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Simvastatin enhances irinotecan-induced apoptosis in human non-small cell lung cancer cells by inhibition of proteasome activity

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Simvastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) is known to stimulate apoptotic cell death and induce cell cycle arrest through inhibition of proteasome. The purpose of this study is to investigate whether simvastatin would be synergistic with irinotecan against human non-small cell lung cancer (NSCLC) cells. Antitumor effect was measured by growth inhibition of cells and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The cytotoxic interaction between irinotecan and simvastatin was assessed using the combination index. Effects on cell cycle distribution and apoptosis were determined by flow cytometry and DNA fragmentation. Proteasome activity was measured by ELISA quantification of 20S proteasome. NF-κB activation was determined using TransAM™ NF-κB p65 Transcription Factor Assay Kit. IκB-α was measured by immunoblot. A combination of irinotecan with simvastatin showed significantly enhanced cell growth inhibition compared with irinotecan alone, which resulted in a synergistic cytotoxicity. Irinotecan and simvastatin combination treatment of A549 and H460 cells increased G1 phase arrest, which was associated with up-regulation of p21WAF1/CIP and p53 compared with irinotecan alone. In addition, simvastatin combination treatment increased irinotecan-related apoptosis as determined by fluorescence microscopy and flow cytometric analysis. We also found that combination therapy showed superior proteasome inhibitory activity leading to effectively suppress NF-κB transcription factor activation. Consistently, this effect was associated with up-regulation of IκB-α. These findings suggest that simvastatin enhances irinotecan-induced apoptosis in human NSCLC cells through inhibition of proteasome activity.

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Acknowledgment

This study was supported by a grant from National Cancer Center 0810130-1.

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Authors and Affiliations

  1. Lung Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea

    In Hae Park, Jin Young Kim, Ji Young Choi & Ji-Youn Han

  2. Lung Cancer Branch, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi, 411-769, Korea

    Ji-Youn Han

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  1. In Hae Park
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Correspondence to Ji-Youn Han.

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Authors In Hae Park and Jin Young Kim contributed equally to this work.

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Park, I.H., Kim, J.Y., Choi, J.Y. et al. Simvastatin enhances irinotecan-induced apoptosis in human non-small cell lung cancer cells by inhibition of proteasome activity. Invest New Drugs 29, 883–890 (2011). https://doi.org/10.1007/s10637-010-9439-x

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