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Molecular Pharmacology

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Research ArticleArticle

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 γ and Retinoid-Independent Pathways

Edoardo Parrella, Maurizio Giannì, Maddalena Fratelli, Maria Monica Barzago, Ivan Raska Jr, Luisa Diomede, Mami Kurosaki, Claudio Pisano, Paolo Carminati, Lucio Merlini, Sabrina Dallavalle, Michele Tavecchio, Cecile Rochette-Egly, Mineko Terao and Enrico Garattini
Molecular Pharmacology September 2006, 70 (3) 909-924; DOI: https://doi.org/10.1124/mol.106.023614
Edoardo Parrella
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Maurizio Giannì
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Maddalena Fratelli
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Maria Monica Barzago
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Ivan Raska Jr
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Luisa Diomede
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Mami Kurosaki
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Claudio Pisano
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Paolo Carminati
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Lucio Merlini
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Sabrina Dallavalle
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Michele Tavecchio
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Cecile Rochette-Egly
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Mineko Terao
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Enrico Garattini
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Abstract

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.

Footnotes

  • This work was made possible by the financial support of the Associazione Italiana per la Ricerca contro il Cancro (AIRC), the Istituto Superiore di Sanità, and the Fondo d'Investimento per la Ricerca di Base (FIRB). The financial support of the Weizmann-Negri Foundation is also acknowledged.

  • ABBREVIATIONS: ATRA, all-trans-retinoic acid; RAR, retinoic acid receptor; RXR, retinoid X receptor; RRM, retinoid-related molecule; CD437, (E)-3-(4′-hydroxy-3′-adamantylbiphenyl-4-yl)acrylic acid; ST1926, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid; BAPTA, 1,2 bis (2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetoxymethyl ester); FURA-2, Fura-2 acetoxymethyl ester; DEVD-amc, N-acetyl-Asp-Glu-Val-Asp-amino-4-methylcoumarin; PBS, phosphate-buffered saline; PI, propidium iodide; RT-PCR, reverse transcription-polymerase chain reaction; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance; WT, wild-type; FACS, fluorescence-activated cell sorting; TNF, tumor necrosis factor; AV, annexin V.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received February 23, 2006.
    • Accepted June 15, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (3)
Molecular Pharmacology
Vol. 70, Issue 3
1 Sep 2006
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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 γ a…
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Research ArticleArticle

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 γ and Retinoid-Independent Pathways

Edoardo Parrella, Maurizio Giannì, Maddalena Fratelli, Maria Monica Barzago, Ivan Raska, Luisa Diomede, Mami Kurosaki, Claudio Pisano, Paolo Carminati, Lucio Merlini, Sabrina Dallavalle, Michele Tavecchio, Cecile Rochette-Egly, Mineko Terao and Enrico Garattini
Molecular Pharmacology September 1, 2006, 70 (3) 909-924; DOI: https://doi.org/10.1124/mol.106.023614

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Research ArticleArticle

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 γ and Retinoid-Independent Pathways

Edoardo Parrella, Maurizio Giannì, Maddalena Fratelli, Maria Monica Barzago, Ivan Raska, Luisa Diomede, Mami Kurosaki, Claudio Pisano, Paolo Carminati, Lucio Merlini, Sabrina Dallavalle, Michele Tavecchio, Cecile Rochette-Egly, Mineko Terao and Enrico Garattini
Molecular Pharmacology September 1, 2006, 70 (3) 909-924; DOI: https://doi.org/10.1124/mol.106.023614
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