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First published on June 20, 2006; DOI: 10.1124/mol.106.023614

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Received for publication February 23, 2006.
Revised June 13, 2006.
Accepted for publication June 15, 2006.

ANTITUMOR ACTIVITY OF THE RETINOID RELATED MOLECULES, ST1926 AND CD437 IN F9 TERATOCARCINOMA: ROLE OF RAR{gamma} AND RETINOID-INDEPENDENT PATHWAYS

Edoardo Parrella 1, Maurizio Gianni' 1, Maddalena Fratelli 1, Maria Monica Barzago 1, Ivan Jr Raska 1, Luisa Diomede 1, Mami Kurosaki 1, Claudio Pisano 2, Paolo Carminati 2, Lucio Merlini 3, Sabrina Dallavalle 3, Michele Tavecchio 4, Cecile Rochette-Egly 5, Mineko Terao 1, Enrico Garattini 1*

1 Laboratory of Molecular Biology, Centro Catullo e Daniela Borgomainerio, Istituto di Ricerche Farmac 2 Sigma-Tau Industrie Farmaceutiche Riunite, Pomezia, Italy 3 Dipartimento di Scienze Molecolari Agroalimentari, Universita degli Studi di Milano, Milano, Italy 4 Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri", via Eritrea 62, 20157 Mil 5 de Genetique et Biologie Moleculaire, 67404, Illkirch, France

* Address correspondence to: E-mail: egarattini{at}marionegri.it

Abstract

The retinoid related molecules (RRMs), ST1926 and CD437, are promising anti-cancer agents. We compared the 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-WT; F9{gamma}-/-, deleted of the RAR{gamma} gene; F9{gamma}51, a F9{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 G2/M phase of the cell cycle and induce apoptosis in all F9 cell lines. Our data indicate that RAR{gamma} and the classical retinoid pathway are not relevant for the anti-proliferative and apoptotic activities of RRMs in vitro. Increases in cytosolic calcium are fundamental for apoptosis, as the process is abrogated by intracellular calcium chelators. Comparison of the gene expression profiles associated with ST1926 and ATRA in F9-WT and F9{gamma}-/- indicates that the RRM activates a conspicuous non-retinoid response in addition to the classical 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 RAR{gamma}-dependent responses relevant to the activity of RRMs in vivo. Indeed, the receptor hinders the anti-tumor activity in vivo, as both syngeneic and immunosuppressed SCID mice bearing F9{gamma}-/- tumors have increased life spans after treatment with ST1926 and CD437 relative to the F9-WT counterparts.


Key words: Apoptosis, Genetics, Mechanisms of cell killing/apoptosis, Transcription targets


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