Nakajima Wataru, Sharma Kanika, Hicks Mark A, Le Ngoc, Brown Rikiara, Krystal Geoffrey W, Harada Hisashi
a Department of Oral and Craniofacial Molecular Biology , School of Dentistry, Massey Cancer Center, Virginia Commonwealth University , Richmond , Virginia , USA.
b Department of Internal Medicine , Virginia Commonwealth University, McGuire Veterans Affairs Medical Center , Richmond , Virginia , USA.
Cancer Biol Ther. 2016;17(1):27-35. doi: 10.1080/15384047.2015.1108485.
Small cell lung cancer (SCLC) is an aggressive tumor type with high mortality. One promising approach for SCLC treatment would be to utilize agents targeting molecular abnormalities regulating resistance to apoptosis. BH3 mimetic antagonists, such as ABT-737 and its orally available derivative ABT-263 (navitoclax) have been developed to block the function of pro-survival BCL-2 family members. The sensitivity of SCLC to these drugs varies over a broad range in vitro and in clinical trials. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is a critical determinant of sensitivity to ABT-737. Thus, pharmacological up-regulation of Noxa could enhance cell death induced by the BH3 mimetics. We find that the combination of ABT-263 and a HDAC inhibitor, vorinostat, efficiently induces apoptosis in a variety of SCLC cell lines, including ABT-263 resistant cell lines. Cell death induced by combined treatment is Noxa- and/or BIM-dependent in some cell lines but in others appears to be mediated by down-regulation of BCL-XL and release of BAK from BCL-XL and MCL-1. These results suggest that combination of HDAC inhibitors and BCL-2 inhibitors could be an alternative and effective regimen for SCLC treatment.
小细胞肺癌（SCLC）是一种侵袭性肿瘤类型，死亡率很高。一种有前景的SCLC治疗方法是利用靶向调节细胞凋亡抗性的分子异常的药物。BH3模拟拮抗剂，如ABT-737及其口服可用衍生物ABT-263（navitoclax）已被开发用于阻断促生存BCL-2家族成员的功能。SCLC对这些药物的敏感性在体外和临床试验中差异很大。我们之前已经表明，Noxa（一种仅含BH3的促凋亡BCL-2家族蛋白）的表达是对ABT-737敏感性的关键决定因素。因此，Noxa的药理学上调可增强BH3模拟物诱导的细胞死亡。我们发现ABT-263与组蛋白去乙酰化酶（HDAC）抑制剂伏立诺他联合使用，可有效诱导多种SCLC细胞系凋亡，包括对ABT-263耐药的细胞系。联合治疗诱导的细胞死亡在某些细胞系中依赖于Noxa和/或BIM，但在其他细胞系中似乎是由BCL-XL的下调以及BAK从BCL-XL和MCL-1的释放介导的。这些结果表明，HDAC抑制剂和BCL-2抑制剂联合使用可能是一种用于SCLC治疗的替代且有效的方案。
