The nuclear retinoic acid receptors (RARs) are transcriptional transregulators, which control the expression of specific gene subsets subsequently to ligand binding and to strictly controlled phosphorylation processes. RARs consist of three subtypes, α (NR1B1), β (NR1B2) and γ (NR1B3), encoded by separate genes. RARs function as ligand-dependent transcriptional regulators, heterodimerized with retinoid X receptors (RXRs). Among them, RAR-α interacts with retinoic acid, a derivative of vitamin A, which plays an important role in cell growth, differentiation, and the formation of organs in embryonic development. In addition, Retinoids have been shown to suppress cancer cell growth and prevent mammary cancer in carcinogen rodent models.

AM580 (also called CD336 or NSC608001 or Ro 40-6055) is a selective RARα agonist, which has a 10-fold greater affinity for RARα than RARβ, is almost inactive against RARγ.

In two transgenic mouse models, mammary tumor virus (MMTV)-neu and MMTV-wnt, AM580 inhibits the wnt pathway, measured by loss of nuclear β-catenin, suggesting partial oncogene dependence of therapy. In addition, AM580 strongly inhibited the neu and wnt1 induced mammary gland hyperplasia, the incidence of microscopic tumors. Moreover, AM580 strongly inhibits lung metastases, leading to a significant increase in tumor-free survival in both models. AM580 also increases RARβ and lowered the level of RARγ. In the MMTV-wnt1 model, AM580 also induces differentiation. Besides, AM580 inhibits proliferation and induces apoptosis occurred in both oncogene-induced tumors.

In acute promyelocytic leukemia (APL) cells, AM580 induces granulocytic maturation. AM580 has a selective cyto-differentiating activity on PML-RAR-containing APL blasts. This selective action is correlated with the ability of AM580 to transactivate retinoic-acid-responsive-element (RARE)-containing genes in the presence of PML-RAR much better than in the presence of RARα.

Taken together, AM580 is a selective RARα agonist with anticancer effects.


[1] Y Lu, et al. Oncogene. 2010 Jun 24;29(25):3665-76.

[2] M Gianní, et al. Blood. 1996 Feb 15;87(4):1520-31.