9-/-, lacking the RAR gene; F951, aF9-/-derivative, complemented for the RAR deficit. Similar to ATRA, ST1926 and CD437 activate cytodifferentiation only in F9-WT cells. Unlike ATRA, ST1926 and CD437 arrest cells in the G₂/M phase of the cell cycle and induce apoptosis in all F9 cell lines. Our data indicate that RAR and the classic retinoid pathway are not relevant for the antiproliferative and apoptotic activities of RRMs in vitro. Increases in cytosolic calcium are fundamental for apoptosis, in that intracellular calcium chelators abrogate the process. Comparison of the gene expression profiles associated with ST1926 and ATRA in F9-WT and F9-/-indicates that the RRM activates a conspicuous nonretinoid response in addition to the classic and RAR-dependent pathway. The pattern of genes regulated by ST1926 selectively, in a RAR-independent manner, provides novel insights into the possible molecular determinants underlying the activity of RRMs in vitro. Furthermore, it suggests that RAR-dependent responses are relevant to the activity of RRMs in vivo. Indeed, the receptor hinders the antitumor activity in vivo, in that both syngeneic and immunosuppressed SCID mice bearing F9-/- tumors have increased life spans after treatment with ST1926 and CD437 relative to their F9-WT counterparts.

Address correspondence to: Enrico Garattini, Laboratory of Molecular Biology, Centro Catullo e Daniela Borgomainerio, Istituto di Ricerche Farmacologiche "Mario Negri", via Eritrea 62, 20157 Milano, Italy. E-mail: egarattini{at}marionegri.it

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