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 gamma and retinoid-independent pathways

作者：Parrella Edoardo; Gianni Maurizio; Fratelli Maddalena; Barzago Maria Monica; Raska Ivan Jr; Diomede Luisa; Kurosaki Mami; Pisano Claudio; Carminati Paolo; Merlini Lucio; Dallavalle Sabrina; Tavecchio Michele; Rochette Egly Cecile; Terao Mineko; Garattini Enrico^*

来源：Molecular Pharmacology, 2006, 70(3): 909-924.

DOI：10.1124/mol.106.023614

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 gamma agonists than ATRA. We used three teratocarcinoma cell lines to evaluate the significance of RAR gamma in the activity of RRMs: F9-wild type (WT); F9 gamma-/-, lacking the RAR gamma gene; F9 gamma 51, aF9 gamma-/- derivative, complemented for the RAR gamma deficit. Similar to ATRA, ST1926 and CD437 activate cytodifferentiation only in F9-WT cells. Unlike ATRA, ST1926 and CD437 arrest cells in the G(2)/M phase of the cell cycle and induce apoptosis in all F9 cell lines. Our data indicate that RAR gamma and the classic retinoid pathway are not relevant for the anti-proliferative 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 gamma(-/-) 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 gamma-independent manner, provides novel insights into the possible molecular determinants underlying the activity of RRMs in vitro. Furthermore, it suggests that RAR gamma-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 gamma-/- tumors have increased life spans after treatment with ST1926 and CD437 relative to their F9-WT counterparts.

• 出版日期2006-9