Bcl-2/Bcl-xL inhibitor ABT-737 sensitizes pancreatic ductal adenocarcinoma to paclitaxel-induced cell death
Bcl-2/Bcl-xL inhibitor ABT-737 sensitizes pancreatic ductal adenocarcinoma to paclitaxel-induced cell death
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DOI：
10.3892/ol.2017.6211
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发表时间：
2017-07-01
期刊：
影响因子：
2.9
通讯作者：
Maesawa, Chihaya
中科院分区：
文献类型：
--
作者：
Kasai, Shuya;Sasaki, Takuya;Maesawa, Chihaya
胰腺导管腺癌（PDA）是一种侵袭性恶性疾病，对多种化疗药物具有耐药性，且常复发。有效消除转移的PDA对于术后治疗结果的积极性至关重要。本研究分析了B细胞淋巴瘤-2（Bcl-2）/超大型B细胞淋巴瘤（Bcl-x（L））抑制剂ABT-737对紫杉醇诱导的PDA细胞死亡的影响。对总共8个PDA细胞系进行免疫印迹以比较Bcl-2/Bcl-x（L）和与紫杉烷抗性相关的其它因子（包括髓样细胞白血病1和β III-微管蛋白（TUBB 3））的表达。单独使用紫杉醇或ABT-737和紫杉醇联合处理后，分析PDA细胞的活力。与紫杉醇单独治疗相比，ABT-737/紫杉醇联合治疗在较低的紫杉醇浓度下诱导PDA细胞死亡。此外，与ABT-737共处理也降低了紫杉醇饱和点的活细胞群。ABT-737在具有高Bcl-2/Bcl-x（L）表达的PDA细胞中使半数最大抑制浓度（IC 50）降低> 2倍，但在具有低Bcl-2/Bcl-x（L）表达和高TUBB 3表达的PDA细胞中不降低。Bcl-x（L）的敲低降低了紫杉醇的IC 50，但TUBB 3的敲低没有降低。ABT-737对紫杉醇诱导的细胞死亡敏感，Bcl-x（L）表达是其敏感性的关键决定因素。ABT-737是Bcl-x（L）高表达PDA联合化疗的潜在候选药物。
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignant disease that is resistant to various chemotherapeutic agents and commonly relapses. Efficient elimination of metastasized PDA is critical for a positive post-surgical treatment outcome. The present study analyzed the effect of the B-cell lymphoma-2 (Bcl-2)/B-cell lymphoma extra-large (Bcl-x(L) inhibitor, ABT-737, on paclitaxel-induced PDA cell death. A total of 8 PDA cell lines were subjected to immunoblotting to compare the expression of Bcl-2/Bcl-x(L) and other factors associated with taxane resistance, including myeloid cell leukemia 1 and beta III-tubulin (TUBB3). The viability of PDA cells was analyzed following treatment with paclitaxel alone or a combination treatment with ABT-737 and paclitaxel. Treatment with the ABT-737/paclitaxel combination induced PDA cell death at a lower concentration of paclitaxel compared with paclitaxel alone. In addition, the viable cell population at the saturation point of paclitaxel was also decreased by co-treatment with ABT-737. ABT-737 lowered the half maximal inhibitory concentration (IC50) by > 2-fold in PDA cells with high Bcl-2/Bcl-x(L) expression, but not in PDA cells with low Bcl-2/Bcl-x(L) expression and high TUBB3 expression. Knockdown of Bcl-x(L) lowered the IC50 of paclitaxel, but knockdown of TUBB3 did not. ABT-737 sensitized PDA to paclitaxel-induced cell death, and Bcl-x(L) expression was a key determinant of its sensitivity. ABT-737 is potential candidate for combination chemotherapy of PDA with high Bcl-x(L) expression levels.