Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-Ras mutations.
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.
Park
In Hae
IH
Center for Lung Cancer, National Cancer Center, 111 Jeongbalsan-ro, Ilsan-donggu, Goyang-si, Gyeonggi-do, 410-769, South Korea.
Kim
Jin Young
JY
Jung
Jae In
JI
Han
Ji-Youn
JY
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D008148:Lovastatin; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib