The efficacy of 9-cis retinoic acid in experimental models of cancer.
9-cis retinoic acid (9-cis RA) is a retinoid receptor pan-agonist that binds with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Using a variety of in vivo and in vitro cancer models, we present experimental data that 9-cis RA has activity as a potential chemotherapeutic agent. Treatment of the human promyelocytic leukemia cell line HL-60 with 9-cis RA decreases cell proliferation, increases cell differentiation, and increases apoptosis. Induction of apoptosis correlates with an increase in tissue transglutaminase (type II) activity. In vivo, 9-cis RA induces complete tumor regression of an early passage human lip squamous cell carcinoma xenograft. Finally, 9-cis RA inhibits the anchorage-independent growth of the human breast cancer cell lines MCF-7 and LY2 (an antiestrogen-resistant MCF-7 variant). Transient co-transfection assays indicate that 9-cis RA inhibits estrogen receptor transcription of an ERE-tk-LUC reporter through RAR or RXR receptors. These data suggest that retinoid receptors can antagonize estrogen-dependent transcription and provides one possible mechanism for the inhibition of cell growth by 9-cis RA in breast cancer cell lines. In summary, these findings present evidence that 9-cis RA has a wide range of activities in human cancer models.
Gottardis
M M
MM
Department of Pharmacology, Ligand Pharmaceuticals, San Diego CA, USA.
Lamph
W W
WW
Shalinsky
D R
DR
Wellstein
A
A
Heyman
R A
RA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*
D014212:Tretinoin