Garlic-derived organosulfur compounds and other novel compounds inhibit proliferation of human colon cancer cells by suppressing microtubule dynamics.

摘要

There is increasing interest in the discovery of novel agents for colorectal cancer prevention and treatment. Epidemiological and experimental studies provide evidence that components of garlic have anticancer activity. We previously reported that the garlic-derived compound S-allylmercaptocysteine (SAMC) causes growth inhibition, mitotic arrest and induction of apoptosis in human colon cancer cells. In the present study we found that these effects of SAMC are associated with depolymerization of cellular microtubules (MTs) in interphase cells and formation of aberrant spindles in mitotic cells, as a consequence of the direct interaction of this compound with tubulin. We also obtained evidence that activation of JNK1 and caspase-3 play important roles in SAMC-induced apoptosis. We then compared the effects of SAMC to that of a series of garlic-derived compounds and other S-cysteinyl derivatives. We found that in SW480 cells two allyl disulfide compounds, SAMC and diallyl disulfide (DADS), inhibit growth, induce apoptosis and arrest the cell cycle at G2/M, while their allyl sulfide analogues, S-allylcysteine and diallyl sulfide, and other saturated sulfide or disulfide compounds, are devoid of these effects. These results emphasize the importance of both the allyl and the disulfide groups in the growth inhibitory effect of this class of compounds. Further mechanistic studies indicate that DADS also exerts its antiproliferative effects by inhibition of MT dynamics thus interfering with normal MT function. Both SAMC and DADS induce apoptosis via a mitochondria-mediated pathway. We found that the synthetic organosulfur compound S-trityl-L-cysteine is a very potent inhibitor of cell growth and also causes mitotic cell cycle arrest, but does not exert a direct effect on MTs.; Sulindac and its derivatives have been shown to exert anticancer activities in various experimental systems. In the present study we investigated the mechanisms of action of OSI-461, a novel synthetic derivative of sulindac sulfone, in SW480 human colon cancer cells. We found that OSI-461 inhibits cell growth, with an IC50 value of 1 muM, arrests the cell cycle at the M phase, and induces apoptosis. Furthermore, when tested at 1--2 muM it suppressed MT dynamics and induced aberrant mitotic spindles, and caused MT depolymerization and inhibited spindle formation when tested at 5 muM. We also obtained evidence that these effects of this compound are independent of its ability on protein kinase G activation.; In summary, the present study suggests that SAMC, DADS and OSI-461 are novel MT-interfering agents and provides new insights into the molecular mechanisms of their antitumor effects.