TY - JOUR T1 - Antitumor Activity of the Retinoid-Related Molecules (<em>E</em>)-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 γ and Retinoid-Independent Pathways JF - Molecular Pharmacology JO - Mol Pharmacol SP - 909 LP - 924 DO - 10.1124/mol.106.023614 VL - 70 IS - 3 AU - Edoardo Parrella AU - Maurizio Giannì AU - Maddalena Fratelli AU - Maria Monica Barzago AU - Ivan Raska, Jr AU - Luisa Diomede AU - Mami Kurosaki AU - Claudio Pisano AU - Paolo Carminati AU - Lucio Merlini AU - Sabrina Dallavalle AU - Michele Tavecchio AU - Cecile Rochette-Egly AU - Mineko Terao AU - Enrico Garattini Y1 - 2006/09/01 UR - http://molpharm.aspetjournals.org/content/70/3/909.abstract N2 - 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 RARγ agonists than ATRA. We used three teratocarcinoma cell lines to evaluate the significance of RARγ in the activity of RRMs: F9-wild type (WT); F9γ-/-, lacking the RARγ gene; F9γ51, aF9γ-/-derivative, complemented for the RARγ 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 RARγ 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 F9γ-/-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 RARγ-independent manner, provides novel insights into the possible molecular determinants underlying the activity of RRMs in vitro. Furthermore, it suggests that RARγ-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 F9γ-/- tumors have increased life spans after treatment with ST1926 and CD437 relative to their F9-WT counterparts. The American Society for Pharmacology and Experimental Therapeutics ER -