Journal of Neoplasms
ISSN: 2639-1716
Current Issue
Volume No: 1 Issue No: 1
share this page

Review Article | Open Access
  • Available online freely | Peer Reviewed
  • Statins and Lung Cancer: A Review of Current Literature

    W Kurtis Childers DO 1       Nathaniel Melton MD 1     Daniel Goldman MD 1     Troy Moritz DO 2    

    1Department of General Surgery, Pinnacle Health System Harrisburg PA

    2Department of Cardiovascular and Thoracic Surgery, Pinnacle Health System Harrisburg PA

    Abstract

    Cardiovascular disease and lung cancer are two of the most common causes of death in the United States. The cardioprotective benefits of statin class drugs is predominantly mediated through the inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, decreasing available mevalonate, and thus limiting in vivo cholesterol biosynthesis. Mevalonate and its metabolites have significant roles in cellular membrane synthesis, which is dysregulated during tumorigenesis, and is therefore a potential source for anti-tumor effects of statins. Similarly, dysregulation of cellular signaling is a hallmark of tumorigenesis. In vitro studies of EGFR, RAS, and AKT signaling pathways in cancer cells can all be reformed back to states more indicative of normally functioning cells when treated with statins. Statins have also been shown to exert beneficial properties in the presence of chemotherapeutic medications and radiation therapies by modulating the deleterious effects of reactive oxygen species, decreasing tumor cell resistance, and minimizing damage to surrounding native tissues. There is abundant of in vitro evidence to support the beneficial effects of statins on lung cancer patients. Prospective studies to determine the value of statin therapy on lung cancer prevention could lead to a significant change in lung cancer treatment.

    Received 10 Feb 2018; Accepted 24 Mar 2018; Published 28 Mar 2018;

    Academic Editor:Hang Su, Univeristy of Texas Health Science Center at San Antonio

    Checked for plagiarism: Yes

    Review by: Single-blind

    Copyright©  2018 W Kurtis Childers DO, et al.

    License
    Creative Commons License    This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Competing interests

    The authors have declared that no competing interests exist.

    Citation:

    W Kurtis Childers DO, Nathaniel Melton MD, Daniel Goldman MD, Troy Moritz DO (2018) Statins and Lung Cancer: A Review of Current Literature . Journal of Neoplasms - 1(1):35-43.
    Download as RIS, BibTeX, Text (Include abstract )
    DOI10.14302/issn.2639-1716.jn-18-1993

    History and Epidemiology of Lung Cancer

    The impact lung cancer has on global health is well known. Lung carcinoma is the leading cause of cancer-related deaths with >1 million deaths worldwide attributable to the disease.1 The American Cancer Society has projected 224,390 Americans will receive a new diagnosis of lung cancer in 2016. This represents a dramatic increase in both incidence and prevalence of the disease, as the United States had approximately 157,426 deaths attributable to lung cancer in 2012.2 While the incidence of lung cancer has increased across all demographics, male mortality from lung cancer actually saw a reduction between 1990 and 2007 while women saw an increase of 6.31% in mortality over that same time span.1,2 This is likely attributable to the early peak of smoking rates in men compared to women. Increasing pack-years, African-American race, low income, lesser education, and occupational exposures are all associated with increased lung cancer rates as well.

    History and Information about Statins

    In 1971, Dr. Akira Endo set out to develop a medication that would theoretically decrease coronary artery disease by decreasing cholesterol production. By 1992, >1 million people had been prescribed a statin class medication.3 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, or statins, work at the level of cholesterol precursor biosynthesis inhibition. HMG-CoA reductase is the rate limiting enzyme in the production of mevalonate, a major precursor of cholesterol production. The functional group of statin class drugs competitively binds the active site of the enzyme resulting in a significant decrease of mevalonate biosynthesis, subsequently significantly inhibiting hepatic cholesterol production. Low-density lipoprotein (LDL) receptors must be upregulated, effectively decreasing circulating blood cholesterol levels.3,4,5

    The Role of Statins in Lung Cancer Incidence and Mortality

    Cancer causation and prevention remains an area of much interest and research. As more medications become commercially available, long-term effects of medication use, and possible epidemiology of cancer prevention or development becomes extrapolated. As being one of the most prescribed medications in the United States, statins remain under constant scrutiny for possible malignancy development.5

    In 2007, a large case-control study was conducted using the database from the Veterans Affairs (VA) Health Care System. Among the 7,280 patients diagnosed with primary lung cancer, the use of statins >6 months was associated with a 55% decrease in lung cancer incidence (OR 0.45; 95% CI 0.42-0.48)6. This initiated a detailed investigation about the pleotropic effects of statins, and their purported benefits of lung cancer incidence.

    Multiple meta-analytic studies have been conducted to correlate the incidence of lung cancer in patients taking statins. In 2008, a meta-analysis consisting of 42 studies was published: 17 randomized control trials, 10 cohort studies, and 15 case-control studies. The study concluded that statins had no effect on the overall incidence of cancer (RR 0.96 CI 0.72-1.2), or lung cancer (RR 0.92, CI 0.83-3.0)7. In 2013, an updated meta-analysis consisting of 20 studies was published: 5 randomized control trials, 8 cohort studies, and 7 case-control studies. As the number of studies was much less than prior, it renders itself to more specific inclusion criteria, and less study variable. Results showed a non-significant decrease of total lung cancer risk among all statin users (RR 0.89, CI 0.78-1.02). The findings of this meta-analysis suggested that there was no significant association between statin use and risk of lung cancer8.

    In respect to lung cancer mortality after diagnosis, only one study was identified to this sort. A retrospective cohort study was conducted consisting of 3,638 lung cancer patients. In patients who had at least 12 prescriptions of statins prior to mortality, endpoint showed a HR of 0.81 (95% CI 0.67-0.98) in cancer-specific mortality. Furthermore, in 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR 0.88; 95% CI 0.83-0.93)9. The use of statins extends beyond the role of lipid lowering. As numerous meta-analysis studies have shown no increase or decrease in the incidence of lung cancer among statin users, the use of statins after diagnosis was shown to decrease lung cancer mortality.

    Mevalonate Pathway and Receptors

    Mevalonate is the byproduct of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) via HMG-CoA reductase.Recent studies have regarded malignant cells to be highly dependent on the end products of the mevalonate pathway10,11.

    Mevalonate is the precursor of two classes of functioning molecules: isoprenoid and prenyl molecules. Mevalonic acid is the precursor for the biosynthesis of isoprenoid molecules such as cholesterol, dolichol, and ubiquinone12. Prenyl groups comprise of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which facilitate essential intracellular functions of various proteins such as Ras and Rho11,12.

    Isoprenoid molecules provide essential systemic functions. Cholesterol is a structural component of plasma membranes. Ubiquinone is part of the electron transport chain in mitochondria, and dolichol is a carrier molecule in glycoprotein synthesis4,13.

    The prenyl molecules FPP and GGPP undergo a process called isoprenylation. This process involves attachment of the FPP and GGPP for key intermediates for post-translational cell signaling. This is fundamental for activation and intracellular transport5.

    Maintenance of cholesterol within the cell membrane continues to be the foundation of fluidity within the cell membrane. One of the hallmark features of all malignancies is rapid cell division, thus increasing the demand for cholesterol for cellular membrane synthesis . Cholesterol within the cell membrane was found to directly interact with EGF receptors, and influence the binding of EGF upon the EGF receptor in a concentration-dependent manner14. Pravastatin has been demonstrated to down-regulate signal transduction through the cell membrane in more than 300 genes of Calu-1 lung cancer cells15. However, simvastatin did not lower the cell cholesterol content, but was found to increase Δ5-desaturase activity, the enzyme necessary for the synthesis of unsaturated fatty acids16.

    The presence of mevalonate, and its metabolites has been proven vital for optimal cell structure and cellular function. The production of isoprenoid and prenyl molecules may be the subject of a possible target of future antitumor medication. Further evidence is supported by the use of statins in in vivo lung cancer cells.

    Lung Cancer Receptors and the Influence of Statins

    EGFR

    Epidermal growth factor receptor (EGFR) is a tyrosine kinase cell membrane receptor, and a key receptor in cell growth, differentiation, migration, and survival17. When EGFR is activated, phosphorylation of the receptor tyrosine kinase triggers a series of downstream signaling for cell proliferation and survival17. This cascade of events is dysregulated in malignant cells, leading to hyperproliferation, and metastatic potential17,18,19. Most recent guidelines from the NCCN recommend testing for the presence of EGFR in all newly diagnosed NSCLC20. EGFR mutations are present in approximately 5-15% of adenocarcinoma and <5% of squamous-cell carcinoma or the lung21. When the receptor is present, potent tyrosine kinase receptor inhibitors can be added to the chemotherapy regimen, with a documented increase in survival in non-metastatic NSCLC19. Mevalonate metabolites have been shown to play a role in transducing EGFR-mediated signaling14.In vitro studies have demonstrated lovastatin to inhibit EGF-induced EGFR autophosphorylation. In multiple studies, when lovastatin was combined with the tyrosine kinase inhibitor gefitinib, synergistic inhibition was demonstrated, inducing a potent apoptotic response in NSCLC22,23. As the results exhibit synergistic inhibition, there is some suggestion that HMG-CoA reductase and EGFR may act cooperatively to target the same receptor23.

    Though EGFR tyrosine kinase inhibitors (TKI) are highly efficacious, acquired resistance is almost inevitable. However, this was shown to be attenuated when gefitinib was combined with simvastatin, as an enhanced caspase-dependent apoptosis was demonstrated in previously EGFR-TKI resistant NSCLC24. Further investigation revealed simvastatin inhibited AKT activation, leading to suppression of beta-catenin activity and thus down-regulation of survivin25.

    RAS

    The RAS family plays a key role in oncogenesis. Family members include HRAS, KRAS, and NRAS. RAS activation triggers a cascade of downstream events, with subsequent phosphorylation, and activation of MEK1/2 and ERK26. KRAS encodes a GTP-binding protein involved in many cellular processes including proliferation, differentiation, and apoptosis27. Carcinogenic mutations of KRAS are detected in approximately 20% of NSCLC, and leads to dysregulated activation28.

    Cells from adenocarcinoma (GLC-82) and squamous cell carcinomas (CALU-1) were exposed to increasing concentrations of simvastatin. Simvastatin significantly inhibited ERK1/2 phosphorylation, and induced caspase-2 activated apoptosis in the GLC-82 and CALU-1 cell lines26.

    The tyrosine kinase inhibitor, gefitinib, is effective at inhibiting KRAS and its progression in NSCLC. Approximately 25% of lung adenocarcinomas exhibit a KRAS mutation, offering resistance to gefitinib, and ultimately rendering the chemotherapy unsuccessful. Mevalonate and its metabolites are essential substrates in the downstream signaling of KRAS. Atorvastatin has been demonstrated in multiple in vitro studies to overcome the gefitinib resistance of the KRAS mutation in NSCLC29,30. Further investigation demonstrated the combination to decrease the expression of RAS protein and inhibit EGFR, an effect not shown in NSCLC cells treated with gefitinib alone. This resulted in proliferation inhibition, and an increase in apoptosis30.

    The progression-free survival (PFS) and overall survival (OS) in patients with stage 3 or 4 lung cancer harboring KRAS mutations was evaluated by investigators. All patients were treated with an EGFR-TKI (erlotinib or gefitinib), while 12 patients were additionally treated with a statin in addition to the EGFR-TKI, and 55 patients were not. The median PFS survival was 1.0 month, and 2.0 months for the EGFR-TKI and EGFR-TKI+statin, respectively (p=0.025). The OS was 5.4 and 14.0 months for the EGFR-TKI and EGFR-TKI+statin, respectively (p=0.130). Suggesting a longer PFS in patients treated with a statin added to the existing therapy31.

    In a study performed by Falcone et al., normal, and lung cancer tissues were exposed to increasing concentrations of simvastatin and rosuvastatin. This study showed a dose-dependent reduction on RAS protein expression when exposed to the 2 trial drugs. This was found to further inhibit the production of MMP-2, MMP-9, and NF-κB, suggesting potential anti-tumor activities of simvastatin and rosuvastatin in NSCLC32.

    AKT

    AKT is a serine/threonine kinase receptor that serves as a common intermediary for downstream signaling of many cellular stimuli.. Activation of AKT serves to stimulate cell survival by inhibition of apoptosis, and promotion of proliferation and angiogenesis33. Much attention has been garnered at the continuing downstream effects of AKT, and its malignant potential.

    Lovastatin treatment diminished tumor growth in vivo and in vitro through inhibition of both the PI3K/AKT, and MAPK pathways34. Simastatin has been suggested to induce apoptosis in A549 lung cancer isolates via AKT singnaling-dependent cell survial35. The combination of atorvastatin and carboplatin is shown to inhibit AKT activity in H1299 lung carcinoma cell lines, both in vivo, and in vitro36.

    Oxidative Stress

    Accumulation of oxidants and free radicals contribute to increased macrophages, neutrophils, and thus, reactive oxygen species (ROS) production. ROS may contribute to various signaling pathways, including MAPK activation. Recent evidence supports this activation to contribute to the development and progression of lung cancer37. Simvastatin has been shown to inhibit the effects of ROS on lung cancer cells in vitro. Inducing an antiproliferative, proapoptotic and antinflammatory effects38.

    Chen et al. demonstrated atorvastatin to decrease VEGF production in NSCLC in vitro and in vivo. Under further investigation, atorvastatin could upregulate the activity of glutathione peroxidase and catalase, prompting elimination of hydrogen peroxide39. Hydrogen peroxide has been shown to increase cellular expression of MMP-2 and MMP-9, which are also components of EGFR activation32. Simvastatin and lovastatin have both been able to inhibit the effects of hydrogen peroxide on surrounding cells38,40.

    Another important defense to antagonize the effects of ROS is superoxide dismutase (SOD), an enzyme functioned to scavenge free radicals in the mitochondria. Simvastatin was shown to inhibit the proliferation of A549 lung cancer cells through oxidative stress by upregulating SOD41. When the same A549 lung cancer cells were exposed to simvastatin in combination with sulindac, there was an induced caspase-dependent apoptosis in the A549 cells, activity greater then that induced with either drug alone35.

    Apoptosis is a known major function of normal cells within the human body. Evasion of apoptosis is another hallmark characteristic of malignant cells. Some chemotherapeutic agents target and activate the normal apoptotic activating proteins, caspase. A549 lung cancer cells were incubated with simvastatin, which exhibited a dose-dependent increase in inducing cell apoptosis. Through its downstream effects, simvastatin blocked cells in the G1 phase,downregulated cyclin D1, and increased caspase-3, -8, and -9 protein expression42,43.

    Radiation Therapy

    The use of radiotherapy is a useful adjunct for the treatment of NSCLC. Despite its useful capacity to treat malignant disease, its impact on surrounding normal tissue remains elusive. Recent studies have demonstrated a gain of motility and invasiveness of tumor cells in the radiated field44. In vitro studies have demonstrated lovastatin to block the irradiation stimulated adhesion and subsequent pro-metastatic effect of radiation therapy45. In a study by Sanli et al., lovastatin inhibited proliferation of A549 lung cancer cells, and induced radiosensitivity46.

    In a recent retrospective cohort study of 252 patients with diagnosed lung cancer and 55 (22%) patients subsequently developed brain metastasis. The risk of brain metastasis from lung cancer was significantly higher in young patients (p<0.0007). The multivariable Cox model did not show a significant association between statin use and brain metastasis from lung cancer (HR 1.20; 95% CI 0.68-2.13)47. Though the available literature is limited on the effects of statins and radiation on lung cancer progression, it supports the antitumor effects. Though antimetastatic properties showed no benefit for brain metastasis of lung cancer, in vivo and in vitro data demonstrated simvastatin prevented proliferation and osteolytic bone metastases of lung adenocarcinoma cells48.

    Chemotherapy

    A minority of patients with diagnosed lung cancer are actually candidates for surgical and curative resection. Even with surgical resection, tumor size, the presence of visceral invasion, or positive lymph nodes can be factors which stage a patient where adjuvant chemotherapy is recommended. A majority of lung cancer patients, who can medically tolerate, will receive some form of chemotherapy. Research has examined the effects of common medications on the antitumor effects of chemotherapy. As stated previously, tyrosine kinase inhibitors remain very important therapeutic medications in patients with susceptible receptors.

    In a phase 2 study, patients with NSCLC were randomized to receive gefitinib plus simvastatin (52 patients) versus gefitinib alone (54 patients)49. Primary endpoints were response rate, and secondary end points were toxicity, progression-free survival (PFS), and overall survival (OS). The response rate was 38.5% and 31.5% for the gefitinib+simvastatin and gefitinib, respectively. PFS survival exhibited a hazard ratio (HR) of 0.891 (95% CI, 0.604-1.315, p=0.549). OS exhibited a HR of 0.876 (95% CI, 0.567-1.354, p=0.491). However, when a subgroup analysis was performed comparing patients with EGFR-mutant tumors versus wild-type EGFR, the response rates and PFS was statistically and significantly in favor for patients treated with gefitinib+simvastatin who had the wild-type EGFR49. Receptor resistance to tyrosine kinase inhibitors has been described as ‘inevitable’ and remains a constant frustration. Atorvastatin has been demonstrated in multiple in vitro studies to overcome the gefitinib resistance of the KRAS mutation in NSCLC29,30.

    Platinum-based chemotherapy is commonly used in the various types of chemotherapy regimens for treatment of lung cancer. Similar to tyrosine kinase inhibitors, resistance developed from malignant cells against platinum-agents is an all to common occurrence. In NSCLC, atorvastatin was found to antagonize platinum-resistance and enhance the efficiency of apoptosis induced by carboplatin36.

    Medical Comorbidities

    Multiple chronic medical conditions are associated with hypercholesterolemia, atherosclerotic disease, and the indicated use of statins. Much investigation continues to be conducted to investigate the pleotropic effects of statins when exposed to medical illnesses where statins are not typically prescribed.

    Chronic obstructive pulmonary disease (COPD) is a debilitating pulmonary disease affecting millions of adults worldwide50. Interestingly, almost one quarter of patients with COPD expire from cancer related deaths50. Van Gestel et al. investigated whether the risk of COPD increased lung cancer mortality, and if lung cancer mortality can be modulated with statins. Of the 1310 patients with COPD in the study, COPD was associated with an increased risk of lung cancer mortality (HR 2.06; 95% CI 1.32-3.20). In the COPD patients who used statins, there was a trend toward a lower risk of cancer mortality among patients who used statins (HR 0.57; 85% CI 0.32-1.01)51. Although this is not statistically significant, it prompts further investigation to determine whether statins affect the natural disease process, the lung cancer, or both.

    Diabetes has been associated with an increased risk of cancer occurrence52. The development and progression of atherosclerosis is also a common occurrence in patients with diabetes, usually indicating the use of statins. In a large cohort study, there is an associated decreased incidence of squamous cell lung cancer in diabetic patients who have ever taken statins (HR 0.69; 95% CI 0.60-0.81). Interestingly, there was no difference in the incidence of adenocarcinoma lung cancer in diabetic patients (0.97; 95% CI 0.88-1.07)53. Common diabetic medications have been combined with statins for possible antitumor potential. Troglitazone and lovastatin were combined in vitro with CL1-0 lung cancer cells. Observed effects demonstrated dramatic synergistic effects with cell cycle regulating proteins CDK2, cyclin A, and RB phosphorylation54.

    Conclusion

    Lung carcinoma is responsible for most malignancy related deaths in the United States, and is an important area for development of preventative therapies. While the cessation of smoking would potentially lead to the greatest risk reduction of lung cancer, a common pharmacologic medication with inherent anti-tumor properties would be extremely valuable to the medical community. Meta-analyses performed have demonstrated that statin class medications aresafe with no increase incidence in cancer development. Through knowledge of receptors and the impact of the mevalonate pathway in lung cancer cells, statins have demonstrated potential anti-tumor properties in vivo. It is therefore hypothesized that statin medications could prove to help minimize the morbidity and mortality of lung cancer patients. Prospective clinical trials should be utilized to elucidate the potential clinical impact.

    Compliance with Ethical Standards

    Author WK Childers declares that he has no conflicts of interest. Author N Melton declares that he has no conflicts of interest. Author D Goldman declares that he has no conflicts of interest. Author T Moritz declares that he has no conflicts of interest.

    Ethical approval:

    This article does not contain any studies with human participants performed by any of the authors.

    Funding:

    There was no funding for this study.

    References

    1.Schachter E N, Neuman T. (2007) Targeted therapies for the prevention of lung cancer. Drugs of Today. 43(12), 897-936.
    2.Siegel R L, Miller K D, Jemal A. (2016) Cancer Statistics2016. , Ca Cancer J Clin 66, 7-30.
    3.Steinberg D. (2006) An interpretive history of the cholesterol controversy, part V: The discovery of the statins and the end of the controversy. , J Lipid Res 47, 1339-1351.
    4.Jakobisiak M, Golab J. (2003) Potential antitumor effects of statins. , Int J Oncol 23(4), 1055-69.
    5.Gazzerro P, Proto M C, Gangemi G, Malfitano A M, Ciaglia E et al. (2012) Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev. 64(1), 102-46.
    6.Khurana V, Bejjanki H R, Caldito G, Owens M W. (2007) Statins reduce the risk of lung cancer in humans – a large case-control study of US veterans. Chest. 131, 1282-8.
    7.Kuoppala J, Lamminpaa A, Pukkala E. (2008) Statins and cancer: A systematic review and meta-analysis. , Eur J Cancer 44(15), 2122-32.
    8.Wang J, Li C, Tao H, Cheng Y, Han L et al. (2013) Statin use and risk of lung cancer: a meta-analysis of observational studies and randomized controlled trials. PLoS One. 8(10), 77950.
    9.Cardwell C R, McMenamin U, Hughes C M, Murray L J. (2015) Statin use and survival from lung cancer: a population-based cohort study. Cancer Epidemiol Biomarkers Prev. 24(5), 833-41.
    10.Chan K K, Oza A M, Siu L L. (2003) The statins as anticancer agents. Clin Canc Res. 9, 10-19.
    11.Goldstein J L, Brown M S. (1990) Regulation of the mevalonate pathway. , Nature 343(6257), 425-430.
    12.Vallianou N G, Kostantinou A, Kougias M, Kazazis C. (2014) Statins and cancer. Anticancer Agents Med Chem. 14(5), 706-712.
    13.Grunler J, Ericsson J, Dallner G. (1994) Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins. Biochem Biophys Acta. 1212, 259-277.
    14.Ringerlike T, Blystad F D, Levy F O, Madshus I H, Stang E. (2002) Cholesterol is important in control of EGF receptor kinase activity but EGF receptors are not concentrated in caveolae. , J Cell Sci 15, 1331-40.
    15.Garnett D J, Greenhough T J. (2012) Statins cause profound effects on gene expression in human cancer cells in vitro: the role of membrane microdomains. Gene Expr;15(5-6):. 225-34.
    16.Bellini M J, Polo M P, de Alaniz MJ, de Bravo MG. (2003) Effect of simvastatin on the uptake and metabolic conversion of palmitic, dihomo-gamma-linoleic and alpha-linolenic acids in A549 cells. Prostaglandins Leukot Essent Fatty Acids. 69(5), 351-7.
    17.Mendelsohn J, Baselga J. (2000) The EGF receptor family as targets for cancer therapy. Oncogene. 19, 6550-65.
    18.Nicholson R I, Gee J M, Harper M E. (2001) EGFR and cancer prognosis. , Eur J Cancer 37, 9-15.
    19.Riely G J, Politi K A, Miller V A, Pao W. (2006) Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res. 12, 7232-41.
    20. (2015) National Comprehensive Cancer Network. Lung Cancer (Version 7.2015). http://www.nccn.org/professionals/physicians_gls/pdf/lung.pdf.AccessedOctober8,2015
    21.Pao W, Girard N. (2011) New driver mutations in non-small-cell lung cancer. Lancet Oncol. 12(2), 175-180.
    22.Mantha A J, Hanson J E, Goss G, Lagarde A E, Lorimer I A et al. (2005) Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor. Clin Cancer Res. 11(6), 2398-407.
    23.Dimitroulakos J, Lorimer I A, Goss G.Strategies to enhance epidermal growth factor inhibition: targeting the mevalonate pathway. Clin Cancer Res 2006; 12(14): 4426s -. 4431.
    24.Hwang K E, Kwon S J, Kim Y S, Park D S, Kim B R et al. (2014) Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR. Exp Cell Res. 323(2), 288-96.
    25.Hwang K E, Na K S, Park D S, Choi K H, Kim B R et al. (2011) Apoptotic induction by simvastatin in human lung cancer A549 cells via Akt signaling dependent down-regulation of survivin. Invest New Drugs. 29(5), 945-52.
    26.Pelaia G, Gallelli L, Renda T, Fratto D, Falcone D et al. (2012) Effects of statins and farnesyl transferase inhibitors on ERK phosphorylation, apoptosis and cell viability in non-small lung cancer cells. Cell Prolif. 45(6), 557-65.
    27.Downward J. (2003) Targeting RAS signaling pathways in cancer therapy. , Nat Rev Cancer 3(1), 11-22.
    28.Gazdar AF WistubaII. (2006) Lung cancer preneoplasia. Annu Rev Path. 1, 331-348.
    29.Chen J, Bi H, Hou J, Zhang X, Zhang C et al. (2013) Atorvastatin overcomes gefitinib resistance in KRAS mutant human non-small cell lung carcinoma cells. Cell Death Dis. 4-814.
    30.Park I H, Kim J Y, Jung J I, Han J Y. (2010) Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-ras mutations. Invest New Drugs. 28(6), 791-9.
    31.Fiala O, Pesek M, Finek J, Minarik M, Benesova L et al. (2015) Statins augment efficacy of EGFR-TKIs in patients with advanced-stage non-small cell lung cancer harbouring KRAS mutation. Tumor Biol. 36, 5801-5805.
    32.Falcone D, Gallelli L, A Di Virgillo, Tucci L, Scaramuzzino M et al. (2013) Effects of simvastatin and rosuvastatin on RAS protein, matrix metalloproteinases and NF-kB in lung cancer and in normal pulmonary tissues. Cell Prolif. 46(2), 172-82.
    33.Manning B D, Cantley L C. (2007) AKT/PKB Signaling: Navigating Downstream. , Cell 129, 1261-1274.
    34.Hanai J, Doro N, Sasaki A T, Kobayashi S, Cantley L C et al. (2012) Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. , J Cell Physiol 227(4), 1709-20.
    35.Hwang K E, Park C, Kwon S J, Ys Kim, Park D S et al. (2013) Synergistic induction of apoptosis by sulindac and simvastatin in A549 human lung cancer cells via reactive oxygen species-dependent mitochondrial dysfunction. , Int J Oncol 43(1), 262-70.
    36.Chen J, Lan T, Hou J, Zhang J, An Y et al. (2012) Atorvastatin sensitizes human non-small cell lung carcinomas to carboplatin via suppression of AKT activation and upregulation of TIMP-1. , Int J Biochem Cell Biol 44(5), 759-69.
    37.Milara J, Cortijo J. (2012) Tobacco, inflammation, and respiratory tract cancer. , Curr Pharm Design; 18(26), 3901-38.
    38.Gallelli L, Falcone D, Scaramuzzino M, Pelaia G, D’Agostino B et al. (2014) Effects of simvastatin on cell viability and proinflammatory pathways in lung adenocarcinoma cells exposed to hydrogen peroxide. , BMC Pharmacol Toxicol 15-67.
    39.Chen J, Liu C, Yuan J, Yang J, Zhang J et al. (2012) Atorvastatin reduces vascular endothelial growth factor (VEGF) expression in human non-small cell lung carcinomas (NSCLCs) via inhibition of reactive oxygen species (ROS) production. Mol Oncol. 6(1), 62-72.
    40.Weitberg A B. (2007) The antioxidant effect of lovastatin on phagocyte-induced DNA damage: implications for cancer prevention. , J Exp Clin Cancer Res 26(4), 583-6.
    41.Li Y, Fu J, Yuan X, Hu C. (2014) Simvastatin inhibits the proliferation of A549 lung cancer cells through oxidative stress and up-regulation of SOD2. Pharmazie. 69(8), 610-4.
    42.Yu X, Pan Y, Ma H, Li W. (2013) Simvastatin inhibits proliferation and induces apoptosis in human lung cancer cells. Oncol Res;20(8):. 35.
    43.Pandyra A A, Mullen P J, Goard C A, Ericson E, Sharma P et al. (2015) Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death. Oncotarget.
    44.Jung J W, Hwang S Y, Hwang J S, Oh E S, Park S. (2007) Ionising radiation induces changes associated with epithelial-mesenchymal transdifferentiation and increased cell motility of A549 lung epithelial cells. , Eur J Cancer 43, 1214-1224.
    45.Hamalukic M, Huelsenbeck J, Schad A, Wirtz S, Kaina B et al. (2011) Rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by HMG-CoA reductase inhibitors. PLoS One; 6(10):e26413
    46.Sanli T, Liu C, Rashid A, Hopmans S N, Tsiani E et al. (2011) Lovastatin sensitizes lung cancer cells to ionizing radiation: modulation of molecular pathways of radioresistance and tumor suppression. , J Thorac Oncol 6(3), 439-50.
    47.Leigh D, Eken J, Deal J R, Ganti A K, Sahmoun A E. (2011) Statins use and risk for brain metastasis from lung cancer. Cancer Invest. 29(1), 68-72.
    48.Liu H, Wang Z, Li W, Chen Y. (2013) Simvastatin prevents proliferation and bone metastases of lung adenocarcinomain vitroandin vivo. Neoplasma. 60(3), 240-6.
    49.Han J Y, Lee S H, Yoo N J, Hyung L S, Moon Y J et al. (2011) A randomized phage II study of gefitinib plus simvastatin versus gefitinib along in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 17(6), 1553-60.
    50.McGarvey L P, John M, Anderson J A, Zvarich M, Wise R A. (2007) Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 62, 411-415.
    51.Van Gestel YR, Hoeks S E, Sin D D, Huzeir V, Stam H et al. (2009) COPD and cancer mortality: the influence of statins. Thorax. 64(11), 963-7.
    52.Johnson J A, Gale E A. (2010) Diabetes, insulin use, and cancer risk: are observational studies part of the solution-or part of the problem?. , Diabetes2010; 59, 1129-31.
    53.Dong Y H, Lin J W, Wu L C, Chen C Y, Chang C H et al. (2014) Examining the association between statins and lung cancer incidence in patients with type 2 diabetes mellitus. J Formos Med Assoc. 113(12), 940-8.
    54.Yao C J, Lai G M, Chan C F, Cheng A L, Yang Y Y et al. (2006) Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone. , Int J Cancer 118(3), 773-9.