[Effects of lidamycin on apoptotic gene expressions and cytoskeleton in human hepatoma bel-7402 cells].
ABSTRACT Lidamycin, one of enediyne antitumor antibiotics, was isolated by our institute. It is the focus of intense due to its unique chemical structure and potent cytotoxicities to tumor cells in vivo and in vitro. In addition to cleavage of DNA, effect of lidamycin on apoptotic gene expressions and cytoskeleton may involve in its high activities. To further elucidate its mechanism, we have observed the effect of lidamycin on the above-mentioned factors in human hepatoma bel-7402 cells.
The gene expressions were determined by Northern blot and dot blotanalysis. The changes of microfilament and microtubule were detected by indirect immunofluorescent method and the apoptotic cells were detected with mitochondria-specific apoptotic dye Mitosensor.
The obvious increment of c-myc and c-fos gene expressions and the inhibition of N-ras gene expression in bel-7402 cells were observed following lidamycin treatment (0.1-10 nmol/L) for 8 h. The arrangement of microfilament in the cells became regular and was similar to nonmalignant normal cells, but there was no effect on microtubule when the bel-7402 cells were treated with lidamycin 10 nmol/L for 8 h. No apoptotic cells were detected with Mitosensor in the lidamycin-treated cells for 8 h.
Lidamycin at lower concentrations can markedly affect the expression of the apoptosis related genes and the distribution of the cytoskeleton in the hepatoma bel-7402 cells. The results are helpful to elucidate the molecular mechanism of potent cytotoxicities of lidamycin to tumor cells.
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ABSTRACT: The natural compounds that interfere with cellular DNA such as enediyne antitumor antibiotics might be important chemotherapeutic agents for the treatment of cancer. In this article, the pharmacology and anticancer activity of the enediyne antitumor agents that are approved for clinical use and undergoing pre-clinical or clinical evaluation are reviewed. Most enediyne compounds have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to other chemotherapeutic drugs. Enediyne derivatives, such as an immunoconjugate composed of an enediyne compound and monoclonal antibody, reveal stronger activity and selectivity for human cancer cells. The mechanism underlying the anticancer activity of these enediyne antitumor agents may mainly lie in their generation of DNA double-strand breaks. Increasing evidence shows that the enediyne-induced DNA double-strand breaks can engage the activation of DNA damage response proteins, arresting cell cycle progression and eventually leading to apoptotic cell death. Continued investigation of the mechanisms of action and development of new enediyne derivatives and conjugates may provide more effective therapeutics for cancer treatments.Current Molecular Pharmacology 01/2008; 1(1):50-60.