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Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-Ras mutations

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Summary

Lovastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. Its inhibitory action on HMG-CoA reductase leads to depletion of isoprenoids, which inhibits post-translational modification of RAS. In this study, we investigated the effect of combining lovastatin with gefitinib on gefitinib-resistant human non-small cell lung cancer (NSCLC) cell lines with K-Ras mutations. Antitumor effects were measured by growth inhibition and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Effects on apoptosis were determined by flow cytometry, DNA fragmentation, and immunoblots. Protein levels of RAS, AKT/pAKT, and RAF/ERK1/2 in cancer cells were analyzed by immunoblot. Compared with gefitinib alone, a combination of gefitinib with lovastatin showed significantly enhanced cell growth inhibition and cytotoxicity in gefitinib-resistant A549 and NCI-H460 human NSCLC cells. In addition, lovastatin combination treatment significantly increased gefitinib-related apoptosis, as determined by fluorescence microscopy and flow cytometric analysis. These effects correlated with up-regulation of cleaved caspase-3, poly (ADP-ribose) polymerase (PARP), and Bax and down-regulation of Bcl-2. The combination of lovastatin and gefitinib effectively down-regulated RAS protein and suppressed the phosphorylation of RAF, ERK1/2, AKT, and EGFR in both cell lines. Taken together, these results suggest lovastatin can overcome gefitinib resistance, in NSCLC cells with K-Ras mutations, by down regulation of RAS protein, which leads to inhibition of both RAF/ERK and AKT pathways.

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Acknowledgment

This study was supported by a grant from the National Cancer Center 0810130-2.

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Authors and Affiliations

  1. Center for Lung Cancer, National Cancer Center, 111 Jeongbalsan-ro, Ilsan-donggu, Goyang-si, Gyeonggi-do, 410-769, South Korea

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

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  1. In Hae Park
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  2. Jin Young Kim
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Correspondence to Ji-Youn Han.

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In Hae Park and Jae In Jung have contributed equally to this work.

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Park, I.H., Kim, J.Y., Jung, J.I. et al. Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-Ras mutations. Invest New Drugs 28, 791–799 (2010). https://doi.org/10.1007/s10637-009-9319-4

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  • DOI: https://doi.org/10.1007/s10637-009-9319-4

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