Mechanism of synergistic action of all-trans- or 9-cis-retinoic acid and interferons in breast cancer cells.
Combination of all-trans-retinoic acid (RA) with either interferon-alpha or -gamma resulted in a synergistic amplification of the anti-proliferative effect on cultured breast cancer cells. RA could be replaced by other biologically active retinoids. The synergism was also observed for the induction of 2'-5'-oligoadenylate synthetase, an enzyme which is involved in anti-viral activity of interferons and possibly in growth regulation of tumor cells. Combination of RA with interferon-gamma increased the down-regulation of specific binding sites for [125I]interferon-gamma. On the other hand interferons had no effect on the cytoplasmic binding protein for RA. Comparing all-trans- with 9-cis-RA, the latter was more effective in inhibiting tumor cell growth and in inducing synergism with interferon-gamma. This would indicate that retinoic X receptors are more important in mediating these effects than the RA receptors (RARs). This assumption is also supported by the failure of Ro-415253, a specific RAR-alpha antagonist, to reduce the synergistic interaction of RA with interferon with respect to growth inhibition.
Marth
C
C
Department of Obstetrics and Gynecology, Innsbruck University Hospital, Austria.
Widschwendter
M
M
Daxenbichler
G
G
D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000502:physiology; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D013237:Stereoisomerism; D014157:Transcription Factors; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D007371:Interferon-gamma