Inducing Apoptosis of NCI-H157 Human Lung Carcinoma Cells via Activation of Caspase Cascade by Combination Treatment with Arsenic Trioxide and Sulindac.

Kim, Hak Ryul; Yang, Sei Hoon; Jeong, Eun Taik

doi:2004.56.4.381

Tuberc Respir Dis > Volume 56(4); 2004 > Article

Original Article

Tuberculosis and Respiratory Diseases 2004;56(4):381-392.
DOI: https://doi.org/10.4046/trd.2004.56.4.381 Published online April 1, 2004.

Inducing Apoptosis of NCI-H157 Human Lung Carcinoma Cells via Activation of Caspase Cascade by Combination Treatment with Arsenic Trioxide and Sulindac.

Hak Ryul Kim, Sei Hoon Yang, Eun Taik Jeong

Department of Internal Medicine, College of Medicine Wonkwang University, Iksan, Korea. yshpul@wonkwang.ac.kr

Abstract

Arsenic trioxide(As2O3) was introduced into the treatment of refractory or relapsed acute promyelocytic leukemia. Some investigators have reported that arsenic trioxide had induced apoptosis in a variety of solid human tumor cell lines, including non-small cell lung cancer. Non-steroidal anti-inflammatory drugs(NSAIDs) are powerful chemopreventive agents for gastrointestinal cancers and the growth of established tumors are reduced by inducing apoptosis. It's also reported that NSAIDs enhanced tumor response to chemotherapeutic drugs or radiation. In this study, we aimed to determine whether combination of arsenic trioxide with sulindac augmented its apoptotic potential in NCI-H157 human lung cancer cells. The human lung cancer cell line NCI-H157 was treated with arsenic trioxide and sulindac. Cell viability was measured by the MTT assay. Apoptosis was measured by nuclear staining and flow cytometric analysis. The catalytic activity of the caspase families were measured by the fluorogenic cleavage of biosubstrates. The western blotting were also performed to define the mechanical basis of apoptosis. Combination treatment of arsenic trioxide and sulindac decreased the viability of NCI-H157 human lung cancer cells in a dose-dependent manner. The catalytic activity of caspase-3, 8 and 9 proteases were increased after combination treatment. Consistently PARP was cleaved from 116kDa to 85kDa fragments, and the expression of ICAD was decreased by time-dependent manner. Also combination treatment increased the expression of Fas and Fas/L. Combination therapy of arsenic trioxide with sulindac augments cell death and induces apoptosis via the activation of caspase cascade in NCI-H157 human lung carcinoma cells.

Key Words: Arsenic trioxide, Sulindac, Apoptosis, Lung Cancer Cell line