Potent inhibition of tumor survival in vivo by β-lapachone plus taxol:: Combining drugs imposes different artificial checkpoints
Potent inhibition of tumor survival in vivo by β-lapachone plus taxol:: Combining drugs imposes different artificial checkpoints
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DOI：
10.1073/pnas.96.23.13369
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发表时间：
1999-11-09
影响因子：
11.1
通讯作者：
Pardee, AB
中科院分区：
文献类型：
--
作者：
Li, CJ;Li, YZ;Pardee, AB
在用两种低分子化合物β-拉帕酮和紫杉醇联合处理后，在培养的广泛的人类癌细胞中可以看到肿瘤集落的消融。它们协同诱导培养的卵巢、乳腺、前列腺、黑色素瘤、肺癌、结肠癌和胰腺癌细胞死亡。这种协同作用依赖于时间表；即必须同时或在β-拉帕酮之后添加紫杉醇，这种联合疗法对小鼠移植前移植的人卵巢和前列腺癌具有异常强大的抗肿瘤活性。几乎没有寄主毒性。细胞可以在细胞周期检查点进行凋亡，这是一种消除缺陷细胞以确保基因组完整性的机制。我们假设，当细胞与激活一个以上不同细胞周期检查点的药物同时处理时，相互冲突的调控信号分子的产生会诱导癌细胞凋亡。β-拉帕酮使细胞周期延迟于G(1)晚期和S期，紫杉醇使细胞滞留在G(2)/M期，两种药物处理的细胞在多个检查点延迟后才开始发生细胞凋亡。我们的发现为开发抗癌治疗提供了一条途径，通过利用细胞周期检查点上容易发生细胞凋亡的“碰撞”。
Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of beta-lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after beta-lapachone, This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. beta-lapachone causes cell-cycle delays in late G(1) and S phase, and taxol arrests cells at G(2)/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone "collisions" at cell-cycle checkpoints.