科研之友
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摘要
Anthracycline antibiotics are extensively used in conventional cancer chemotherapy of solid tumors and hematological malignancies. The clinical efficacy of these drugs, mainly doxorubicin and daunorubicin is however, limited by severe side effects, particularly the cardiotoxicity. Despite the development of numerous compounds which improve antitumour activity or reduce toxicity, only a very limited number of anthracycline derivatives is commercially available. One of these new drugs with reduced cardiac toxicity in comparison to anthracycline of the first generation is aclarubicin, produced by Streptomyces galilaeus. Although, aclarubicin is used less intensively than doxorubicin or daunorubicin in conventional anticancer protocols, it is beneficial in clinical trials of acute non-lymphocytic leukaemia in patients, who are resistant to the first-line chemotherapy, because of lack of cross-resistance to others anthracyclines. Molecules of aclarubicin are consisted of a planar polyaromatic ring system named aclavinone which contains a quinone moiety. This structure is linked by a O-glycosidic bond to three saccharides (rhodosamine, 2-deoxyfucose and cinerulose A). In comparison to the other anticancer antibiotics, there is little information, in respect of the mechanism of ACL antineoplastic efficacy. The mechanisms of action of this trisaccharide anthracycline are different from the classical monosaccharide doxorubicin and daunorubicin. Fluorescence microscopic observations indicate that aclarubicin localizes mainly in the cytoplasm of the cells in contrast to the anthracyclines of first generation which are observed mainly in the nucleus. Extension of the time of incubation with aclarubicin does not change its localization in the cell. This review presents also the current knowledge about interaction of aclarubicin with cell membrane, its transport across the membrane on the way of flip-flop mechanism and role of this structure in multidrug resistance. Aclarubicin is a strong DNA intercalating agent that prevents the binding of topoisomerase II to DNA. Recent studies have shown that aclarubicin also inhibits topoisomerase I in a concentration-dependent manner. Exposure of cell to aclarubicin is accompanied by the occurrence of DNA damage as determined by the single-cell microgel assay (comet assay). However, the primary intracellular effect of aclarubicin. is more likely to be an inhibition of RNA synthesis. Aclarubicin exerts also a potent inhibitory effect on migration and invasion of the cancer cells. Drug generates also reactive oxygen species but substantially less, in comparison to other anthracyclines. Several studies have indicate that reactive oxygen species are capable of damaging not only cellular macromolecules but they also cause cell death either by apoptosis or necrosis. Anthracycline antibiotics induce cell death with mitochondrial or receptor apoptosis pathway. Ceramide, p53 protein or Bcl-2 protein family may function as mediators of apoptosis. It has been observed p53 protein increase in ACL-treated cells. Numerous studies also have shown that anthracyclines of first generation induce both apoptosis and necrosis. By contrast ACL-treated cells died prevalently by apoptosis. Apoptosis and necrosis mode of cell death depends on cell types, their sensitivity to ACL and the time of incubation.
- 出版日期2008
