Hägg Maria, Berndtsson Maria, Mandic Aleksandra, Zhou Rong, Shoshan Maria C, Linder Stig
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute and Hospital, Stockholm, Sweden.
Mol Cancer Ther. 2004 Apr;3(4):489-97.
Anticancer drugs often show complex mechanisms of action, including effects on multiple cellular targets. Detailed understanding of these intricate effects is important for the understanding of cytotoxicity. In this study, we examined apoptosis induction by ellipticines, a class of cytotoxic plant alkaloids known to inhibit topoisomerase II. The potent ellipticine derivative 6-propanamine ellipticine (6-PA-ELL) induced rapid apoptosis in MDA-MB-231 breast cancer cells, preceded by a conformational change in Bak and cytochrome c release. Experiments using knock-out mouse embryo fibroblasts established that Bak was of particular importance for cytotoxicity. 6-PA-ELL increased the expression of the endoplasmic reticulum chaperones GRP78/BiP and GRP94, suggesting induction of endoplasmic reticulum stress. Induction of GRP78 expression was dependent on the endoplasmic reticulum stress response element (ERSE) of the GRP78 promoter. Examination of different ellipticine derivatives revealed a correlation between pro-apoptotic activity and the ability to induce GRP78 expression. Furthermore, 6-PA-ELL was found to induce splicing of the mRNA encoding the XBP1 transcription factor, characteristic of endoplasmic reticulum stress, and to induce activation of the endoplasmic reticulum-specific caspase-12 in mouse colon cancer cells. We finally demonstrate that 6-PA-ELL induces apoptotic signaling also in enucleated cells, consistent with the existence of a cytoplasmic target for this compound. Our data suggest that induction of endoplasmic reticulum stress may contribute to the cytotoxicity of ellipticines.
抗癌药物通常表现出复杂的作用机制，包括对多个细胞靶点的作用。详细了解这些复杂的效应对于理解细胞毒性很重要。在本研究中，我们检测了玫瑰树碱（一类已知可抑制拓扑异构酶II的细胞毒性植物生物碱）诱导的细胞凋亡。强效玫瑰树碱衍生物6-丙胺基玫瑰树碱（6-PA-ELL）在MDA-MB-231乳腺癌细胞中诱导快速凋亡，其发生在Bak构象改变和细胞色素c释放之前。使用基因敲除小鼠胚胎成纤维细胞进行的实验表明，Bak对细胞毒性尤为重要。6-PA-ELL增加了内质网伴侣蛋白GRP78/BiP和GRP94的表达，提示内质网应激的诱导。GRP78表达的诱导依赖于GRP78启动子的内质网应激反应元件（ERSE）。对不同玫瑰树碱衍生物的检测揭示了促凋亡活性与诱导GRP78表达能力之间的相关性。此外，发现6-PA-ELL可诱导编码XBP1转录因子的mRNA剪接，这是内质网应激的特征，并可在小鼠结肠癌细胞中诱导内质网特异性半胱天冬酶-12的激活。我们最终证明，6-PA-ELL在去核细胞中也能诱导凋亡信号，这与该化合物存在细胞质靶点一致。我们的数据表明，内质网应激的诱导可能有助于玫瑰树碱的细胞毒性。
