adarotene and Neoplasms

ST1926 is a novel related adamantyl retinoid endowed with potent antiproliferative and apoptogenic activity. The drug induced an early G1/S cell cycle arrest which was associated with a typical DNA damage response including modulation of genes involved in cell cycle regulation and DNA repair. The evidence of the drug ability to induce a significant extent of DNA strand breaks after short-term exposure is consistent with the cellular response. ST1926 is active by oral administration both on hematological and on solid tumors. The more marked antitumor effect showed by ST1926 in immuno-competent mice rather than in tumor xenografts suggests a contribution of indirect host-mediated antitumor effects in addition to a direct antiproliferative activity against tumor cells.

Topics: Adamantane; Animals; Antineoplastic Agents; Apoptosis; Cinnamates; Disease Models, Animal; Humans; Leukemia, Myeloid, Acute; Mice; Neoplasms; Sensitivity and Specificity; Treatment Outcome; Tumor Cells, Cultured

(E)-4-[3-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure-anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3'-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.

Topics: Adamantane; Antineoplastic Agents; Apoptosis; Cell Division; Cell Line, Tumor; Cinnamates; Dimerization; Enzyme Inhibitors; Humans; Models, Molecular; Neoplasms; Protein Tyrosine Phosphatase, Non-Receptor Type 11