Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
Mol Pharmacol. 2012 May;81(5):748-58. doi: 10.1124/mol.112.077586. Epub 2012 Feb 22.
Prior studies in breast cancer cells have shown that lapatinib and obatoclax interact in a greater than additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses to the central nervous system (CNS) tumor cells and to further define mechanisms of drug action. Lapatinib and obatoclax killed multiple CNS tumor isolates. Cells lacking PTEN (phosphatase and tensin homolog on chromosome 10) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null cells restored drug sensitivity, and knockdown of PTEN promoted drug resistance. On the basis of knockdown of ERBB1-4 (erythroblastic leukemia viral oncogene homolog 1-4), we discovered that the inhibition of ERBB1/3/4 receptors were most important for enhancing obatoclax lethality rather than ERBB2. In parallel, we noted in CNS tumor cells that knockdown of BCL-xL (B-cell lymphoma-extra large)and MCL-1 (myeloid cell leukemia-1) interacted in an additive fashion to facilitate lapatinib lethality. Pretreatment of tumor cells with obatoclax enhanced the lethality of lapatinib to a greater extent than concomitant treatment. Treatment of animals carrying orthotopic CNS tumor isolates with lapatinib- and obatoclax-prolonged survival. Altogether, our data show that lapatinib and obatoclax therapy could be of use in the treatment of tumors located in the CNS.
先前在乳腺癌细胞中的研究表明，拉帕替尼和 obatoclax 以大于相加的方式相互作用，导致细胞死亡，并通过一种有毒的自噬形式实现这一作用。本研究旨在将我们的分析扩展到中枢神经系统（CNS）肿瘤细胞，并进一步定义药物作用的机制。拉帕替尼和 obatoclax 杀死了多种 CNS 肿瘤分离物。缺乏 PTEN（染色体 10 上的磷酸酶和张力蛋白同源物）功能的细胞对药物联合致死作用相对耐药；在 PTEN 缺失细胞中表达 PTEN 恢复了药物敏感性，而敲低 PTEN 则促进了耐药性。基于 ERBB1-4（红细胞白血病病毒癌基因同源物 1-4）的敲低，我们发现抑制 ERBB1/3/4 受体对于增强 obatoclax 的致死作用比 ERBB2 更为重要。同时，我们在 CNS 肿瘤细胞中注意到，敲低 BCL-xL（B 细胞淋巴瘤-extra large）和 MCL-1（髓样细胞白血病-1）以相加的方式相互作用，促进了拉帕替尼的致死作用。与同时处理相比，肿瘤细胞先用 obatoclax 预处理会增强拉帕替尼的致死作用。用 lapatinib 和 obatoclax 治疗携带原位 CNS 肿瘤分离物的动物延长了存活时间。总的来说，我们的数据表明，拉帕替尼和 obatoclax 疗法可能对治疗位于中枢神经系统的肿瘤有用。
