Sensitization for anticancer drug-induced apoptosis by betulinic acid
Sensitization for anticancer drug-induced apoptosis by betulinic acid
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DOI：
10.1593/neo.04442
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发表时间：
2005-02-01
期刊：
影响因子：
4.8
通讯作者：
Debatin, KM
中科院分区：
文献类型：
--
作者：
Fulda, S;Debatin, KM
我们先前描述了桦木酸（BetA），一种天然存在的五环三萜类化合物，通过线粒体途径诱导肿瘤细胞凋亡。在这里，我们第一次提供证据表明，BetA与抗癌药物合作，诱导细胞凋亡，抑制肿瘤细胞的克隆存活。BetA和抗癌药物的联合治疗共同诱导线粒体膜电位的丧失和细胞色素c和Smac从线粒体的释放，导致半胱天冬酶的激活和细胞凋亡。Bcl-2的过表达阻断了线粒体的扰动，也抑制了BetA和抗癌药物的协同作用，表明协同作用涉及线粒体途径。值得注意的是，对于具有不同作用模式的各种细胞毒性化合物（例如，阿霉素、顺铂、紫杉醇、VP 16或放线菌素D）。重要的是，BetA和抗癌药物协同诱导不同肿瘤细胞系（包括p53突变细胞）和原发性肿瘤细胞的凋亡，但不诱导人成纤维细胞的凋亡，这表明存在一定的肿瘤特异性。这些结果表明，使用BetA作为敏化剂在化疗为基础的联合方案可能是一种新的策略，以提高抗癌治疗的疗效，这值得进一步研究。
We previously described that betulinic acid (BetA), a naturally occurring pentacyclic triterpenoid, induces apoptosis in tumor cells through the mitochondrial pathway. Here, for the first time, we provide evidence that BetA cooperated with anticancer drugs to induce apoptosis and to inhibit clonogenic survival of tumor cells. Combined treatment with BetA and anticancer drugs acted in concert to induce loss of mitochondrial membrane potential and the release of cytochrome c and Smac from mitochondria, resulting in activation of caspases and apoptosis. Overexpression of Bcl-2, which blocked mitochondrial perturbations, also inhibited the cooperative effect of BetA and anticancer drugs, indicating that cooperative interaction involved the mitochondrial pathway. Notably, cooperation of BetA and anticancer drugs was found for various cytotoxic compounds with different modes of action (e.g., doxorubicin, cisplatin, Taxol, VP16, or actinomycin D). Importantly, BetA and anticancer drugs cooperated to induce apoptosis in different tumor cell lines, including p53 mutant cells, and also in primary tumor cells, but not in human fibroblasts indicating some tumor specificity. These findings indicate that using BetA as sensitizer in chemotherapy-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy, which warrants further investigation.