phytoestrogens and Lung-Neoplasms

All the currently available cancer therapeutic options are expensive but none of them are safe. However, traditional plant-derived medicines or compounds are relatively safe. One widely known such compound is beta-sitosterol (BS), a plant derived nutrient with anticancer properties against breast cancer, prostate cancer, colon cancer, lung cancer, stomach cancer, ovarian cancer, and leukemia. Studies have shown that BS interfere with multiple cell signaling pathways, including cell cycle, apoptosis, proliferation, survival, invasion, angiogenesis, metastasis and inflammation. Most of the studies are incomplete partly due to the fact that BS is relatively less potent. But the fact that it is generally considered as nontoxic, the opposite of all currently available cancer chemo-therapeutics, is missed by almost all research communities. To offset the lower efficacy of BS, designing BS delivery for "cancer cell specific" therapy hold huge potential. Delivery of BS through liposome is one of such demonstrations that has shown to be highly promising. But further research did not progress neither in the field of drug delivery of BS nor in the field on how BS mediated anticancer activities could be improved, thus making BS an orphan nutraceutical. Therefore, extensive research with BS as potent anticancer nutraceutical is highly recommended.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Colonic Neoplasms; Dietary Supplements; Drug Delivery Systems; Female; Humans; Leukemia; Liposomes; Lung Neoplasms; Male; Neoplasms; Orphan Drug Production; Phytoestrogens; Prostatic Neoplasms; Signal Transduction; Sitosterols

Topics: Breast Neoplasms; Endometrial Neoplasms; Epidemiologic Studies; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Lung Neoplasms; Male; Neoplasms; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors; Stomach Neoplasms

Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development.. The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women.. We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models.. After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk.. This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.

Topics: Biomarkers; Case-Control Studies; China; Female; Humans; Isoflavones; Lignans; Lung; Lung Neoplasms; Phytoestrogens; Prospective Studies; Risk Factors; Smoking

Phytoestrogens (PEs) have estrogen-like activity and were found to lower incidences of several hormone-dependent cancers. Emerging evidence suggests that estrogen may play a role in lung cancer carcinogenesis. We aim to evaluate dietary PE intake and lung cancer risk using data from the Prostate, Lung, Colorectal and Ovarian cancer screening trial. A total of 1706 lung cancer cases were identified. The association between lung cancer risk and PE intake (in quartiles) was calculated using the Cox proportional hazard models adjusting for potential confounders. Stratified analyses by smoking status, sex and histology were also performed. The highest quartile of total PE intake was associated with a reduced risk of lung cancer compared with the lowest quartile [hazard ratio (HR) = 0.85, 95% confidence interval (CI): 0.73-0.99 for >1030 μg/day versus <290 μg/day] (P trend = 0.56). Similar patterns were observed among ever smokers (HR = 0.84, 95% CI: 0.71-0.98), non-small cell histology (HR = 0.84, 95% CI: 0.72-0.99), male (HR = 0.84, 95% CI: 0.69-1.03) and female (HR = 0.80, 95% CI: 0.64-0.99 for 510-1030 μg/day, HR = 0.84, 95% CI: 0.67-1.06 for >1030 μg/day versus <290 μg/day) subjects with no significant linear trend observed. Despite a lower consumption compared with the Asian population, increased PE intake still appears to decrease lung cancer risk in a Caucasian-dominant population. Future studies are needed to replicate these results in independent cohorts and shed a light on the potential mechanism of the protective effect of PEs on lung carcinogenesis and the interaction between PEs, smoking and endogenous estrogens.

Topics: Aged; Colorectal Neoplasms; Female; Humans; Lung Neoplasms; Male; Middle Aged; Ovarian Neoplasms; Phytoestrogens; Proportional Hazards Models; Prostatic Neoplasms; Risk Factors

Epidermal growth factor receptor (EGFR) activating mutations play crucial roles in the tumorigenesis of human non-small cell lung cancer (NSCLC). The mechanism regarding how EGFR signaling regulates myeloid cell leukemia sequence 1 (Mcl-1) protein stability and ubiquitination remains undefined.. MTS assay was used for natural product library screening. The effect of formononetin (Formo) on NSCLC cells was determined by MTS assay and soft agar assay. Molecular modeling was performed to analyze the potential different binding modes between Formo and EGFR WT or mutants. Mcl-1 protein level and the inhibitory effect of Formo on EGFR signaling were examined by immunoblot, in vitro kinase assay, in vitro pulldown and ATP competition assays, co-immunoprecipitation assay, ubiquitination analysis, in vivo xenograft model, and immunohistochemical staining.. Formo was identified as an EGFR inhibitor by a 98 commercially available natural product screening. Formo suppresses WT and mutant EGFR kinases activity in vitro, ex vivo, and in vivo. Molecular modeling indicates that Formo docks into the ATP-binding pocket of both WT and mutant EGFR. Formo inhibits EGFR-Akt signaling, which in turn activates GSK3β and promotes Mcl-1 phosphorylation in NSCLC cells. Treatment with Formo enhances the interaction between Mcl-1 and SCF. This study highlights the importance of promoting ubiquitination-dependent Mcl-1 turnover might be an alternative strategy to enhance the anti-tumor efficacy of EGFR-TKI.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; ErbB Receptors; Female; Humans; Isoflavones; Lung Neoplasms; Mice; Mice, Nude; Models, Molecular; Myeloid Cell Leukemia Sequence 1 Protein; Phytoestrogens

Genistein is an important chemopreventive agent against atherosclerosis and cancer. However, whether genistein is effective in the treatment of lung cancer, and its underlying mechanism, remains to be determined. The present study demonstrated that genistein treatment of A549 lung cancer cells decreased viability in a dose‑ and time‑dependent manner, and induced apoptosis. Additionally, A549 cells exhibited significantly increased reactive oxygen species formation and cytochrome‑c leakage, and activated caspase‑3, B‑cell lymphoma 2‑associated X protein and apoptosis inducing factor expression levels, which are involved in the mitochondrial apoptosis pathway. Furthermore, the phosphatidylinositol‑4,5‑biphosphate 3‑kinase (PI3K)/protein kinase B (AKT)/hypoxia‑inducible factor‑1α (HIF‑1α) and nuclear factor‑κB (NF‑κB)/cyclooxygenase‑2 (COX‑2) signaling pathways were significantly downregulated by genistein treatment. In conclusion, reduced proliferation and increased apoptosis in A549 lung cancer cells was associated with inhibition of the PI3K/AKT/HIF‑1α/ and NF‑κB/COX‑2 signaling pathways, which implicates genistein as a potential chemotherapeutic agent for the treatment of lung cancer.

Topics: A549 Cells; Anticarcinogenic Agents; Apoptosis; Cell Survival; Cyclooxygenase 2; Genistein; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung; Lung Neoplasms; NF-kappa B; Phosphatidylinositol 3-Kinases; Phytoestrogens; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Vascular Endothelial Growth Factor A

One promising method to visualize cancer cells is based on the detection of the fluorescent photosensitizer protoporphyrin IX (PpIX) synthesized from 5-aminolevulinic acid (ALA), but this method cannot be used in cancers that exhibit poor PpIX accumulation. PpIX appears to be pumped out of cancer cells by the ABC transporter G2 (ABCG2), which is associated with multidrug resistance. Genistein is a phytoestrogen that appears to competitively inhibit ABCG2 activity. Therefore, we investigated whether genistein can promote PpIX accumulation in human lung carcinoma cells. Here we report that treatment of A549 lung carcinoma cells with genistein or a specific ABCG2 inhibitor promoted ALA-mediated accumulation of PpIX by approximately 2-fold. ABCG2 depletion and overexpression studies further revealed that genistein promoted PpIX accumulation via functional repression of ABCG2. After an extended period of genistein treatment, a significant increase in PpIX accumulation was observed in A549 cells (3.7-fold) and in other cell lines. Systemic preconditioning with genistein in a mouse xenograft model of lung carcinoma resulted in a 1.8-fold increase in accumulated PpIX. Long-term genistein treatment stimulated the expression of genes encoding enzymes involved in PpIX synthesis, such as porphobilinogen deaminase, uroporphyrinogen decarboxylase, and protoporphyrinogen oxidase. Accordingly, the rate of PpIX synthesis was also accelerated by genistein pretreatment. Thus, our results suggest that genistein treatment effectively enhances ALA-induced PpIX accumulation by preventing the ABCG2-mediated efflux of PpIX from lung cancer cells and may represent a promising strategy to improve ALA-based diagnostic approaches in a broader set of malignancies. Cancer Res; 76(7); 1837-46. ©2016 AACR.

Topics: Animals; Biomarkers; Humans; Lung Neoplasms; Mice; Mice, Nude; Phytoestrogens; Protoporphyrins; Xenograft Model Antitumor Assays

Although case-control studies support the idea that soy foods or isoflavone intake is associated with a decreased risk of lung cancer, little evidence is available from prospective cohort studies. Moreover, no prospective study has addressed this association in men.. We investigated the association between isoflavone intake and lung cancer incidence.. We conducted a population-based prospective cohort study in 36,177 men and 40,484 women aged 45-74 y with no history of cancer at baseline in 1995-1999. Participants responded to a validated questionnaire, which included 138 food items. We used Cox proportional hazards regression analysis to estimate the hazard ratios (HRs) and 95% CIs of lung cancer incidence according to isoflavone intake, which was estimated by genistein content from soy foods.. During 11 y (671,864 person-years) of follow-up, we documented 481 male and 178 female lung cancer cases. In men we found an inverse association between isoflavone intake and risk of lung cancer in never smokers (n = 13,051; multivariate HR in the highest compared with the lowest quartile of isoflavone intake: 0.43; 95% CI: 0.21, 0.90; P for trend = 0.024) but not in current or past smokers. A similar, nonsignificant inverse association was seen in never-smoking women (n = 38,211; HR: 0.67; 95% CI: 0.41, 1.10; P for trend = 0.135). We also tested effect modification by smoking status (P for interaction = 0.085 in men and 0.055 in men and women combined).. In a large-scale, population-based, prospective study in Japan, isoflavone intake was associated with a decreased risk of lung cancer in never smokers.

Topics: Aged; Carcinoma; Diet Surveys; Female; Food Analysis; Genistein; Glycine max; Humans; Isoflavones; Japan; Lung Neoplasms; Male; Middle Aged; Phytoestrogens; Plant Extracts; Proportional Hazards Models; Prospective Studies; Risk Factors; Sex Factors; Smoking; Soy Foods; Surveys and Questionnaires

This study investigated the effects of a phytoestrogen-containing standardized soy extract (SSE) on the growth of nonsmall cell lung cancer (NSCLC; A549) xenografts in female athymic mice. Tumor-bearing mice received either sterile water or SSE [50 or 100 mg/(kg x d), per os], 5 d/wk, until the mean tumor weight in each group was at least 900 mg. Treatment with SSE reduced tumor growth in the high-dose group compared with control (P < 0.01); tumors in both treated groups had reduced proliferation and greater apoptosis compared with controls (P < 0.05). SSE treatment also induced diffuse central necrosis, reducing the viable tissue mass within the tumor. Whereas tumor levels of epidermal growth factor receptor were comparable in control and treated mice, the expression of phosphorylated protein kinase B (p-Akt) was lower in tumors of mice treated with 100 mg SSE/(kg x d) than in controls (P < 0.01). The protein level of phosphorylated mitogen-activated protein kinase also tended to be lower (P = 0.07) in this group than in controls. Estrogen receptor (ER)alpha and ERbeta were present in tumors, but their expression levels did not differ among groups. Serum insulin-like growth factor-1 concentrations also were not affected by the treatments. In conclusion, we found that soy phytochemicals slow the in vivo growth of NSCLC xenografts; the modulation of the Akt-signaling pathway observed in tumors of SSE-treated mice may have a role in the activity observed. Our research provides further support for the concept that consumption of phytoestrogens may be effective in delaying lung cancer progression.

Topics: Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Glycine max; Humans; Ki-67 Antigen; Lung Neoplasms; MAP Kinase Signaling System; Mice; Mice, Nude; Neoplasm Transplantation; Phytoestrogens; Plant Extracts; Receptors, Estrogen; Transplantation, Heterologous

Human breast cancer incidence, histopathologic grade, invasiveness, and mortality risk vary significantly throughout each year. In order to better understand this seasonal cancer biology, we investigated the circannual pattern of post-resection breast cancer metastasis, under genetically and environmentally controlled conditions.. Over a span of 14 consecutive years, we conducted 22 similar experiments to investigate metastatic biology of breast cancer among 1,214 C3HeB/FeJ female mice. All mice were kept in temperature-controlled environment with 12 h light:12 h dark photoperiod, with food and water freely available, from birth until death. At 10-13 weeks of age, each mouse received 20,000 viable syngeneic mammary cancer cells subcutaneously and the tumor bearing leg was resected 10-12 days after tumor inoculation for potential cure. Once 10% of resected mice were found moribund, due to autopsy proven pulmonary metastases, all remaining mice were sacrificed and metastatic lung nodules were counted.. The incidence of post-resection pulmonary metastasis was not randomly distributed throughout the year, but peaked prominently in Summer and Winter. Although tumor volume at resection was strongly associated with metastatic potential, a significantly higher probability of pulmonary metastasis was observed if surgery was performed in Summer and Winter, regardless of tumor volume at resection, compared to Spring and Fall.. These results support the likelihood that human breast cancer seasonality is real and of biological origin. There are implications of this cancer chronobiology for breast cancer prevention, screening, diagnosis, and treatment.

Topics: Animals; Estrus; Female; Humidity; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Multivariate Analysis; Phytoestrogens; Probability; Seasons; Temperature

Topics: Diet; Humans; Lignans; Lung Neoplasms; Phytoestrogens; Risk

Despite lung-specific in vitro and in vivo studies that support a chemopreventive role for phytoestrogens, there has been little epidemiologic research focused on dietary intake of phytoestrogens and risk of lung cancer.. To examine the relationship between dietary intake of phytoestrogens and risk of lung cancer.. Ongoing US case-control study of 1674 patients with lung cancer (cases) and 1735 matched healthy controls. From July 1995 through October 2003, participants were personally interviewed with epidemiologic and food frequency questionnaires to collect demographic information and to quantify dietary intake of 12 individual phytoestrogens.. Risk of lung cancer, estimated using unconditional multivariable logistic regression analyses stratified by sex and smoking status and adjusted for established and putative lung cancer risk factors.. Reductions in risk of lung cancer tended to increase with each increasing quartile of phytoestrogen intake. The highest quartiles of total phytosterols, isoflavones, lignans, and phytoestrogens were each associated with reductions in risk of lung cancer ranging from 21% for phytosterols (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.64-0.97; P = .03 for trend) to 46% for total phytoestrogens from food sources only (OR, 0.54; 95% CI, 0.42-0.70; P<.001 for trend). Sex-specific effects were also apparent. For men, statistically significant trends for decreasing risk with increasing intake were noted for each phytoestrogen group, with protective effects for the highest quartile of intake ranging from 24% for phytosterols (OR, 0.76; 95% CI, 0.56-1.02; P = .04 for trend) to 44% for isoflavones (OR, 0.56; 95% CI, 0.41-0.76; P<.001 for trend), while in women, significant trends were only present for intake of total phytoestrogens from food sources only, with a 34% (OR, 0.66; 95% CI, 0.46-0.96; P = .01 for trend) protective effect for the highest quartile of intake. The apparent benefits of high phytoestrogen intake were evident in both never and current smokers but less apparent in former smokers. In women, statistically significant joint effects were evident between hormone therapy use and phytoestrogen intake. Specifically, high intake of the lignans enterolactone and enterodiol and use of hormone therapy were associated with a 50% (OR, 0.50; 95% CI, 0.31-0.68; P = .04 for interaction) reduction in risk of lung cancer.. While there are limitations and concerns regarding case-control studies of diet and cancer, these data provide further support for the limited but growing epidemiologic evidence that phytoestrogens are associated with a decrease in risk of lung cancer. Confirmation of these findings is still required in large-scale, hypothesis-driven, prospective studies.

Topics: Aged; Case-Control Studies; Diet; Diet Surveys; Female; Food; Humans; Isoflavones; Lignans; Logistic Models; Lung Neoplasms; Male; Middle Aged; Phytoestrogens; Phytosterols; Risk Factors; Smoking; United States

Angiogenesis is important in tumor growth, progression and metastatic dissemination. Vascular endothelial growth factor (VEGF) is one key factor in promotion of breast cancer angiogenesis. VEGFs are bioactive in the extracellular space where they become available to the endothelial cells. Phytoestrogens such as lignans have been shown to alter breast cancer incidence and be cancer-protective in rats. We show that supplementation of 10% flaxseed, the richest source of mammalian lignans, to nude mice with established human breast tumors reduced tumor growth and metastasis. Moreover, flaxseed decreased extracellular levels of VEGF, which may be one mechanistic explanation to the decreased tumor growth and metastasis.

Topics: Animals; Body Weight; Down-Regulation; Endothelial Growth Factors; Estrogens, Non-Steroidal; Extracellular Space; Female; Flax; Humans; Intercellular Signaling Peptides and Proteins; Isoflavones; Lung Neoplasms; Lymphatic Metastasis; Lymphokines; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Transplantation; Phytoestrogens; Plant Preparations; Seeds; Transplantation, Heterologous; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors