Effect of Polyphenolic Composition BP-C2 on Lung Carcinogenesis Induced by Urethane in Progeny of Irradiated Male BALB/c Mice.

We studied the effects of polyphenolic composition BP-C2, comprising molybdenum with lignin derivatives, on lung carcinogenesis induced by urethane in the progeny of F0 male BALB/c mice preconceptionally exposed to radiation in a dose of 1 Gy. The multiplicity of lung tumors in the progeny of irradiated mice was higher than in the progeny of non-irradiated male parents by 50% in females and 43% in males (p<0.05). In F1 mice (progeny of irradiated F0 male parents treated with BP-C2), the multiplicity of lung tumors was also higher, but this increase was less pronounced: 35% in females (p=0.3852) and 23% in males (p=0.0766). We have demonstrated that administration of BP-C2 to irradiated parents (F0) efficiently inhibits carcinogenesis in their F1 progeny. The use of BP-C2 in irradiated male parents and their progeny not only reduced the multiplicity of tumors, but also normalized body weights in the F1 progeny. Our study demonstrates potential of the polyphenolic composition BP-C2 for chemoprophylaxis of radiation-induced transgenerational carcinogenesis.

Multiple targets of Nrf 2 inhibitor; trigonelline in combating urethane-induced lung cancer by caspase-executioner apoptosis, cGMP and limitation of cyclin D1 and Bcl2.

OBJECTIVE: Among other types of cancerous lesions, lung cancer is one of the prevalent causes of death. Trigonelline is a plant alkaloid, a significant constituent in coffee, and has shown health benefits in several disorders. The present study aims to investigate the potential therapeutic role of trigonelline in lung cancer. MATERIALS AND METHODS: Seventy-five BALB/C mice were assigned to five groups and treated for 150 days as follows (1): normal control group; (2) trigonelline only (50 mg/kg/ P.O) daily for the last thirty days; (3) urethane (1.5 g/kg B.w/i.p) at day one and sixty; (4) urethane and carboplatin (15 mg/kg i.p) for the last thirty days; and (5) urethane and trigonelline for the last thirty days. Tumor size was measured while blood and lung were collected for biochemical, western blotting analysis, and histological examinations. RESULTS: Urethane demonstrated significant changes in all biochemical and molecular parameters and histological examinations. In animals pretreated with urethane, trigonelline significantly reduced tumor size and restored Nrf2, NF-кB p65, Bcl-2, Cyclin D1, ICAM-1, and MMP-2, along with improving cGMP and active caspase three and refining histological architectures. CONCLUSIONS: Nrf2 signaling may be a promising therapeutic target for adenocarcinoma protection or management. Due to its multiple therapeutic effects on Nrf2, cyclin D1, NF-кB pathways, and the BAX/Bcl2 axis, trigonelline significantly induced cell cycle arrest and apoptosis.https://www.europeanreview.org/wp/wp-content/uploads/Graphical_Abstract-1.jpg.

K-Ras-Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated.

K-RAS is frequently mutated in human lung adenocarcinomas (ADCs), and the p53 pathway plays a central role in cellular defense against oncogenic K-RAS mutation. However, in mouse lung cancer models, oncogenic K-RAS mutation alone can induce ADCs without p53 mutation, and loss of p53 does not have a significant impact on early K-RAS-induced lung tumorigenesis. These results raise the question of how K-RAS-activated cells evade oncogene surveillance mechanisms and develop into lung ADCs. RUNX3 plays a key role at the restriction (R)-point, which governs multiple tumor suppressor pathways including the p14ARF-p53 pathway. In this study, we found that K-RAS activation in a very limited number of cells, alone or in combination with p53 inactivation, failed to induce any pathologic lesions for up to 1 year. By contrast, when Runx3 was inactivated and K-RAS was activated by the same targeting method, lung ADCs and other tumors were rapidly induced. In a urethane-induced mouse lung tumor model that recapitulates the features of K-RAS-driven human lung tumors, Runx3 was inactivated in both adenomas (ADs) and ADCs, whereas K-RAS was activated only in ADCs. Together, these results demonstrate that the R-point-associated oncogene surveillance mechanism is abrogated by Runx3 inactivation in AD cells and these cells cannot defend against K-RAS activation, resulting in the transition from AD to ADC. Therefore, K-RAS-activated lung epithelial cells do not evade oncogene surveillance mechanisms; instead, they are selected if they occur in AD cells in which Runx3 has been inactivated.

Destrin Contributes to Lung Adenocarcinoma Progression by Activating Wnt/ß-Catenin Signaling Pathway.

Lung cancer, especially lung adenocarcinoma, is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin filament turnover. Recent evidence has shown that high expression of cofilin-1 is associated with invasion and poor prognosis of several types of human tumors, but the detailed mechanism is still entirely unclear, particularly in lung cancer tumorigenesis and malignancy. Here, we report that DSTN was highly expressed in a mouse lung cancer model induced by urethane and in clinical lung adenocarcinoma tissue samples. Its expression level was positively correlated with cancer development, as well as metastasis to the liver and lymph nodes. Consistently, it was directly associated with the poor prognosis of lung adenocarcinoma patients. Furthermore, we also found that DSTN promotes cell proliferation, invasion, and migration in vitro, and facilitates subcutaneous tumor formation and lung metastasis via intravenous injection in vivo. Mechanically, DSTN associates with and facilitates nuclear translocation of ß-catenin, which promotes epithelial-to-mesenchymal transition (EMT). Taken together, our results indicated that DSTN enhances lung cancer malignancy through facilitating ß-catenin nuclear translocation and inducing EMT. Combined with multivariate analyses, DSTN might potentially serve as a therapeutic target and an independent prognostic marker of lung adenocarcinoma. IMPLICATIONS: This finding indicates that DSTN facilitates ß-catenin nuclear translocation and promotes malignancy in lung adenocarcinoma.

Impact of the Lysine-urethane Adhesive TissuGlu® on Postoperative Complications and Interventions After Drain-free Mastectomy.

BACKGROUND/AIM: The influence of a polyurethane-based tissue adhesive (TissuGlu®) on common complications following breast surgery was investigated. PATIENTS AND METHODS: Within a Randomized-Controlled-Trial 70 women (n=35 TissuGlu®, n=35 drain) underwent a mastectomy with or without sentinel lymph node excision (SLNE), followed by a 90-day postoperative follow-up. RESULTS: Postoperative interventions: Non-inferiority of the application of TissuGlu® was seen. Pain-Level/ Hospitalization: A statistically significant pain reduction from day four onwards (p<0.001) and a shorter hospitalization period (p<0.001) was observed. In contrast, the TissuGlu® group showed increased mean puncture incidence (p=0.013), and increased puncture volume (p=0.021). CONCLUSION: Application of the polyurethane-based tissue adhesive TissuGlu® after mastectomy, with or without SLNE, showed potential for improvement of the clinical outcome. In contrast, high intervention rates and increased puncture volume, caused by recurring seromas following application of the surgical adhesive TissuGlu®, have a negative impact on the patient-specific convalescence.

Targeting Opsin4/Melanopsin with a Novel Small Molecule Suppresses PKC/RAF/MEK/ERK Signaling and Inhibits Lung Adenocarcinoma Progression.

The identification of oncogenic biomolecules as drug targets is an unmet need for the development of clinically effective novel anticancer therapies. In this study, we report for the first time that opsin 4/melanopsin (OPN4) plays a critical role in the pathogenesis of non-small cell lung cancer (NSCLC) and is a potential drug target. Our study has revealed that OPN4 is overexpressed in human lung cancer tissues and cells, and is inversely correlated with patient survival probability. Knocking down expression of OPN4 suppressed cells growth and induced apoptosis in lung cancer cells. We have also found that OPN4, a G protein-coupled receptor, interacted with Gα11 and triggered the PKC/BRAF/MEK/ERKs signaling pathway in lung adenocarcinoma cells. Genetic ablation of OPN4 attenuated the multiplicity and the volume of urethane-induced lung tumors in mice. Importantly, our study provides the first report of AE 51310 (1-[(2,5-dichloro-4-methoxyphenyl)sulfonyl]-3-methylpiperidine) as a small-molecule inhibitor of OPN4, suppressed the anchorage-independent growth of lung cancer cells and the growth of patient-derived xenograft tumors in mice. IMPLICATIONS: Overall, this study unveils the role of OPN4 in NSCLC and suggests that targeting OPN4 with small molecules, such as AE 51310 would be interesting to develop novel anticancer therapies for lung adenocarcinoma.

Carbonyl compounds and furan derivatives with toxic potential evaluated in the brewing stages of craft beer.

Carbonyl compounds and furan derivatives may form adducts with DNA and cause oxidative stress to human cells, which establishes the carcinogenic potential of these compounds. The occurrence of these compounds may vary according to the processing characteristics of the beer. The objective of this study was, for the first time, to investigate the free forms of target carbonyl compounds [acetaldehyde, acrolein, ethyl carbamate (EC) and formaldehyde] and furan derivatives [furfural and furfuryl alcohol (FA)] during the brewing stages of ale and lager craft beers. Samples were evaluated using headspace-solid phase microextraction and gas chromatography with mass spectrometric detection in selected ion monitoring mode (HS-SPME-GC/MS-SIM). Acetaldehyde, acrolein, formaldehyde and furfuryl alcohol were found in all brewing stages of both beer types, while EC and furfural concentrations were below the LOD and LOQ of the method (0.1 and 0.01 µg L-1, respectively). Boiling and fermentation of ale brewing seem to be important steps for the formation of acrolein and acetaldehyde, respectively, while boiling resulted in an increase of FA in both types of beer. Conversely, pasteurisation and maturation reduced the levels of these compounds in both types of beer. An increase in concentration of acrolein has not been verified in lager brew probably due to the difference in boiling time between these two types of beer (60 and 90 min for ale and lager, respectively).

Biotinylated naringenin intensified anticancer effect of gefitinib in urethane-induced lung cancer in rats: favourable modulation of apoptotic regulators and serum metabolomics.

Co-therapy through biotin modified nanoparticles (NPs) of gefitinib (Gnb) and naringenin (Nar) was investigated for its therapeutic and synergistic potential against lung cancer. The biotin-conjugated polymeric NPs (bty-Nar/Gnb) were developed using oil in water emulsion technique and optimized using central composite design. The formulations were subjected to various in vitro (A549 cell lines) and in vivo evaluations in urethane-induced lung cancer. Co-administration of Gnb and Nar NPs displayed a significant reduction in tumour volume while restoring the biochemical parameters and serum metabolites to normal levels. Significant down-regulation of anti-apoptotic proteins (P-16, MMP-9 and Bcl-2) and up-regulation of pro-apoptotic proteins (caspase-9 and BAX) was displayed with co-therapy. This investigation demonstrated the superiority of co-therapy over individual therapy for improved therapeutic efficacy and is favourable for developing a safe, effective and targeted delivery for lung carcinoma therapy.

6-Gingerol as an arginase inhibitor prevents urethane-induced lung carcinogenesis by reprogramming tumor supporting M2 macrophages to M1 phenotype.

6-Gingerol (6-G) is the main bioactive component in Ginger (Zingiber officinale Roscoe). The aim of this study was to explore the contribution of macrophage polarization in 6-G-associated anti-cancer effects. In a urethane-induced lung carcinogenic model, lung carcinogenesis was positively correlated with macrophage (F4/80+) infiltration in lung interstitial in the control group. Furthermore, higher numbers of arginase+/F4/80+ M2 cells than iNOS+/F4/80+ M1 cells were observed in interstitial macrophages. Moreover, macrophage depletion by liposome-encapsulated clodronate (LEC) could significantly prevent lung carcinogenesis, whereas pexidartinib promoted lung carcinogenesis. After 6-G treatment, lung carcinogenesis was ameliorated with increased M1 macrophages and decreased M2 macrophages in the lung interstitial. ELISA showed that the levels of IFN-γ and IL-12 increased and the levels of IL-10 and TGF-ß1 decreased in the alveolar cavity compared to those in the control group. Unexpectedly, the carcinogenesis-preventing efficacy of 6-G was promoted in LEC-treated mice, but completely aborted in pexidartinib-treated mice. In the in vitro experiment, 6-G reset the IL-4-induced arginase+ M2 cells toward iNOS+ M1 cells and exhibited reduced levels of arginase 1 and ROS and elevated levels of L-arginine and NO. LEC and nor-NOHA selectively suppressed M2 macrophages but had a negligible effect on M1 macrophages, whereas pexidartinib decreased both M2 and M1 macrophages. The iNOS+ macrophage-promoting efficacy of 6-G was increased by LEC, but was completely eliminated by pretreatment with pexidartinib or nor-NOHA. M2 macrophage-resetting efficacy of 6-G was confirmed in a Lewis lung cancer allograft model. This study indicated a reprogramming effect of 6-G as an arginase inhibitor on tumor supporting macrophages.

Mulberry Fruit Extract Affords Protection against Ethyl Carbamate-Induced Cytotoxicity and Oxidative Stress.

Ethyl carbamate (EC) is a food and environmental toxicant and is a cause of concern for human exposure. Several studies indicated that EC-induced toxicity was associated with oxidative stress. Mulberry fruits are reported to have a wide range of bioactive compounds and pharmacological activities. The present study was therefore aimed to investigate the protective property of mulberry fruit extract (MFE) on EC-induced cytotoxicity and oxidative stress. Chemical composition analysis showed that total phenolic content and total flavonoid content in MFE were 502.43 ± 5.10 and 219.12 ± 4.45 mg QE/100 g FW. Cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside were the major anthocyanins in MFE. In vitro antioxidant studies (DPPH, ABTS, and FRAP assays) jointly exhibited the potent antioxidant capacity of MFE. Further study indicated that MFE protected human liver HepG2 cells from EC-induced cytotoxicity by scavenging overproduced cellular ROS. EC treatment promoted intracellular glutathione (GSH) depletion and caused mitochondrial membrane potential (MMP) collapse, as well as mitochondrial membrane lipid peroxidation, whereas MFE pretreatment significantly inhibited GSH depletion and restored the mitochondrial membrane function. Overall, our study suggested that polyphenolic-rich MFE could afford a potent protection against EC-induced cytotoxicity and oxidative stress.

Inhibition Role of Atherogenic Diet on Ethyl Carbamate Induced Lung Tumorigenesis in C57BL/6J Mice.

With emerging evidence connecting cholesterol dysregulation with disturbed pulmonary homeostasis, we are wondering if diet induced hypercholesterolemia would influence the susceptibility to chemical induced lung tumorigenesis in mice. Six to eight week-old male C57BL/6J mice were fed with either a high-cholesterol atherogenic diet (HCD) or matching normal diet (ND), respectively. Following 3 weeks diet adapting, a multi-dose intraperitoneal injections of ethyl carbamate (urethane, 1 g/kg body weight) were established and lung tumorigenesis assessments were taken after 15 weeks latency period. Compared to the urethane treated ND-fed mice, the HCD-fed mice exhibited significantly decreased lung tumor multiplicity and attenuated pulmonary inflammation, which including reduced influx of leukocytes and down regulated tumor-promoting cyto-/chemokine profile in bronchoalveolar lavage fluid, decreased TLR2/4 expression and NF-κB activation in the lung. As a sensor regulating intracellular cholesterol homeostasis, nuclear receptor LXR-α was up-regulated significantly in the urethane treated HCD-fed mice lungs compared to the ND-fed mice lungs, accompanied with decreased pulmonary free cholesterol content and suppressed tumor cell proliferation. These results suggested that intrapulmonary cholesterol homeostasis, other than systematic cholesterol level, is important in lung tumorigenesis, and LXR activation might partly contribute to the inhibitory role of atherogenic diet on lung tumorigenesis.

Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation.

Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is still a matter of debate. To begin to investigate the role of these two Rb family proteins in lung tumorigenesis, we have generated a conditional triple knockout mouse model (TKO) in which the three Rb family members can be inactivated in adult mice. We found that ablation of all three family members in the lung of mice induces tumorlets, benign neuroendocrine tumors that are remarkably similar to their human counterparts. Upon chemical carcinogenesis, DHPN and urethane accelerate tumor development; the TKO model displays increased sensitivity to DHPN, and urethane increases malignancy of tumors. All the tumors developing in TKO mice (spontaneous and chemically induced) have neuroendocrine features but do not progress to fully malignant tumors. Thus, loss of Rb and its family members confers partial tumor susceptibility in neuroendocrine lineages in the lungs of mice. Our data also imply the requirement of other oncogenic signaling pathways to achieve full transformation in neuroendocrine lung lesions mutant for the Rb family.

Effects of Repeated Anesthesia Containing Urethane on Tumor Formation and Health Scores in Male C57BL/6J Mice.

Repeated injection of urethane (ethyl carbamate) is carcinogenic in susceptible strains of mice. Most recent cancer studies involving urethane-induced tumor formation use p53(+/-) mice, which lack one copy of the p53 tumor suppressor gene. In contrast, the same protocol elicits at most a single tumor in wildtype C57BL/6 mice. The effect of repeatedly injecting urethane as a component of a ketamine-xylazine anesthetic mixture in the highly prevalent mouse strain C57BL/6 is unknown. Male C57BL/6J mice (n = 30; age, 3 mo) were anesthetized once monthly for 4 mo by using 560 mg/kg urethane, 28 mg/kg ketamine, and 5.6 mg/kg xylazine. The physical health of the mice was evaluated according to 2 published scoring systems. The average body condition score (scale, 1 to 5; normal, 3) was 3.3, 3.3, and 3.4 after the 2nd, 3rd, and 4th injections, respectively. The visual assessment score was 0 (that is, normal) at all time points examined. Within 1 wk after the 4th injection, the mice were euthanized, necropsied, and evaluated histopathologically. No histopathologic findings were noteworthy. We conclude that repeated monthly injection with urethane as a component of an anesthetic cocktail does not cause clinically detectable abnormalities or induce neoplasia in C57BL/6J mice. These findings are important because urethane combined with low-dose ketamine, unlike other anesthetic regimens, allows for accurate recording of neuronal activity in both the brain and retina. Longitudinal neuronal recordings minimize the number of mice needed and improve the analysis of disease progression and potential therapeutic interventions.

Intranasal Administration of Type V Collagen Reduces Lung Carcinogenesis through Increasing Endothelial and Epithelial Apoptosis in a Urethane-Induced Lung Tumor Model.

Type V collagen (Col V) is a "minor" component of normal lung extracellular matrix, which is subjected to decreased and abnormal synthesis in human lung infiltrating adenocarcinoma. We previously reported that a direct link between low amounts of Col V and decreased cell apoptosis may favor cancer cell growth in the mouse lung after chemical carcinogenesis. Moreover, this collagen species was able to trigger DNA fragmentation and impair survival of neoplastic cells. In this study, we have extended our investigation with the aim to obtain further evidence that the death induced by Col V-treatment is of the caspase-9 apoptotic type. We used (1) optical and electron microscopy, (2) quantitation of TUNEL-labeled cells and (3) analysis of the expression levels of Col V and selected genes coding for apoptosis-linked factors, by conventional RT-PCR. BALB/c mice were injected intraperitoneally with 1.5 g/kg body weight of urethane. After urethane injection, the animals received intranasal administration of 20 µg/20 µl of Col V every day during 2 months. We report here that Col V treatment was able to determine significant increase in Col V protein and gene expression and in the percentage of TUNEL-positive cells, to up-regulate caspase-9, resulting in low growth of tumor cells. Our data validate chemical carcinogenesis as a suitable "in vivo" model for further and more detailed studies on the molecular mechanisms of the death response induced by Col V in lung infiltrating adenocarcinoma opening new strategies for treatment.

A specific nuclear DNA background is required for high frequency lymphoma development in transmitochondrial mice with G13997A mtDNA.

We previously found that mouse mitochondrial DNA (mtDNA) with a G13997A mutation (G13997A mtDNA) controls not only the transformation of cultured lung carcinoma cells from poorly metastatic into highly metastatic cells, but also the transformation of lymphocytes into lymphomas in living C57BL/6 (B6) mice. Because the nuclear genetic background of the B6 strain makes the strain prone to develop lymphomas, here we examined whether G13997A mtDNA independently induces lymphoma development even in mice with the nuclear genetic background of the A/J strain, which is not prone to develop lymphomas. Our results showed that the B6 nuclear genetic background is required for frequent lymphoma development in mice with G13997A mtDNA. Moreover, G13997A mtDNA in mice did not enhance the malignant transformation of lung adenomas into adenocarcinomas or that of hepatocellular carcinomas from poorly metastatic into highly metastatic carcinomas. Therefore, G13997A mtDNA enhances the frequency of lymphoma development under the abnormalities in the B6 nuclear genome, and does not independently control tumor development and tumor progression.

Effects of selenium on Pteridium aquilinum and urethane-induced lung carcinogenesis.

The results of our previous study demonstrated that ptaquiloside, the main toxic agent found in Pteridium aquilinum, suppresses natural killer (NK) cell-mediated cytotoxicity. However, the ability of ptaquiloside to suppress the cytotoxicity of NK cells was prevented by selenium supplementation. NK cells play an important role in the innate immune response and have the ability to kill tumor cells. Therefore, we hypothesized that selenium may prevent the higher susceptibility to urethane-induced lung carcinogenesis that has been observed in mice treated with P. aquilinum. The immunosuppressive effects of ptaquiloside have been associated with a higher number of urethane-induced lung nodules in mice. Hence, we assessed the effects of P. aquilinum-induced immunosuppression on urethane-induced lung carcinogenesis in C57BL/6 mice that had been supplemented with selenium. For these experiments, mice were treated with both an aqueous extract of P. aquilinum (20 g/kg/day) and selenium (1.3 mg/kg) by gavage once daily for 14 days followed by a once-weekly intraperitoneal injection of urethane (1 g/kg) for 10 weeks that was accompanied by gavage 5 days a week. Lung adenomas in mice that had been treated with P. aquilinum plus urethane occurred with a frequency that was 44% higher than that in mice that had been treated with only urethane. In mice that had been supplemented with selenium and treated with P. aquilinum plus urethane, the occurrence of lung adenomas was reduced to 26%. These results suggest that selenium prevents the immunosuppressive effects of P. aquilinum on urethane-induced lung carcinogenesis.

CCAAT/enhancer-binding protein-α suppresses lung tumor development in mice through the p38α MAP kinase pathway.

The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is a basic leucine zipper transcription factor and is expressed in alveolar type II cells, alveolar macrophages and Clara cells in the lung. Although decrease or absence of C/EBPα expression in human non-small cell lung cancer suggests a possible role of C/EBPα as a lung tumor suppressor, there is no direct proof for this hypothesis. In this study, we investigated, for the first time, the role of C/EBPα in lung tumors in vivo using transgenic mice with lung epithelial specific conditional deletion of Cebpa (Cebpα(Δ/Δ) mice) and a urethane-induced lung tumor model. C/EBPα expression in the lung was dispensable, and its deletion was not oncogenic under unstressed conditions. However, at 28 wk after urethane injection, the number and size of tumors and the tumor burden were significantly higher in Cebpα(Δ/Δ) mice than in littermate control mice. Urethane-injected Cebpα(Δ/Δ) mice showed highly proliferative adenomas and adenocarcinomas in the lung, and survival time after urethane-injection was significantly shorter than that in control mice. In control mice, C/EBPα was strongly induced in the tumor tissues at 28 weeks after urethane-injection, but became weakened or absent as tumors progressed after long-term observation for over 1 year. Using intraperitoneal injection of p38 inhibitor (SB203580), we demonstrated that the induction of C/EBPα is strongly regulated by the p38 MAP kinase in murine alveolar epithelial cells. A high correlation was demonstrated between the expression of C/EBPα and p38α MAP kinase in tumor cells, suggesting that C/EBPα silencing in tumor cells is caused by down-regulation of p38α MAP kinase. In conclusion, the role of C/EBPα as a lung tumor suppressor was demonstrated for the first time in the present study, and the extinguished C/EBPα expression through p38α inactivation leads tumor promotion and progression.

Chemopreventive effects of pterostilbene on urethane-induced lung carcinogenesis in mice via the inhibition of EGFR-mediated pathways and the induction of apoptosis and autophagy.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths globally. Due to the lack of successful chemopreventive agents for lung cancer, there is an emerging need to evaluate new and effective agents for lung cancer prevention. Pterostilbene, a naturally occurring analogue of resveratrol, has been reported to be an effective chemopreventive agent against many cancers. The aim of this study is to investigate the chemopreventive effects of pterostilbene in urethane-induced murine lung tumors. Pretreatment with pterostilbene at 50 or 250 mg/kg significantly reduced tumor multiplicity by 26 and 49%, respectively. Pterostilbene also significantly inhibited tumor volume by 25 and 34% and decreased the tumor burden per mouse by 45 and 63%, respectively. The mechanisms by which pterostilbene suppresses lung tumorigenesis have been investigated in lung tissues and homogenates. The results indicate that the pterostilbene-mediated chemopreventive effects in vivo were a result of the inhibition of epidermal growth factor receptor (EGFR) and its downstream pathways, leading to retarded cell cycle progression, and of the induction of apoptosis and autophagy during urethane-induced lung tumorigenesis.

[Effect of aconiti lateralis radix praeparata and taraxaci herba on Chinese medicine signs and symptoms of urethane-induced lung cancer in mice].

OBJECTIVE: To study Chinese medicine (CM) signs and symptoms of urethane-induced lung cancer in mice, and observe the effect of Aconiti Lateralis Radix Praeparata and Taraxaci Herba on symptoms in mice and tumor progress. METHOD: The mice were intraperitoneally injected with urethane twice a week for consecutively five weeks to establish a lung cancer model. The changes in their appearance, body temperature and auricle microcirculation were observed in carcinogenic process. CM signs and symptoms of urethane-induced lung cancer in mice were evaluated with energy metabolism, erythrocytic ATP emzymatic activity and hemorrheological index. During the tumor model was induced, Aconiti Lateralis Radix Praeparata and Taraxaci Herba were used to treat the mice and observe their effect on symptoms in mice and tumor progress. RESULT: During urethane was used to induce lung cancer, the mice had gradually become chill, lazy, hunched, with reduction in temperature, cyanosis in auricle and tail. Meanwhile, their energy metabolism and erythrocytic ATP enzymatic activity reduced, whereas their whole blood viscosity and erythrocytic aggregate index increased. Taraxaci Herba showed an effect on enhancing above symptoms and signs but had no effect on tumor progress. Aconiti Lateralis Radix Praeparata showed an effect on reducing above symptoms and signs and preventing tumor progress. CONCLUSION: Mice with urethane-induced lung cancer show CM signs and symptoms of congealing cold with blood stasis. The treatment with Aconiti Lateralis Radix Praeparata can alleviate symptoms and signs in mice and prevent tumor progress.

Epithelial nuclear factor-κB signaling promotes lung carcinogenesis via recruitment of regulatory T lymphocytes.

The mechanisms by which chronic inflammatory lung diseases, particularly chronic obstructive pulmonary disease, confer enhanced risk for lung cancer are not well-defined. To investigate whether nuclear factor (NF)-κB, a key mediator of immune and inflammatory responses, provides an interface between persistent lung inflammation and carcinogenesis, we utilized tetracycline-inducible transgenic mice expressing constitutively active IκB kinase ß in airway epithelium (IKTA (IKKß trans-activated) mice). Intraperitoneal injection of ethyl carbamate (urethane), or 3-methylcholanthrene (MCA) and butylated hydroxytoluene (BHT) was used to induce lung tumorigenesis. Doxycycline-treated IKTA mice developed chronic airway inflammation and markedly increased numbers of lung tumors in response to urethane, even when transgene expression (and therefore epithelial NF-κB activation) was begun after exposure to carcinogen. Studies using a separate tumor initiator/promoter model (MCA+BHT) indicated that NF-κB functions as an independent tumor promoter. Enhanced tumor formation in IKTA mice was preceded by increased proliferation and reduced apoptosis of alveolar epithelium, resulting in increased formation of premalignant lesions. Investigation of inflammatory cells in lungs of IKTA mice revealed a substantial increase in macrophages and lymphocytes, including functional CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Importantly, Treg depletion using repetitive injections of anti-CD25 antibodies limited excessive tumor formation in IKTA mice. At 6 weeks following urethane injection, antibody-mediated Treg depletion in IKTA mice reduced the number of premalignant lesions in the lungs in association with an increase in CD8 lymphocytes. Thus, persistent NF-κB signaling in airway epithelium facilitates carcinogenesis by sculpting the immune/inflammatory environment in the lungs.