Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status

Cemeus, Catia; Zhao, Tong; Barrett, Gordon M.; Lorimer, Ian A. J.; Dimitroulakos, Jim

doi:10.1007/s11060-008-9627-0

Cited by 60 publications

(47 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While these cell lines did not possess the ATP-binding site activating mutations, which confer increased sensitivity to gefitinib, combining lovastatin with gefitinib induced more significant inhibition of AKT activation than either agent alone [7]. Additionally, lovastatin significantly enhanced the sensitivity to gefitinib treatment regardless of PTEN loss in glioblastoma cell lines [22]. These results suggest Fig.…”

Section: Discussionmentioning

confidence: 85%

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

et al. 2009

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 85%

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

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Finally, statins (mainly lovastatin) potentiated the antiproliferative effects of gefitinib, a potent tyrosine kinase inhibitor of EGFR, in SCC, non-small-cell lung cancer, colorectal cancer cell lines (Mantha et al, 2005), and glioblastoma-derived cell lines (Cemeus et al, 2008), probably through enhanced inhibition of the PI3K/Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Gazzerro

Proto²,

Gangemi³

et al. 2011

Pharmacol Rev

401

370

View full text Add to dashboard Cite

“…Multiple reports indicate a beneficial role for lipid-lowering drugs, including fibrates and statins, as anticancer agents (1)(2)(3)(4)(5)(6)(7). For example, a 10-year, all-cause mortality study involving 7,722 patients treated with different fibrates revealed that the use of these drugs is associated with a significantly lower total mortality rate and a reduced probability of death from cancer (8).…”

mentioning

confidence: 99%

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Wilk

Wyczechowska

Zapata

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

e Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPAR␣). FF and several other agonists of PPAR␣ have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPAR␣-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPAR␣-dependent metabolic switch from glycolysis to fatty acid ␤-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells. F enofibrate (FF) is a common lipid-lowering drug and a potent agonist of peroxisome proliferator-activated receptor alpha (PPAR␣). Multiple reports indicate a beneficial role for lipid-lowering drugs, including fibrates and statins, as anticancer agents (1-7). For example, a 10-year, all-cause mortality study involving 7,722 patients treated with different fibrates revealed that the use of these drugs is associated with a significantly lower total mortality rate and a reduced probability of death from cancer (8). In cell culture and animal studies, various members of the fibrate family, which are all agonists of PPAR␣, demonstrate interesting anticancer effects, which are not fully understood. FF inhibited tumor growth by reducing both inflammation and angiogenesis in host tissue (5). Clofibrate attenuated ovarian cancer cell proliferation (9, 10), and gemfibrozil (GEM) inhibited the invasiveness of glioblastoma cells (11). In our previous work, FF synergized with staurosporine to reduce melanoma lung metastases (3, 12), significantly reduced glioblastoma invasiveness (13), and triggered apoptotic death in medulloblastoma (14) and human glioblastoma cell lines by inducing the FOXO3A-Bim apoptotic pathway (15). All of these studies encouraged the use of FF as a supplemental anticancer drug, a concept supported by recent clinical trials in which chronic administration of FF along with chemotherapeutic agents used at relatively low doses minimizes the toxicity and acute side effects of chemotherapy while maintaining efficacy for patients wit...

show abstract

Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status

Cited by 60 publications

References 33 publications

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

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

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Contact Info

Product

Resources

About