Biological evaluation on different human cancer cell lines of novel colchicine analogs

Three new 7-O-substituted deacetamidothiocolchicine derivatives have been e valuated for their antitumor activity against various human tumor cell line s, some of which express the multidrug resistance (MDR) phenotype, for thei r impact on the cell cycle and their binding to tubulin. Colchicine and thi ocolchicine were used as reference compounds. Thiocolchicine was the most a ctive agent on MDR-negative cells in terms of growth inhibition, whereas fo r multidrug-resistant cells, thiocolchicone was the most active compound (I C50 = 14 nM). As indicated by statistical analysis, a perfect agreement for the potency order (IC50 values) of the compounds between all the MDR-negat ive cancer cells (k = 1.00), a poor agreement between MDR-positive and MDR- negative cancer lines, and a moderate agreement (k = 0.50) between the two resistant cancer cells MCF-7 ADRr and CEM VBL were observed. To gain furthe r insight into the mechanism of the antitumor activity of colchicinoids, th e most active compounds, colchicone and thiocolchicone, were selected to ev aluate their effect on cell cycle, apoptosis, and tubulin interaction. The highest recruitment activity into the G(2)/M phase of the cell cycle was de tected in thiocolchicone-treated breast cancer cells. Interestingly, after 72 h of culture: when the cell cycle block subsided, a consistent amount of DNA fragmentation, a hallmark of apoptosis, was evident. Morphological ana lysis of MCF-7 ADRr cells confirmed this hypothesis and revealed that thioc olchicone was able to induce apoptosis in this MDR-bearing model. We also d emonstrated, using flow cytometry, that thiocolchicone interacts with alpha - and beta-tubulin, thereby affecting the expression of both subunits.