Induction of apoptosis through tubulin inhibition in human cancer cells by new chromene-based chalcones.

CONTEXT As microtubules are highly involved in cellular growth, it appears to be a preferential target for cancer treatment. Therefore, many efforts have been performed to discover drugs that affect on microtubule function. Several microtubule inhibitors are in various stages of laboratory evaluations and clinical trials. OBJECTIVE A series of chromene-based chalcones with chlorine, methoxy, fluorine, tetrahydropyranyloxy and cyanide substituents were prepared and evaluated for cytotoxic effects against K562 and SK-N-MC cell lines, and the inhibitory effect on tubulin polymerization was studied as well. MATERIALS AND METHODS MTT, tubulin polymerization assays and binding measurements were evaluated by using related spectroscopy. Immunocytochemical study, morphological observations and apoptosis assay were examined using a fluorescence microscope and a flow cytometer. RESULTS (E)-3-(6-Chloro-2H-chromen-3-yl)-1-(3,4,5-trimethoxyphenyl) prop-2-en-1-one (compound 14) proved to be the most active in this series as an inhibitor of tubulin assembly [IC₅₀, 19.6 µM] and cytotoxic agent on K562 cells [IC₅₀, 38.7 µM]. Furthermore, these compounds exhibited a strong inhibitory effect on tubulin polymerization and reduced the in vitro assembly and bundling of proto-filaments. Also, compound 14 bound to the tubulin with a dissociation constant of 9.4 ± 0.7 µM and induced conformational changes in this protein. DISCUSSION AND CONCLUSION This study suggests that the compound 14 could be a good antitumor agent because of its biological functions. Compound 14 appears to bind directly to tubulin and thereby perturbs microtubule stability and the function of the spindle apparatus, which causes cancer cells to arrest and undergo apoptosis.