No abstract

Potential antiproliferative effect of isoxazolo-and thiazolo coumarin derivatives on breast cancer mediated bone and lung metastasesThe study highlights the current progress in the development of coumarin scaffolds for drug discovery as novel anticancer agents in metastatic breast cancer. Eight compounds, combining the coumarin core and five membered heterocycles (isoxazoles and thiazoles) in hydrazinyldiene--chroman-2,4-diones, were characterized in terms of a potential antiproliferative effect on bone (SCP1833) and lung (SCP4175) metastatic breast cancer cell lines using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Cell viability was evaluated after 48 and 72 h of treatment and the 50 % inhibitory concentrations were determined. The results demonstrated dose-and time-dependent activity, with the most potent molecules having a thiazole moiety, without or with additional methyl group(s) attached to the carbon(s) at position(s) 5 and/or 4 in the thiazole ring. These molecules possessed significantly higher potency against both test cell lines compared to 4-hydroxycoumarin.

This study evaluates the effects of previously synthesized hydrazinyldiene-chroman-2,4-diones on cell proliferation and apoptosis, cell cycle distribution and migration capacity of MCF-7 breast cancer cells in synergy with doxorubicin. Physicochemical properties of the synthesized compounds were correlated with their structure and activity. Significant cell viability decrease in comparison with the effect of doxorubicin alone and the reference 4-hydroxycoumarin was observed when combination treatment comprising doxorubicin and the title compounds was applied. Synergistic effect with doxorubicin was also observed in down-regulation of phospho-Thr 308Akt levels, confirming reduced proliferation and increased apoptosis. Combined treatment increased the percentage of cells arrested at the G 2 /M stage. Additive inhibition of cell migration was also observed, pointing to the possibility of reducing the risk of metastases. With their solubility profile and log D 7.4 , all the synthesized compounds follow Lipinski's rule of five for good permeability (absorption) potential.

Possible synergistic effect of tamoxifen (2 μM) and hydrazinyldiene-chroman-2,4-diones (10-100 μM) was examined with an aim to create more effective treatment for ER+ breast cancer. Anti-breast cancer effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells using MTT and alamarBlue assays. Cell viability was evaluated after 48h-treatment and the ICs50 of the coumarin derivatives were determined. The apoptotic effect was evaluated by detection of PARP cleavage and reduced activity of the survival kinase Akt. The results demonstrated dose-dependent activity, with a percent of growth inhibition after combination treatment being significantly higher (53% to 79%, 10 μM and 100 μM, respectively) than the one in the cell lines treated with tamoxifen (29% to 37%) and the synthesized coumarin derivatives alone (11% to 68%, 10 μM and 100 μM, respectively). The ICs50 of the synthesized compounds significantly decreased in synergy with tamoxifen (33% to 51%). Coumarin derivative having thiazole moiety with additional methyl groups attached to the carbons at positions 5 and 4 in the thiazole ring showed to be the most potent, with IC50 20 µM when administered alone and 10 µM in synergy with tamoxifen. The levels of phospho-Thr308 Akt were down-regulated by the combination treatment, pointing to tyrosine kinase phosphorylation inhibition. In conclusion, the novel coumarin derivatives enhance the activity of tamoxifen and this combination may be suitable for prevention of ER+ breast cancer or development of related compounds. Further studies are needed to elucidate precisely the type of receptor involved in the activity and the mechanism of action.