Background : Cardiac glycosides such as digitoxin have been shown to directly cause apoptotic death of cancer cells both in vitro, and in vivo. However, the mechanism connecting cardiac glycoside action to apoptosis is not known. It has been reported that compounds resembling digitoxin are able to reduce c-MYC expression. Furthermore, it has been previously shown that the transcription of c-MYC depends on nuclear factor of activated T-cells (NFAT) binding sites in the c-MYC promoter. We have therefore hypothesized that NFAT might mediate digitoxin effects on c-MYC mRNA message. Materials and Methods : We have chosen to study this process in HeLa cells where structurally intact c-MYC genes in 8q24 co-localize with human papilloma virus 18 at all integration sites. Results : Here we show that within the 1 ^st h following treatment with digitoxin, a significant reduction in c-MYC mRNA occurs. This is followed by a precipitous loss of c-MYC protein, activation of caspase 3, and subsequent apoptotic cell death. To test the NFAT-dependence mechanism, we analyzed the effects of digitoxin on NFAT isoform-dependent auto-activation of a NFAT-luciferase expression system. Drug dependent effects on expression varied according to each of the four canonical NFAT isoforms (1, 2, 3 or 4). The most digitoxin-sensitive NFAT isoform was NFAT1. Using c-MYC chromatin immune precipitation, we find that digitoxin inhibits interaction of NFAT1 with the proximal c-MYC promoter. Conclusions : These results suggest that the carcinotoxic activity of digitoxin includes suppression of NFAT-driven c-MYC expression.

Lung cancer is a heterogeneous group of diseases. There has been much research in lung cancer over the past decade which has advanced our ability to treat these patients with a more personalized approach. The scope of this paper is to review the literature and give a broad understanding of the current molecular targets for which we currently have therapies as well as other targets for which we may soon have therapies. Additionally, we will cover some of the issues of resistance with these targeted therapies. The molecular targets we intend to discuss are epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF), anaplastic large-cell lymphoma kinase (ALK), KRAS, C-MET/RON, PIK3CA. ROS-1, RET Fibroblast growth factor receptor (FGFR). Ephrins and their receptors, BRAF, and immunotherapies/vaccines. This manuscript only summarizes the work which has been done to date and in no way is meant to be comprehensive.

Lung cancer is the leading cause of cancer deaths worldwide, and current therapies are disappointing. Elucidation of the cell(s) of origin of lung cancer may lead to new therapeutics. In addition, the discovery of putative cancer-initiating cells with stem cell properties in solid tumors has emerged as an important area of cancer research that may explain the resistance of these tumors to currently available therapeutics. Progress in our understanding of normal tissue stem cells, tumor cell of origin, and cancer stem cells has been hampered by the heterogeneity of the disease, the lack of good in vivo transplantation models to assess stem cell behavior, and an overall incomplete understanding of the epithelial stem cell hierarchy. As such, a systematic computerized literature search of the MEDLINE database was used to identify articles discussing current knowledge about normal lung and lung cancer stem cells or progenitor cells. In this review, we discuss what is currently known about the role of cancer-initiating cells and normal stem cells in the development of lung tumors.

Introduction and Hypothesis: Nuclear atypia with features of multi nuclei have been detected in human melanoma specimens. We found that the K type human endogenous retroviral element (HERV K) is expressed in such cells. Since cellular syncytia can form when cells are infected with retroviruses, we hypothesized that HERV K expressed in melanoma cells may contribute to the formation of multinuclear atypia cells in melanoma. Experiments and Results: We specifically inhibited HERV K expression using RNA interference (RNAi) and monoclonal antibodies and observed dramatic reduction of intercellular fusion of cultured melanoma cells. Importantly, we identified loss of heterozygosity (LOH)of D19S433 in a cell clone that survived and proliferated after cell fusion. Conclusion: Our results support the notion that proteins encoded by HERV K can mediate intercellular fusion of melanoma cells, which may generate multinuclear cells and drive the evolution of genetic changes that provide growth and survival advantages.

Background: Prostate stem cell antigen (PSCA), an organ-dependent tumor suppressor, is down regulated in gallbladder cancer (GBC). It is anticipated that the missense allele C of the single nucleotide polymorphism (SNP) rs2294008 (T/C) in the translation initiation codon of the gene affects the gene's biological function and has some influence on GBC susceptibility. We examined the biological effect of the C allele on the function of the gene and the relation between the C allele and GBC susceptibility. Materials and Methods: Functional analysis of the SNP was conducted by introducing PSCA cDNA harboring the allele to a GBC cell line TGBC- 1TKB and performing colony formation assays in vitro and tumor formation assays in mice. The effect on transcriptional regulation was assessed by reporter assays. The association study was conducted on 44 Japanese GBC cases and 173 controls. Results: The PSCA cDNA harboring the C allele showed lower cell growth inhibition activity (20% reduction) than that with the T allele. Concordantly, when injected into subcutaneous tissues of mice, the GBC cell line stably expressing the cDNA with the C allele formed tumors of almost the same size as that of the control cells, but the cell line expressing the cDNA with the T allele showed slower growth. The upstream DNA fragment harboring the C allele had more transcriptional activity than that with the T allele. The C allele showed positive correlation to GBC but no statistical significant odds ratio (OR = 1.77, 95% confidence interval 0.85-3.70, P value = 0.127 in dominant model). Conclusions: The missense allele was shown to have a biological effect, attenuating antitumor activities of PSCA, and consequently it may be a potential risk for GBC development. An association study in a larger sample size may reveal a significant association between the allele and GBC.

Lung cancer is one of the deadliest cancers worldwide, with the highest incidence and mortality amongst all cancers. While the prognosis of lung cancer is generally grim, with 5-year survival rates of only 15%, there is hope, and evidence, that early detection of lung cancer can reduce mortality. Today, only computed tomography screening has shown to lead to early detection and reduction in mortality, but is limited by being anatomic in nature, unable to differentiate between inflammatory and neoplastic pathways, and therefore, susceptible to false positives. There is increasing interest in biomarkers for lung cancer, especially those that predict metastatic risk. Some biomarkers like DNA mutations and epigenetic changes potentially require tissue from the at-risk site; some like serum proteins and miRNAs are minimally invasive, but may not be specific to the lung. In comparison, emerging biomarkers from exhaled breath, like volatile organic compounds (VOC), and exhaled breath condensate, e.g., small molecules and nucleic acids, have the potential to combine the best of both. This mini review is intended to provide an overview of the field, briefly discussing the potential of what is known and highlighting the exciting recent developments, particularly with miRNAs and VOCs.

Lung cancer is the leading cause of cancer-related mortality globally and the American cancer society estimates approximately 226,160 new cases and 160,340 deaths from lung cancer in the USA in the year 2012. The majority of lung cancers are diagnosed in the later stages which impacts the overall survival. The 5-year survival rate for pathological st age IA lung cancer is 73% but drops to only 13% for stage IV. Thus, early detection through screening and prevention are the keys to reduce the global burden of lung cancer. This article discusses the current state of lung cancer screening, including the results of the National Lung Cancer Screening Trial, the consideration of implementing computed tomography screening, and a brief overview of the role of bronchoscopy in early detection and potential biomarkers that may aid in the early diagnosis of lung cancer.

Tobacco use in cancer patients is associated with increased cancer treatment failure and decreased survival. Nicotine is one of over 7,000 compounds in tobacco smoke and nicotine is the principal chemical associated with addiction. The purpose of this article is to review the tumor promoting activities of nicotine. Nicotine and its metabolites can promote tumor growth through increased proliferation, angiogenesis, migration, invasion, epithelial to mesenchymal transition, and stimulation of autocrine loops associated with tumor growth. Furthermore, nicotine can decrease the biologic effectiveness of conventional cancer treatments such as chemotherapy and radiotherapy. Common mechanisms appear to involve activation of nicotinic acetylcholine receptors and beta-adrenergic receptors leading to downstream activation of parallel signal transduction pathways that facilitate tumor progression and resistance to treatment. Data suggest that nicotine may be an important mechanism by which tobacco promotes tumor development, progression, and resistance to cancer treatment.

The last few years have witnessed an explosion of the use of minimally invasive techniques for the detection, diagnosis, and treatment of all stages of lung cancer. The use of these techniques has improved the risk-benefit ratio of surgery and has made it more acceptable to patients considering lung surgery. They have also facilitated the delivery of multi-modality therapy to patients with advanced lung cancer. This review article summarizes current surgical techniques that represent the "cutting edge" of thoracic surgery for lung cancer.

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer mortality. The majority of patients present with advanced (stage III-IV) disease. Such patients are treated with a variety of therapies including surgery, radiation, and chemotherapy. Despite decades of work, however, overall survival in this group has been resistant to any substantial improvement. This review briefly details the evolution to the current standard of care for advanced NSCLC, advances in systemic therapy, and novel techniques (stereotactic body radiation therapy [SBRT], and transcervical extended mediastinal lymphadenectomy [TEMLA] or video-assisted mediastinal lymphadenectomy [VAMLA]) that have been used in localized NSCLC. The utility of these techniques in advanced stage therapy and potential methods of combining these novel techniques with systemic therapy to improve survival are discussed.

Bronchoscopic techniques have seen significant advances in the last decade. The development and refinement of different types of endobronchial ultrasound and navigation systems have led to improved diagnostic yield and lung cancer staging capabilities. The complication rate of these minimally invasive procedures is extremely low as compared to traditional transthoracic needle biopsy and surgical sampling. These advances augment the safe array of methods utilized in the work up and management algorithms of lung cancer.

Background: MicroRNAs (miRNAs) are small noncoding RNA molecules with an essential role in regulation of gene expression. miRNA expression profiles differ between tumor and normal control tissue in many types of cancers and miRNA profiling is seen as a promising field for finding new diagnostic and prognostic tools. Materials and Methods: In this study, we have analyzed expression of three miRNAs, miR-21, miR-125b, and miR-203, and their potential target proteins p53 and p63, known to be deregulated in squamous cell carcinoma of the head and neck (SCCHN), in two distinct and one mixed subsite in squamous cell carcinoma in the oral cavity. Results: We demonstrate that levels of miRNA differ between tumors of different subsites with tongue tumors showing significant deregulation of all three miRNAs, whereas gingival tumors only showed significant downregulation of miR-125b and the mixed group of tumors in tongue/floor of the mouth showed significant deregulation of miR-21 and miR-125b. In the whole group of oral squamous cell carcinoma (SCC), a significant negative correlation was seen between miR-125b and p53 as well as a significant correlation between TP53 mutation status and miR-125b. Conclusion: The present data once again emphasize the need to take subsite into consideration when analyzing oral SCC and clearly show that data from in vitro studies cannot be transferred directly to the in vivo situation.

Background: Dietary arginine and meat consumption are implicated in colorectal cancer (CRC) progression via polyamine-dependent processes. Polymorphism in the polyamine-regulatory gene, ornithine decarboxylase 1 (Odc1, rs2302615) is prognostic for CRC-specific mortality. Here, we examined joint effects of meat consumption and Odc1 polymorphism on CRC-specific mortality. Materials and Methods: The analytic cohort was comprised of 329 incident stage I-III CRC cases diagnosed 1994-1996 with follow- up through March 2008. Odc1 genotyping was conducted using primers that amplify a 172-bp fragment containing the polymorphic base at +316. Dietary questionnaires were administered at cohort entry. Multivariate Cox proportional hazards regression analysis for CRC-specific mortality was stratified by tumor, node, metastasis (TNM) stage, and adjusted for clinically relevant variables, plus meat consumption (as a continuous variable, i.e., the number of medium-sized servings/week), Odc1 genotype, and a term representing the meat consumption and Odc1 genotype interaction. The primary outcome was the interaction of Odc1 and meat intake on CRC-specific mortality, as assessed by departures from multiplicative joint effects. Results: Odc1 genotype distribution was 51% GG, 49% GA/AA. In the multivariate model, there was a significant interaction between meat consumption and Odc1 genotype, P-int = 0.01. Among Odc1 GA/AA CRC cases in meat consumption Quartiles 1-3, increased mortality risk was observed when compared to GG cases (adjusted hazards ratio (HR) = 7.06 [95% CI 2.34-21.28]) - a difference not found among cases in the highest dietary meat consumption Quartile 4. Conclusions: Effects of meat consumption on CRC-specific mortality risk differ based on genetic polymorphism at Odc1. These results provide further evidence that polyamine metabolism and its modulation by dietary factors such as meat may have relevance to CRC outcomes.

There are striking disparities in health status, access to health care, and risk factors among racial and ethnic minorities and the general population in Texas. The disparities are multifactorial comprising genetic, sociocultural, and environmental variables. The Texas Center for Health Disparities (TCHD), a NIMHD Center of Excellence (COE), aims to prevent, reduce, and eliminate health disparities in the communities through research, education, and community-based programs. As part of the center's outreach activities, an annual conference is organized to build awareness and knowledge on health disparities. The overall theme for the 2012 conference was "Battling Breast Cancer Disparities: Frontline Strategies". The scientific program consisted of three sessions: "Breakthroughs in Breast Cancer", "Triple Negative Breast Cancer," and "Hormone Resistant Breast Cancer" featuring different aspects of bench-research from molecular biology, proteomics, and genetics to the clinical aspects such as detection, diagnosis, and finally to community-based approaches. This article summarizes the proceedings of the meeting providing salient strategies and best practices presented by the speakers.

Development and progression of pancreatic cancer involves general metabolic disorder, local chronic inflammation, and multistep activation of distinct oncogenic molecular pathways. These pathologic processes result in a highly invasive and metastatic tumor phenotype that is a major obstacle to curative surgical intervention, infusional gemcitabine-based chemotherapy, and radiation therapy. Many clinical trials with chemical compounds and therapeutic antibodies targeting growth factors, angiogenic factors, and matrix metalloproteinases have failed to demonstrate definitive therapeutic benefits to refractory pancreatic cancer patients. Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, has emerged as a therapeutic target in common chronic and progressive diseases, including cancer. Here we review accumulating evidence for a pathologic role of GSK3β in promoting tumor cell survival, proliferation, invasion, and resistance to chemotherapy and radiation in pancreatic cancer. We also discuss the putative involvement of GSK3β in mediating metabolic disorder, local inflammation, and molecular alteration leading to pancreatic cancer development. Taken together, we highlight potential therapeutic as well as preventive effects of GSK3β inhibition in pancreatic cancer.

Background: Oral squamous cell carcinoma (OSCC) is the sixth largest group of malignancies globally and the single largest group of malignancies in the Indian subcontinent. Despite the advances in treatment and therapeutic modalities the five year survival rate of OSCC has not changed in the last few decades, and remains less than 40%. Several studies have focused on defining molecular markers that can either detect cancer at an early stage or can predict patient's outcome. However, such markers are still undefined. Keratins (K) are epithelia predominant intermediate filament proteins which are expressed in a differentiation dependent and site specific manner. Keratins are being used as biomarkers in different epithelial disorders including cancer. They are associated with desmoplakin and α6β4 integrin which are components of desmosomes and hemidesmosomes respectively. Materials and Methods: 4-Nitroquinoline 1-Oxide (4NQO) was used as a carcinogen for the development of various stages of oral carcinogenesis in rat lingual mucosa. Two-Dimentional gel electrophoresis was performed for the separation of Keratins followed by western blotting for their specific identification. Western blotting and RT PCR was carried out for desmoplakin and α6β4 integrin respectively to understand their levels. Immunohistochemical analysis was carried out to further study the localization of desmoplakin and α6 integrin. Results: In this study we have analysed the alterations in Keratins and associated proteins during sequential stages of 4NQO induced rat oral carcinogenesis. Our results showed that the alterations primarily begin after the dysplastic changes in the lingual epithelium like the elevation of Keratins 5/6a, ectopic expression of Keratin 8, increase in suprabasal expression of α6 integrin and increase in desmoplakin levels. Most of these alterations persisted till the development of SCC except desmoplakin, the levels of which were downregulated in papillomatous lesions and SCC. Many of these alterations have also been documented in human oral carcinogensis. Conclusion: Thus, 4NQO model of rat lingual carcinogenesis reproduces majority of the changes that are seen in human oral carcinogenesis and it can be exploited for the development of biomarkers.

Backgrounds: Meju is the main ingredient and the starter culture of traditional Korean fermented soybean foods; these fermented soybean products are well-known for their various health benefits, including anticancer effects. We developed the grain-type meju using probiotic mixed starter cultures to improve the qualities and functionalities of fermented soybean products, as well as the meju itself. In this study, the inhibitory effects of the grain-type meju were investigated in azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced colon carcinogenesis mice model. Materials and Methods: AOM and DSS colon carcinogenesis was induced in female C57BL/6 mice and meju was orally administered for 4 weeks. The body weight, colon length, and colon weight of mice were determined, and colonic tissues were histologically observed. The serum levels of proinflammatory cytokines and the levels of inflammation- and apoptosis-related genes in colonic tissue were also analyzed. Results: The administration of meju using probiotic mixed starter cultures ameliorated the symptoms of colon cancer and reduced number of neoplasia, and reduced serum proinflammatory cytokine levels and iNOS and COX-2 expression levels in colonic tissue. It increased Bax and reduced Bcl-2 expression levels and increased p21 and p53 expression in colonic tissues. Conclusion: The meju showed inhibitory effects on the progression of colon cancer induced by AOM and DSS by ameliorating the symptoms of colon cancer, reducing the number of neoplasias and regulating proinflammatory cytokine levels and the expressions of inflammation- and apoptosis-related genes in the colonic tissue.

Background : CyclinD1 is an essential sensor and activator of cell cycle initiation and progression; overexpression of cyclinD1 is linked to various human cancers, including breast cancer. The elevated cyclinD1 in some types of cancers is believed to be associated with tumor progression and response to systemic treatments. Aims : In this study, we anticipate to address the questions in human breast cancer; the function of cyclinD1 in mediating chemoresponses; and the signaling pathway cooperating with cyclinD1 to interfere with the drug functions. Materials and Methods: Using the cell clones, concurrent ectopic expression of the wild-type or K112E-mutated human cyclinD1 protein in the MCF7 and MDA-MB231 (MB231) breast cancer cells to study the function of cyclinD1 in responses to the chemotherapeutic treatments. Three drugs, cisplatin (CDDP), 5-fluorouracil (5-FU), and Gemzar were used in this study; the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle and cell death analysis, clonogenic survival assay, acridine orange (AO)/ethidium bromide (EB) staining, and Western blot assay were conducted to evaluate the drugs' effects in the cell clones. Results: The cell clones expressing the D1 protein in MCF7 and MB231 cells result in distinct effects on the responses to chemotherapeutic treatments. Particularly with Gemzar, ectopic expression of cyclinD1 protein in MCF7 cells results in a potentiated effect, which is CDK4 kinase activity dependent, whereas in MB231 cells, an opposite effect was observed. Moreover, our results suggested that the distinct chemosensitivities among those cell clones were not resulted from accelerated cell cycle, cell proliferation driven by the cyclinD1CDK4/6-Rb-E2F signaling chain, rather, they were results of the cell cycle-independent functions led by cyclinD1 alone or in complex with CDK4. Conclusions: Our results suggest that the functions of cyclinD1 protein in modulating chemoresponses in the MCF7 and MB231 cells are independent to its function as cell cycle initiator through activation of CDK4/6. Furthermore, the signals modulated by cyclinD1 upon treatment are determined by the drug and the cellular network.

One of the key features of hepatocellular carcinoma (HCC) is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR), a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of "clonal deletion and inhibition" therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss "combination chemoprevention" using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.

Background: Caloric restriction (CR), a lowering of caloric intake without malnutrition, is associated with longevity. CR also decreases incidences of age-related diseases including cancer. The sirtuins (SIRTs) have been implicated as a key mediator for the beneficial effects of CR on longevity. However, the underlying mechanisms by which CR decreases cancer risk have not yet been fully elucidated. Materials and Methods: The present study was conducted to determine whether CR would modify the growth of preneoplastic colonic aberrant crypt foci (ACF). We also analyzed the expression of SIRTs to elucidate the molecular mechanisms of cancer-preventive effects of CR. F344 rats were fed a CR diet (60% of ad libitum diet) or a basal diet ad libitum. Then, the animals were given subcutaneous injection of either 1, 2-dimethylhydrazine (DMH) that enhances cell proliferation of colonic mucosa or saline. All animals were sacrificed at 5 weeks after the beginning of the experiment. Results: The number of ACF in colonic mucosa was significantly decreased in DMH-treated rats with CR as compared to in those without CR. No ACF was found in DMH-untreated animals with or without CR. Also, we found that CR decreased the cell proliferation of colonic mucosa in DMH-treated rats. The expressions of anti-apoptotic gene, Survivin, and cell cycle progression-associated gene, Cyclin D1, were increased by DMH-treatment. Both of the genes expressions were declined by CR in those of DMH-treated rats. The expressions of all SIRT1-7 mRNAs were significantly increased by CR in DMH-treated rats. Conclusion: As previous studies demonstrated that SIRT1 down-regulates Survivin and Cyclin D1, our findings suggest that at least SIRT1 protect colonic mucosa from formation and development of ACF by increasing apoptosis and reducing excessive cell growth in colon epithelial cells.

Background: Lung cancer is a leading cause of cancer death. There has been found a substantial gap in the understanding of lung cancer genesis at the molecular level. We developed urethane (ethyl carbamate) induced lung tumor mice model to understand the mechanism and molecules involved in the cancer genesis. There might be many molecules involved, but we subsequently emphasized here the study of alternation in the expression of NF- κB, Stat3, and inflammatory cytokines interleukin-1β and interleukin-6 to hypothesize that the microenvironment created by these molecules is promoting tumor formation. Materials and Methods: 7-8 week old Balb/c mice of either sex were given intraperitoneal (i.p.) injection of urethane (1g/kgbw) for eight consecutive weeks. Histopathological analysis was done to detect abnormality or invasions occurred in the lung tissues. Automated cell counter was used to count the number of inflammatory cells. The expression of NF-κB, Stat3, and IL-1β was observed at translational level by western blot, while the expression of IL-1β and IL-6 was observed at transcriptional level by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) method. Secretion of IL-1β and IL-6 in the blood was measured by enzyme-linked immunosorbent assay (ELISA) method at different time intervals. Results: Histopathological analysis showed various lung cancer stages hyperplasia, atypical adenomatous hyperplasia, and adenocarcinoma. Increased population of inflammatory cells, persistant expression of NF-κB, Stat3, pStat3, and IL-1β at translational level, while at transcriptional level constitutive enhanced expression of IL-1β and IL-6 followed by increased secretion of IL-1β and IL-6 in the blood were observed in urethane-injected mice in comparison to phosphate buffer saline (PBS) injected mice at 12, 24, and 36 weeks . Conclusions: Overexpression of key molecules such as NF-κB, Stat3, pStat3, IL-1β, and IL-6 might have caused chronic inflammation, leading to the progression of lung cancer.

Background: Sulforaphane (SFN), an activator of nuclear factor erythroid-2 related factor 2 (Nrf2), is a promising chemopreventive agent which is undergoing clinical trial for several diseases. Studies have indicated that there is gain of Nrf2 function in lung cancer and other solid tumors because of mutations in the inhibitor Kelch-like ECH-associated protein 1 (Keap1). More recently, several oncogenes have been shown to activate Nrf2 signaling as the main prosurvival pathway mediating ROS detoxification, senescence evasion, and neoplastic transformation. Thus, it is important to determine if there is any risk of enhanced lung tumorigenesis associated with prolonged administration of SFN using mouse models of cancer. Materials and Methods: We evaluated the effect of prolonged SFN treatment on oncogenic K-ras (K-ras ^LSL-G12D )-driven lung tumorigenesis. One week post mutant-K-ras expression, mice were treated with SFN (0.5 mg, 5 d/wk) for 3 months by means of a nebulizer. Fourteen weeks after mutant K-ras expression (K-ras ^LSL-G12D ), mice were sacrificed, and lung sections were screened for neoplastic foci. Expression of Nrf2-dependent genes was measured using real time RT-PCR. We also determined the effect of prolonged SFN treatment on the growth of preclinical xenograft models using human A549 (with mutant K-ras and Keap1 allele) and H1975 [with mutant epidermal growth factor receptor (EGFR) allele] nonsmall cell lung cancer cells. Results: Systemic SFN administration did not promote the growth of K-ras ^LSL-G12D -induced lung tumors and had no significant effect on the growth of A549 and H1975 established tumor xenografts in nude mice. Interestingly, localized delivery of SFN significantly attenuated the growth of A549 tumors in nude mice, suggesting an Nrf2-independent antitumorigenic activity of SFN. Conclusions: Our results demonstrate that prolonged SFN treatment does not promote lung tumorigenesis in various mouse models of lung cancer.