Syrovets T, Büchele B, Gedig E, Slupsky J R, Simmet T
Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Germany.
Mol Pharmacol. 2000 Jul;58(1):71-81. doi: 10.1124/mol.58.1.71.
Acetyl-boswellic acids (acetyl-BA) are pentacyclic triterpenes derived from the gum resin of frankincense. We have previously shown that these compounds are effective cytotoxic agents, acting through a mechanism that appears to involve the inhibition of topoisomerase activity. We have now investigated the mechanism of action of acetyl-BA and show that these compounds are more potent inhibitors of human topoisomerases I and IIalpha than camptothecin, and amsacrine or etoposide, respectively. Our data demonstrate that acetyl-BA and, to a lesser extent, some other pentacyclic triterpenes, such as betulinic acid, ursolic acid, and oleanolic acid, inhibit topoisomerases I and IIalpha through a mechanism that does not involve stabilization of the cleavable complex or the intercalation of DNA. Surface plasmon resonance analysis revealed that topoisomerases I and IIalpha bind directly to an immobilized derivative of acetyl-BA. This acetyl-BA derivative interacts with human topoisomerases through high-affinity binding sites yielding K(D) values of 70.6 nM for topoisomerase I and 7.6 nM for topoisomerase IIalpha. Based on our data, we propose that acetyl-BA inhibit topoisomerases I and IIalpha through competition with DNA for binding to the enzyme. Thus, acetyl-BA are a unique class of dual catalytic inhibitors of human topoisomerases I and IIalpha.
乙酰基乳香酸（acetyl-BA）是从乳香的树胶脂中提取的五环三萜类化合物。我们之前已经表明，这些化合物是有效的细胞毒性剂，其作用机制似乎涉及抑制拓扑异构酶活性。我们现在研究了乙酰基-BA的作用机制，结果表明这些化合物对人拓扑异构酶I和IIα的抑制作用分别比喜树碱、安吖啶或依托泊苷更强。我们的数据表明，乙酰基-BA以及在较小程度上的其他一些五环三萜类化合物，如桦木酸、熊果酸和齐墩果酸，通过一种不涉及稳定可裂解复合物或DNA嵌入的机制来抑制拓扑异构酶I和IIα。表面等离子体共振分析表明，拓扑异构酶I和IIα直接与固定化的乙酰基-BA衍生物结合。这种乙酰基-BA衍生物通过高亲和力结合位点与人拓扑异构酶相互作用，拓扑异构酶I的解离常数（K(D)）值为70.6 nM，拓扑异构酶IIα的解离常数（K(D)）值为7.6 nM。基于我们的数据，我们提出乙酰基-BA通过与DNA竞争结合酶来抑制拓扑异构酶I和IIα。因此，乙酰基-BA是一类独特的人拓扑异构酶I和IIα的双催化抑制剂。
