Format

Send to

Choose Destination
Cell Death Dis. 2018 Sep 24;9(10):986. doi: 10.1038/s41419-018-1040-9.

Sensitizing non-small cell lung cancer to BCL-xL-targeted apoptosis.

Author information

1
Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX, 77030, USA.
2
Xiangya School of Medicine, Central South University, 410008, Changsha, Hunan, China.
3
Department of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
4
Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX, 77030, USA. hshen@houstonmethodist.org.
5
Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. hshen@houstonmethodist.org.
6
Houston Methodist Cancer Center, Houston, TX, 77030, USA. hshen@houstonmethodist.org.

Abstract

Lung cancer is the leading cause of death in the United States, with non-small cell lung cancers (NSCLC) accounting for 85% of all cases. By analyzing the expression profile of the pro-apoptotic and anti-apoptotic proteins, we have assigned NSCLCs into two distinct groups. While single agent treatment with the BCL-2/BCL-xL/BCL-w inhibitor ABT-263 (navitoclax) did not trigger apoptosis in either group, cells with a moderate to high level of MCL-1 expression were sensitive to ABT-263 treatment when MCL-1 expression was suppressed with a gene-specific siRNA. In contrast, those with a low MCL-1 expression did not undergo apoptosis upon combination treatment with ABT-263 and MCL-1 siRNA. Further studies revealed that cells with a low MCL-1 expression had low mitochondrial priming, and treatment with the chemotherapy drug docetaxel raised the mitochondrial priming level and consequently sensitized cells to ABT-263. These results establish a rationale for molecular profiling and a therapeutic strategy to treat NSCLC patients with pro-apoptotic anti-cancer drugs based on their MCL-1 expression level.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center