State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
School of Life Science and Technology, Dalian University of Technology, Dalian, China.
Biochem Pharmacol. 2018 Sep;155:102-109. doi: 10.1016/j.bcp.2018.06.019. Epub 2018 Jun 25.
Targeting Bcl-2 with ABT-199 (Venetoclax) shows limited single-agent activity against many cancers in both preclinical and clinical investigations. Combination therapies have attracted great attention. The principal purpose of this study was to investigate the mechanism of synergism between ABT-199 and paclitaxel. Moreover, we analyzed the biomarker to identify tumors which are most likely to respond to this combination. We evaluated the effect of this combination in a panel of nine cancer cell lines including cervical cancer, lung cancer, ovarian cancer, lymphoma, leukemia and breast cancer. Combination index (CI) assay showed that four of nine call lines exhibited synergistic respond to ABT-199/paclitaxel combination due to enhanced intrinsic apoptosis. However, paclitaxel-induced Bcl-2 phosphorylation impaired the synergistic effect by impeding the freeing of Bax and Bim by ABT-199 because ABT-199 cannot hit phosphorylated Bcl-2 (pBcl-2). By means of a correlation analysis of JNK level with CI value in combination with overexpressing or silencing JNK protein in cancer cells, we identified basal JNK1 level as a potential biomarker for predicting the level of pBcl-2 upon paclitaxel treatment, and thus for predicting a synergistic response. A cut-off value of 0.37 for relative JNK1 expression level was determined using receiver operating characteristic (ROC) analysis to distinguish between synergistic and non-synergistic response cancers. A more accurate and valid cut-off value for JNK1 will be gained based on a large-scale clinical samples analysis.
针对 Bcl-2 的 ABT-199（维奈托克）在临床前和临床研究中对许多癌症的单一药物活性有限。联合治疗引起了广泛关注。本研究的主要目的是研究 ABT-199 与紫杉醇协同作用的机制。此外，我们分析了生物标志物，以确定最有可能对这种组合产生反应的肿瘤。我们评估了该组合在包括宫颈癌、肺癌、卵巢癌、淋巴瘤、白血病和乳腺癌在内的九种癌细胞系中的作用。组合指数（CI）测定表明，由于增强的内在凋亡，九种细胞系中的四种对 ABT-199/紫杉醇组合表现出协同反应。然而，紫杉醇诱导的 Bcl-2 磷酸化通过阻碍 ABT-199 释放 Bax 和 Bim 而损害了协同作用，因为 ABT-199 不能作用于磷酸化的 Bcl-2（pBcl-2）。通过对 JNK 水平与 CI 值的相关性分析，结合在癌细胞中过表达或沉默 JNK 蛋白，我们确定了基础 JNK1 水平作为预测紫杉醇治疗时 pBcl-2 水平的潜在生物标志物，从而预测协同反应。使用接收者操作特征（ROC）分析确定相对 JNK1 表达水平的 0.37 作为区分协同和非协同反应癌症的截止值。基于大规模临床样本分析，将获得更准确和有效的 JNK1 截止值。
