Overexpression of TNFSF11 reduces GPX4 levels and increases sensitivity to ferroptosis inducers in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD), the most common and lethal subtype of lung cancer, continues to be a major health concern worldwide. Despite advances in targeted and immune therapies, only a minority of patients derive substantial benefits. As a result, the urgent need for novel therapeutic strategies to improve lung cancer treatment outcomes remains undiminished. METHODS: In our study, we employed the TIMER database to scrutinize TNFSF11 expression across various cancer types. We further examined the differential expression of TNFSF11 in normal and tumor tissues utilizing the TCGA-LUAD dataset and tissue microarray, and probed the associations between TNFSF11 expression and clinicopathological parameters within the TCGA-LUAD dataset. We used the GSE31210 dataset for external validation. To identify genes strongly linked to TNFSF11, we engaged LinkedOmics and conducted a KEGG pathway enrichment analysis using the WEB-based Gene SeT AnaLysis Toolkit. Moreover, we investigated the function of TNFSF11 through gene knockdown or overexpression approaches and explore its function in tumor cells. The therapeutic impact of ferroptosis inducers in tumors overexpressing TNFSF11 were also investigated through in vivo and in vitro experiments. Through these extensive analyses, we shed light on the potential role of TNFSF11 in lung adenocarcinoma, underscoring potential therapeutic targets for this malignancy. RESULTS: This research uncovers the overexpression of TNFSF11 in LUAD patients and its inverse correlation with peroxisome-related enzymes. By utilizing gene knockdown or overexpression assays, we found that TNFSF11 was negatively associated with GPX4. Furthermore, cells with TNFSF11 overexpression were relatively more sensitive to the ferroptosis inducers. CONCLUSIONS: Our research has provided valuable insights into the role of TNFSF11, revealing its negative regulation of GPX4, which could be influential in crafting therapeutic strategies. These findings set the stage for further exploration into the mechanisms underpinning the relationship between TNFSF11 and GPX4, potentially opening up new avenues for precision medicine in the treatment of LUAD.

Youth participation in substance use prevention: A national profile, 2011-2019.

PURPOSE: Prevention efforts are critical to avoid the negative consequences of substance use in adolescents. This study aimed to examine national trends and sociodemographic differences in adolescents' participation in school-based substance use prevention (SUP) education, community-based SUP programs, as well as family conversations about substance use. METHODS: Publicly available data for adolescents aged 12-17 from the annual cross-sectional surveys of the National Survey on Drug Use and Health 2011-2019 were analyzed. RESULTS: Across the survey years, up to 74.9%, 12.2%, and 58.1% of adolescents reported having participated in school-based SUP education, community-based SUP programs, and family conversations about the danger of substance use in the past-year, respectively. From 2011 to 2019, statistically significant decreases were observed in adolescents' participation in school-based SUP education (OR = 0.97, 95% CI: 0.96, 0.98, p < 0.001) and community-based SUP programs (OR = 0.98, 95% CI: 0.97, 0.99, p < 0.001). Meanwhile, no significant changes were observed in adolescents' participation in family conversations about the dangers of substance use. Overall, lower levels of participation in school-based and community-based SUP programs were found in adolescents aged 16-17. Adolescents living in rural areas showed lower levels of participation in school-based SUP programs and family conversations about SUP. Racial/ethnic minority adolescents overall were less likely to participate in conversations with parents about SUP than Whites. CONCLUSIONS: Further development and implementation of developmentally appropriate, gender-specific, culturally sensitive, and contextually informed SUP programs at school, community, and family levels are needed.

Mental health, functional impairment, and barriers to mental health access among cancer patients in Vietnam.

OBJECTIVE: This study evaluated the prevalence and severity of depression and anxiety symptomatology, barriers to mental health access, and correlates of functional impairment among cancer inpatients. METHODS: This cross-sectional study recruited adult cancer patients (N = 300) in June and July 2022 at the largest oncological hospital in Vietnam. Multivariable linear regression analyses examined the association between demographics, clinical characteristics, and patients' functional impairment. RESULTS: Approximately 46.3% and 27.0% showed some depression and anxiety symptomatology, while 8.0% and 3.0% experienced major depressive and anxiety symptoms, respectively. Patients reported the most impairment in mobility and capacity for life activities. More functional impairment was identified in patients with gastrointestinal cancers, those receiving radiation therapy alone, and those scoring higher on depression and anxiety than in those with cancers originating in the head, neck, or lung or those receiving chemotherapy alone. Reports of better overall health status were negatively associated with functional impairment. Patients reported extensive perceived barriers to seeking psychiatric care, including not knowing where to get mental health support (86.7%), wanting to manage mental health independently (73.7%), and thinking mental health will resolve on its own (73.7%), and denying mental health concerns (61.0%). CONCLUSION: High frequency and severity of depression and anxiety symptomatology underscore the importance of integrating mental health services into existing oncological treatment protocols. Increasing mental health literacy and provision of psychoeducation is critical to addressing barriers to mental health service access. Integration of functional impairment evaluations into hospital admission and discharge planning is also needed.

Photocatalytic synthesis of alkyl-alkyl sulfones via direct C(sp3)-H bond functionalization.

We report a highly efficient one-pot, three-component strategy for the construction of alkyl-alkyl sulfones through a photoinduced TBADT-catalyzed C(sp3)-H sulfonylation of unactivated hydrocarbon compounds. A wide range of commercially available hydrocarbon compounds and bioactive molecules can be successfully applied to the catalytic system, affording the corresponding alkyl-alkyl sulfones in good to excellent yields (>50 examples, up to 87% yield).

Increased levels of N6-methyladenosine in peripheral blood RNA: a perspective diagnostic biomarker and therapeutic target for non-small cell lung cancer.

OBJECTIVES: Due to lack of effective biomarkers for non-small cell lung cancer (NSCLC), many patients are diagnosed at an advanced stage, which leads to poor prognosis. Dysregulation of N6-methyladenosine (m6A) RNA contributes significantly to tumorigenesis and tumor progression. However, the diagnostic value of m6A RNA status in peripheral blood to screen NSCLC remains unclear. METHODS: Peripheral blood samples from 152 NSCLC patients and 64 normal controls (NCs) were applied to assess the m6A RNA levels. Bioinformatics and qRT-PCR analysis were performed to identify the specific immune cells in peripheral blood cells and investigate the mechanism of the alteration of m6A RNA levels. RESULTS: Robust elevation of m6A RNA levels of peripheral blood cells was exhibited in the NSCLC group. Moreover, the m6A levels increased as NSCLC progressed, and reduced after treatment. The m6A levels contained area under the curve (AUC) was 0.912, which was remarkably greater than the AUCs for CEA (0.740), CA125 (0.743), SCC (0.654), and Cyfra21-1 (0.730). Furthermore, the combination of these traditional biomarkers with m6A levels elevated the AUC to 0.970. Further analysis established that the expression of m6A erasers FTO and ALKBH5 were both markedly reduced and negatively correlated with m6A levels in peripheral blood of NSCLC. Additionally, GEO database and flow cytometry analysis implied that FTO and ALKBH5 attributes to peripheral CD4+ T cells proportion and activated the immune functions of T cells. CONCLUSIONS: These findings unraveled that m6A RNA of peripheral blood immune cells was a prospective biomarker for the diagnosis of NSCLC.

Human Capital Development Factors and Black Adolescent Tobacco and Cannabis Use.

INTRODUCTION: This study examined the association of four domains of human capital development (cognitive development, social and emotional development, physical health, and mental health) and exclusive and concurrent tobacco and cannabis use (TCU) among black youth. AIMS AND METHODS: Nationally representative annual cross-sectional data for black adolescents (12-17 years; N = 9017) in the National Survey on Drug Use and Health 2015-2019 were analyzed. Analyses examined the influence of human capital factors (cognitive development, social and emotional development, physical health, and mental health) on exclusive and concurrent TCU. RESULTS: In total, 50.4% were males; prevalence of 12-month tobacco use fluctuated insignificantly between 5.6% and 7.6% across survey years. Similarly, prevalence of 12-month cannabis use remained relatively stable around 13%, with no significant linear change. Prevalence of concurrent TCU also fluctuated insignificantly between 3.5% and 5.3%. Investment in cognitive development decreased the odds of tobacco (aOR = 0.58, p < .001), cannabis (aOR = 0.64, p < .001), and concurrent tobacco and cannabis (aOR = 0.58, p < .001) use. Similarly, investment in social and emotional development reduced the odds of tobacco (aOR = 086, p < .001), cannabis (aOR = 0.83, p < .001), and concurrent tobacco and cannabis (aOR = 0.81, p < .001) use. Good physical health reduced the odds of tobacco (aOR = 0.52, p < .1), cannabis (aOR = 0.63, p < .05), and concurrent TCU (aOR = 0.54, p < .05). Major depressive episodes increased the likelihood of cannabis use (aOR = 1.62, p < .001). CONCLUSIONS: Investment in cognitive, social, and emotional aspects of human capital development, and physical health among black youth is protective against TCU. Efforts to sustain human capital development among black adolescents may contribute to reducing TCU disparities. IMPLICATIONS: This is one of few studies to examine human capital development factors and their associations with TCU among black youth. Efforts to eliminate tobacco/cannabis-related disparities among black youth should also invest in social, emotional, cognitive, and physical health development opportunities.

Potential inhibitors for blocking the interaction of the coronavirus SARS-CoV-2 spike protein and its host cell receptor ACE2.

BACKGROUND: The outbreak of SARS-CoV-2 continues to pose a serious threat to human health and social. The ongoing pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious threat to public health and economic stability worldwide. Given the urgency of the situation, researchers are attempting to repurpose existing drugs for treating COVID-19. METHODS: We first established an anti-coronavirus drug screening platform based on the Homogeneous Time Resolved Fluorescence (HTRF) technology and the interaction between the coronavirus spike protein and its host receptor ACE2. Two compound libraries of 2,864 molecules were screened with this platform. Selected candidate compounds were validated by SARS-CoV-2_S pseudotyped lentivirus and ACE2-overexpressing cell system. Molecular docking was used to analyze the interaction between S protein and compounds. RESULTS: We identified three potential anti-coronavirus compounds: tannic acid (TA), TS-1276 (anthraquinone), and TS-984 (9-Methoxycanthin-6-one). Our in vitro validation experiments indicated that TS-984 strongly inhibits the interaction of the coronavirus S protein and the human cell ACE2 receptor. Additionally, tannic acid showed moderate inhibitory effect on the interaction of S protein and ACE2. CONCLUSION: This platform is a rapid, sensitive, specific, and high throughput system, and available for screening large compound libraries. TS-984 is a potent blocker of the interaction between the S-protein and ACE2, which might have the potential to be developed into an effective anti-coronavirus drug.

Photocatalytic Synthesis of Diarylmethyl Silanes via 1,6-Conjugate Addition of Silyl Radicals to p-Quinone Methides.

A novel photocatalytic method for the preparation of diarylmethyl silanes was reported through silyl radicals addition strategy to p-QMs (p-quinone methides). This protocol could tolerate a variety of functional groups affording the corresponding silylation products with moderate to excellent yields. The resulting silylation products could be easily converted into a series of bioactive GPR40 agonists and useful p-QMs precursors for the synthesis of compounds possessing both quaternary carbon centers and silicon substituents through simple operation. A plausible mechanism of silyl radicals to p-QMs was proposed on the basis of experimental results and previous literature.

Developing Bi-Gold Compound BGC2a to Target Mitochondria for the Elimination of Cancer Cells.

Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often cause drug resistance and cancer relapse. Auranofin is a mono-gold anti-rheumatic drug, and it has been repurposed as an anticancer agent working by the induction of both ROS increase and mitochondrial dysfunction. Hypothetically, increasing auranofin's positive charges via incorporating more gold atoms to enhance its mitochondria-targeting capacity could enhance its anti-cancer efficacy. Hence, in this work, both mono-gold and bi-gold compounds were designed and evaluated to test our hypothesis. The results showed that bi-gold compounds generally suppressed cancer cells proliferation better than their mono-gold counterparts. The most potent compound, BGC2a, substantially inhibited the antioxidant enzyme TrxR and increased the cellular ROS. BGC2a induced cell apoptosis, which could not be reversed by the antioxidant agent vitamin C, implying that the ROS induced by TrxR inhibition might not be the decisive cause of cell death. As expected, a significant proportion of BGC2a accumulated within mitochondria, likely contributing to mitochondrial dysfunction, which was further confirmed by measuring oxygen consumption rate, mitochondrial membrane potential, and ATP production. Moreover, BGC2a inhibited colony formation and reduced stem-like side population (SP) cells of A549. Finally, the compound effectively suppressed the tumor growth of both A549 and PANC-1 xenografts. Our study showed that mitochondrial disturbance may be gold-based compounds' major lethal factor in eradicating cancer cells, providing a new approach to developing potent gold-based anti-cancer drugs by increasing mitochondria-targeting capacity.

Localization and enzyme kinetics of aminopeptidase N3 from Toxoplasma gondii.

Aminopeptidase N is an important metalloenzyme from the M1 zinc metallopeptidase family, which is present in numerous apicomplexan parasites, including Plasmodium, Eimeria, and Cryptosporidium. Aminopeptidase N is a potential drug target, and hence, its properties have been widely investigated. In the current study, the cellular localization and enzyme characteristics of Toxoplasma gondii aminopeptidase N3 (TgAPN3) were evaluated in vitro. Cellular localization analysis revealed that TgAPN3 and GRA protein were co-located in the organelle and parasitophorous vacuole of T. gondii. The secretion assay showed that TgAPN3 could be co-secreted from the tachyzoites with GRA protein. A functional recombinant Toxoplasma aminopeptidase N3 (rTgAPN3) was produced in Escherichia coli. The enzyme activity was first determined using a fluorogenic H-Ala-MCA substrate. Some activity of rTgAPN3 was observed between pH 3.0 and 8.0, with a peak at pH 7.0. The activity was significantly enhanced in the presence of Co2+ ions. Substrate specificity of rTgAPN3 was then evaluated. The enzyme showed a preference for substrates containing N-terminal Ala residues, followed by Tyr and Cys. The rTgAPN3 activity was significantly inhibited by bestatin and phebestatin. In general, TgAPN3 was a structurally conserved member of the M1 family, although it also displayed unique biochemical characteristics. These results lay the foundation for a functional study of TgAPN3 and constitute its putative identification as a drug target.

Crowdsourcing for Food Purchase Receipt Annotation via Amazon Mechanical Turk: A Feasibility Study.

BACKGROUND: The decisions that individuals make about the food and beverage products they purchase and consume directly influence their energy intake and dietary quality and may lead to excess weight gain and obesity. However, gathering and interpreting data on food and beverage purchase patterns can be difficult. Leveraging novel sources of data on food and beverage purchase behavior can provide us with a more objective understanding of food consumption behaviors. OBJECTIVE: Food and beverage purchase receipts often include time-stamped location information, which, when associated with product purchase details, can provide a useful behavioral measurement tool. The purpose of this study was to assess the feasibility, reliability, and validity of processing data from fast-food restaurant receipts using crowdsourcing via Amazon Mechanical Turk (MTurk). METHODS: Between 2013 and 2014, receipts (N=12,165) from consumer purchases were collected at 60 different locations of five fast-food restaurant chains in New Jersey and New York City, USA (ie, Burger King, KFC, McDonald's, Subway, and Wendy's). Data containing the restaurant name, location, receipt ID, food items purchased, price, and other information were manually entered into an MS Access database and checked for accuracy by a second reviewer; this was considered the gold standard. To assess the feasibility of coding receipt data via MTurk, a prototype set of receipts (N=196) was selected. For each receipt, 5 turkers were asked to (1) identify the receipt identifier and the name of the restaurant and (2) indicate whether a beverage was listed in the receipt; if yes, they were to categorize the beverage as cold (eg, soda or energy drink) or hot (eg, coffee or tea). Interturker agreement for specific questions (eg, restaurant name and beverage inclusion) and agreement between turker consensus responses and the gold standard values in the manually entered dataset were calculated. RESULTS: Among the 196 receipts completed by turkers, the interturker agreement was 100% (196/196) for restaurant names (eg, Burger King, McDonald's, and Subway), 98.5% (193/196) for beverage inclusion (ie, hot, cold, or none), 92.3% (181/196) for types of hot beverage (eg, hot coffee or hot tea), and 87.2% (171/196) for types of cold beverage (eg, Coke or bottled water). When compared with the gold standard data, the agreement level was 100% (196/196) for restaurant name, 99.5% (195/196) for beverage inclusion, and 99.5% (195/196) for beverage types. CONCLUSIONS: Our findings indicated high interrater agreement for questions across difficulty levels (eg, single- vs binary- vs multiple-choice items). Compared with traditional methods for coding receipt data, MTurk can produce excellent-quality data in a lower-cost, more time-efficient manner.

Examining Mechanisms and Moderators of the Relationship Between Discriminatory Health Care Encounters and Attempted Suicide Among U.S. Transgender Help-Seekers.

This study examined how experiences of service denial and discrimination in three health care settings-doctors' offices, emergency rooms, and mental health clinics-might contribute to attempted suicide among transgender adults. Mechanisms of this relationship were examined, including treatment receipt and the use of substances to cope with mistreatment. Perceived emotional social support was also tested as a potential protective factor against the deleterious effects of service denial and discrimination on treatment receipt, substance use, and attempted suicide. The analysis included 4190 respondents from the National Transgender Discrimination Survey. Structural equation modeling was employed to test hypothesized relationships. Being denied a greater number of services and discriminated against in more settings were associated with lower levels of treatment receipt. Service denial was also correlated with increased rates of coping-motivated substance use and elevated rates of attempted suicide. Treatment receipt mediated the relationships between service denial/discrimination and substance use. Substance use mediated the relationship between treatment receipt and attempted suicide. Higher levels of support were protective to treatment receipt when denied services in one setting, but no longer retained protective effects when denied in two or three settings. Results have critical implications for service access and delivery and policies that protect transgender help-seekers in the health care system.

Regulation of stem-like cancer cells by glutamine through ß-catenin pathway mediated by redox signaling.

BACKGROUND: Cancer stem cells (CSCs) are thought to play an important role in tumor recurrence and drug resistance, and present a major challenge in cancer therapy. The tumor microenvironment such as growth factors, nutrients and oxygen affect CSC generation and proliferation by providing the necessary energy sources and growth signals. The side population (SP) analysis has been used to detect the stem-like cancer cell populations based on their high expression of ABCG2 that exports Hoechst-33342 and certain cytotoxic drugs from the cells. The purpose of this research is to investigate the effect of a main nutrient molecule, glutamine, on SP cells and the possible underlying mechanism(s). METHODS: Biochemical assays and flow cytometric analysis were used to evaluate the effect of glutamine on stem-like side population cells in vitro. Molecular analyses including RNAi interfering, qRT-PCR, and immunoblotting were employed to investigate the molecular signaling in response to glutamine deprivation and its influence on tumor formation capacity in vivo. RESULTS: We show that glutamine supports the maintenance of the stem cell phenotype by promoting glutathione synthesis and thus maintaining redox balance for SP cells. A deprivation of glutamine in the culture medium significantly reduced the proportion of SP cells. L-asparaginase, an enzyme that catalyzes the hydrolysis of asparagine and glutamine to aspartic acid and glutamate, respectively, mimics the effect of glutamine withdrawal and also diminished the proportion of SP cells. Mechanistically, glutamine deprivation increases intracellular ROS levels, leading to down-regulation of the ß-catenin pathway. CONCLUSION: Glutamine plays a significant role in maintaining the stemness of cancer cells by a redox-mediated mechanism mediated by ß-catenin. Inhibition of glutamine metabolism or deprivation of glutamine by L-asparaginase may be a new strategy to eliminate CSCs and overcome drug resistance.

New Mild and Simple Approach to Isothiocyanates: A Class of Potent Anticancer Agents.

In our current work, acetyl chloride-mediated synthesis of phenethyl isothiocyanate (PEITC) derivatives proves to be convenient and provides the expected products at good to excellent yields. Biological evaluation and structure-activity relationship analysis found that the novel compound 7 showed the best anticancer activity against human cancer cell line Panc1 and HGC27 compared with PEITC. Compounds 6 and 7 induced more apoptosis in pancreatic cancer cells but less toxicity in non-cancer cells. Further biological study demonstrated that 7 substantially increased intracellular reactive oxygen species (ROS) and depleted glutathione (GSH), leading to an oxidative stress to kill cancer cell.

Relayed Regioselective Alkynylation/Olefination of Unsymmetrical Cyclic Diaryliodonium Species Catalyzed by Cu and Pd: Affording Fluorescent Cytotoxic Benzoxazoles.

Although cyclic diaryliodonium species have the potential to act as valuable synthons for cascade transformations, they still remain largely unexplored. The regioselectivity associated with unsymmetrical cyclic diaryliodonium species has previously been known to pose a challenge. A regioselective relayed alkynylation and olefination of unsymmetrical cyclic diaryliodonium species has been achieved by installation of a directing amido group. These relayed transformations were delayed until an oxazole ring had formed, delivering a series of unique fluorescent benzoxazoles. Moreover, some of these synthetic benzoxazoles showed apparent inhibitory activity against malignant cancer cells. Further confocal visualization revealed that benzoxazoles targeted cell nuclei. These findings might provide a novel structural scaffold to develop desirable anticancer agents.

Children's active commuting to school: an interplay of self-efficacy, social economic disadvantage, and environmental characteristics.

BACKGROUND: Active commuting to school (ACS) can promote children's physical activity and may help prevent childhood obesity. Previous researchers in various disciplines, e.g., health, urban planning, and transportation, have identified various predictors of ACS. However, little research has been carried out into investigating the effect of self-efficacy on ACS. The purpose of this study is to investigate the roles of children's and parents' self-efficacy in children's ACS, controlling for sociodemographic and objective environmental characteristics. METHODS: This study is part of the Texas Childhood Obesity Prevention Policy Evaluation (T-COPPE) project, which includes data from 857 parent/child pairs from 74 schools who lived within two miles of school in Texas. Measures included children's usual modes of commuting to school, participants' sociodemographics, perceived self-efficacy toward ACS, sources of children's self-efficacy, school settings, and objective environmental constraints. Multilevel structural equation modeling (SEM) was employed to test the hypothesized pathways using Mplus 7.0. RESULTS: Around 18% of the children were active commuters. Two sources of children's self-efficacy were identified, i.e., emotional states (ß = 0.36, p < 0.001) and social modeling (ß = 0.28, p < 0.01). Compared with children's self-efficacy (ß = 0.16, p < 0.001), parents' self-efficacy (ß = 0.63, p < 0.001) had a stronger influence on children's ACS. Participants' social economic disadvantage (ß = 0.40, p < 0.001), environmental constraints (ß = -0.49, p < 0.001), and school setting (ß = -0.17, p = 0.029) all had statistically significant direct effects on children's ACS. CONCLUSIONS: Future initiatives should consider both parents' and children's self-efficacy in developing strategies for promoting children's ACS. Social disadvantage and environmental constraints also need to be addressed for effective interventions. The work reported here provides support for the continuing exploration of the role of self-efficacy in children's ACS.

Base-mediated decomposition of amide-substituted furfuryl tosylhydrazones: synthesis and cytotoxic activities of enynyl-ketoamides.

Base-mediated decomposition of amide-substituted furfuryl tosylhydrazones afforded practical access to novel multifunctionalized enynyl-ketoamides. In addition, furfuryl tosylhydrazones with stable furan rings underwent an interesting tosyl-group migration to form sulfones, which have potential synthetic applications. Some of the obtained enynyl-ketoamides demonstrated good cytotoxicities against human tumor cell lines.

Selective killing of K-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase.

INTRODUCTION: Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy. Increase of reactive oxygen species (ROS) has also been observed in a wide spectrum of cancers. This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer. METHODS: ROS level, NADPH oxidase (NOX) activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-ras (G12V) compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo. RESULTS: K-ras transfection caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase (PI3K) pathway. Importantly, capsaicin preferentially inhibited the enzyme activity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells. Furthermore, capsaicin effectively inhibited cell proliferation, prevented invasiveness of K-ras-transformed pancreatic cancer cells, and caused minimum toxicity to parental E6E7 cells. In vivo, capsaicin exhibited antitumor activity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells. CONCLUSIONS: K-ras oncogenic signaling causes increased ROS stress through NOX, and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors. Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.