Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism
Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism
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DOI：
10.1021/jm070569b
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发表时间：
2007-09-06
影响因子：
7.3
通讯作者：
Koch, Tad H.
中科院分区：
文献类型：
--
作者：
Kalet, Brian T.;McBryde, Meagan B.;Koch, Tad H.
多柔比星的机制进行了比较与多唑烷，多柔比星甲醛共轭物。多唑烷对67种人类癌细胞系（但不是心肌细胞）生长抑制的IC 50比多柔比星低32倍。与多柔比星的生长抑制相比，多唑烷的生长抑制与DNA交联剂的生长抑制相关性更好。阿霉素通过拓扑异构酶11依赖性机制诱导HCT-116结肠癌细胞和HL-60白血病细胞的G2/M期阻滞。多恶唑烷不能诱导HCT-116细胞的G2/M期阻滞，但诱导凋亡的效果比阿霉素好4倍。多唑烷对HL-60/MX2细胞（HL-60细胞的拓扑异构酶11缺陷衍生物）生长抑制的IC 50比多柔比星的IC 50低1420倍，多唑烷诱导凋亡的IC 50比多柔比星高15倍。此外，多沙唑烷在拓扑异构酶11活性测定中几乎没有影响。这些数据表明，阿霉素和多唑烷通过不同的机制诱导细胞凋亡，多唑烷的细胞毒性是拓扑异构酶11独立的。
The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin-formaidehyde conjugate. The IC50 for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Growth inhibition by doxazolidine correlates better with growth inhibition by DNA cross-linking agents than with growth inhibition by doxorubicin. Doxorubicin induces G2/M arrest in HCT-116 colon cancer cells and HL-60 leukemia cells through a well-documented topoisomerase 11 dependent mechanism. Doxazolidine fails to induce a G2/M arrest in HCT-116 cells but induces apoptosis 4-fold better than doxorubicin. The IC50 for doxazolidine growth inhibition of HL-60/MX2 cells, a topoisomerase 11 deficient derivative of HL-60 cells, is 1420-fold lower than the IC50 for doxorubicin, and doxazolidine induces apoptosis 15-fold better. Further, doxazolidine has little effect in a topoisomerase 11 activity assay. These data indicate that doxorubicin and doxazolidine induce apoptosis via different mechanisms and doxazolidine cytotoxicity is topoisomerase 11 independent.