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.
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 RARgamma agonists than ATRA. We used three teratocarcinoma cell lines to evaluate the significance of RARgamma in the activity of RRMs: F9-wild type (WT); F9gamma-/-, lacking the RARgamma gene; F9gamma51, aF9gamma-/-derivative, complemented for the RARgamma 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 RARgamma 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 F9gamma-/-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 RARgamma-independent manner, provides novel insights into the possible molecular determinants underlying the activity of RRMs in vitro. Furthermore, it suggests that RARgamma-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 F9gamma-/- tumors have increased life spans after treatment with ST1926 and CD437 relative to their F9-WT counterparts.
Parrella
Edoardo
E
Institut de Genetique et Biologie Moleculaire, Illkirch, France.
Giannì
Maurizio
M
Fratelli
Maddalena
M
Barzago
Maria Monica
MM
Raska
Ivan
I
Diomede
Luisa
L
Kurosaki
Mami
M
Pisano
Claudio
C
Carminati
Paolo
P
Merlini
Lucio
L
Dallavalle
Sabrina
S
Tavecchio
Michele
M
Rochette-Egly
Cecile
C
Terao
Mineko
M
Garattini
Enrico
E
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002934:Cinnamates / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects; D004195:Disease Models, Animal; D016195:G2 Phase / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D018243:Teratocarcinoma / Q000473:pathology*; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
D000218:Adamantane; D000970:Antineoplastic Agents; D002118:Calcium; D002934:Cinnamates; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; C099555:CD 437