Abstract
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.
Highlights
The balance between proliferation and cell death, mainly apoptosis, is crucial in determining the overall growth and regression of tumor
The results showed that only synthesized coumarin derivatives, but not 4-HC induced anti-proliferative effect in MCF-7 cell lines
Apoptotic effects of Tam and coumarin derivatives on breast cancer cells We investigated whether the combination of Tam and 4-HC or coumarin derivatives synergistically affected apoptosis of MCF-7 cells
Summary
The balance between proliferation and cell death, mainly apoptosis, is crucial in determining the overall growth and regression of tumor. For this reason, traditional cytotoxic agents, such as DNA intercalating agents, DNA cross-linking agents, topoisomerase inhibitors, cytoskeleton disrupting agents and antimetabolites have usually been targeted to damage the aberrantly dividing cancer cells by interrupting the cell division process (Hengartner, 2000; Johnstone et al, 2002; Mehlen and Puisieux, 2006). To achieve the best outcome for the cancer patients, often several anti-cancer agents that inhibit multiple targets or redundant pathways are combined in the treatment regimen (Li et al, 2014; LoRusso et al, 2012). Treatment combinations, including combination of nonspecific small molecule chemotherapeutic agents have been successfully applied to various cancer types, including (metastatic) breast cancer (Lee and Nan, 2012)
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