bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Impact of Fish Oil on the Chemopreventive Efficacy of Tamoxifen against Development of N-Methyl-N-Nitrosourea–Induced Rat Mammary Carcinogenesis
Authors: Manni Andrea , Xu Haifang , Washington Sharlene , Aliaga Cesar , Cooper Timothy , Richie John P. , Bruggeman Richard , Prokopczyk Bogdan , Calcagnotto Ana , Trushin Neil , Mauger David , Verderame Michael F. , El-Bayoumy Karam
Published: March 2024

Abstract
The antiestrogen tamoxifen reduces breast cancer incidence in high-risk women but is unable to inhibit the development of hormone-independent tumors. Omega-3 polyunsaturated fatty acids (n-3 PUFA), known ligands of the peroxisome proliferator activated receptor-γ (PPARγ), generally exert tumor-suppressive effects. Based on the known crosstalk between the estrogen and the PPARγ receptors, we tested the hypothesis that the combination of tamoxifen with n-3 PUFA results in a superior antitumor action over the individual interventions. In this study, we report for the first time that the combination of a fish oil diet rich in n-3 PUFA and tamoxifen seemed to inhibit N-methyl-N-nitrosourea–induced mammary carcinogenesis, tumor multiplicity, and volume to a greater extent than the individual interventions. The potential superiority of the combination was particularly evident at a suboptimal dose of tamoxifen, which, by itself, was unable to significantly decrease tumor development. Because activation of PPARγ is known to inhibit oxidative stress, we examined the effects of our interventions on circulating and tumor levels of glutathione, a major intracellular antioxidant. Our results indicate that reduction in the level of oxidative stress may be a potential mechanism by which the n-3 PUFA–rich diet potentiated the tumor-suppressive effect of tamoxifen. Our interventions were well tolerated without evidence of toxicity. Combined administration of tamoxifen and n-3 PUFA is a promising new approach to breast cancer prevention. Because of its safety, this combination can quickly be translated to the clinic if its superiority can be supported by future studies. Cancer Prev Res; 3(3); 322–30
Data from The Next Phase of Chemoprevention Research
Authors: Cohen Ezra E.W. , Schilsky Richard L.
Published: March 2024

Abstract
Phase 0 clinical trials are meant to explore mechanism of action, pharmacokinetics, pharmacodynamics, or biodistribution of investigational compounds in an efficient manner with relatively few subjects. Phase 0 designs have been applied sparingly in cancer research, but this issue of the journal provides an example of their utility reported by Reid and colleagues (beginning on page 347). Indeed, aspects of the phase 0 design lend themselves well to chemoprevention research, suggesting that this approach will become more common in the near future. Cancer Prev Res; 4(3); 293–5. ©2011 AACR.
Data from Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat
Authors: Skibinski Christine G. , Thompson Henry J. , Das Arunangshu , Manni Andrea , Bortner James D. , Stanley Anne , Stanley Bruce A. , El-Bayoumy Karam
Published: March 2024

Abstract
We used a proteomic approach to gain insights into the mechanisms of protection at the protein level by a high n-3:n-6 ratio in the absence and presence of Tamoxifen. Four groups were treated with 1-methyl-1-nitrosourea (MNU) and fed the following diets with varied n-3:n-6 ratios; group 1 = 1:1; groups 2 and 3 = 10:1 and 25:1, respectively; group 4: (25:1) plus Tamoxifen (1 mg/kg diet). The plasma from six rats/group was pooled and analyzed with the isobaric tags for relative and absolute quantitation method; 148 proteins were identified with 95% confidence by ProteinPilot 4.0. In plasma of rats fed 10:1, 25:1 n-3:n-6, and 25:1 plus Tamoxifen, the number of proteins that met our criteria (P ≤ 0.05, error factor ≤ 2) were 10, 14, and 19 proteins, respectively. Selected proteins were further validated by Western blotting. Compared to 1:1, both 10:1 and 25:1 diets upregulated vitamin D binding protein, gelsolin, and 14-3-3 sigma, reported to have tumor suppressive effects, whereas alpha-1B-glycoprotein, which has been reported to be elevated in the serum of breast cancer patients was decreased. Compared to 25:1, the 25:1 plus Tamoxifen diet downregulated apolipoprotein E, haptoglobin, and inter-α-inhibitor H4 heavy chain. Ingenuity pathway analysis determined that the trends of specific proteins were related to lipid metabolism in the 25:1 n-3:n-6 group, whereas the 25:1 n-3:n-6 plus Tamoxifen group included proteins involved in cancer and inflammation. Our results show that several proteins were altered in a manner consistent with chemoprevention. Such proteins may serve as biomarkers to monitor efficacy of n-3 and Tamoxifen in future clinical chemoprevention trials. Cancer Prev Res; 6(9); 979–88. ©2013 AACR.
Data from Biomarkers for Personalizing Omega-3 Fatty Acid Dosing
Authors: Jiang Yan , Djuric Zora , Sen Ananda , Ren Jianwei , Kuklev Dmitry , Waters Ian , Zhao Lili , Uhlson Charis L. , Hong Yu H. , Murphy Robert C. , Normolle Daniel P. , Smith William L. , Brenner Dean E.
Published: March 2024

Abstract
Prostaglandin E2 (PGE2) has been linked to a higher risk of colorectal cancer. PGE2 in colon tissue can be reduced by increasing dietary eicosapentaenoic acid (EPA). The dose-dependent relationships between dietary EPA, serum EPA:arachidonate (AA) ratio, urinary PGE2 metabolites, and colonic eicosanoids were evaluated to develop biomarkers for prediction of colonic PGE2. Male rats were fed diets containing EPA:ω6 fatty acid ratios of 0, 0.1, 0.2, 0.4, or 0.6 for 5 weeks. Increasing the dietary EPA:ω6 fatty acid ratio increased EPA:AA ratios in serum and in the proximal, transverse, and distal colon (P < 0.001). The urinary PGE2 metabolite was reduced (P = 0.006). EPA-rich diets reduced colonic tissue PGE2 concentrations by 58% to 66% and increased PGE3 by 19- to 28-fold. Other AA–derived eicosanoids were reduced by 35% to 83%. The changes were not linear, with the largest changes in eicosanoids observed with the lower doses. A mathematical model predicts colonic tissue eicosanoids from the EPA:AA ratio in serum and the EPA dose. Every 10% increase in serum EPA:AA was associated with a 2% decrease in the (geometric) mean of PGE2 in the distal colon. These mathematical relationships can now be applied to individualized EPA dosing in clinical trials. Cancer Prev Res; 7(10); 1011–22. ©2014 AACR.
Data from C-reactive Protein and Risk of Colorectal Adenoma According to Celecoxib Treatment
Authors: Chan Andrew T. , Sima Camelia S. , Zauber Ann G. , Ridker Paul M. , Hawk Ernest T. , Bertagnolli Monica M.
Published: March 2024

Abstract
Inflammation, as measured by the circulating inflammatory marker high-sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data about CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial showed that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined whether serum hsCRP modified these results. We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive 3 years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at years 1 and 3. Among 1,680 patients, the estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP <1 mg/L, compared with 43% [relative risk (RR) = 1.02; 95% CI = 0.85–1.22] for hsCRP 1–3 mg/L, and 41% (RR = 1.10; 95% CI = 0.90–1.34) for hsCRP >3 mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3 mg/L) compared with low (≤3 mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (95% CI = 1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53–1.83) and 1.11 (95% CI = 0.61–2.02). hsCRP may predict risk of celecoxib-associated cardiovascular toxicity but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention. Cancer Prev Res; 4(8); 1172–80. ©2011 AACR.
Data from Lycopene Attenuated Hepatic Tumorigenesis via Differential Mechanisms Depending on Carotenoid Cleavage Enzyme in Mice
Authors: Ip Blanche C. , Liu Chun , Ausman Lynne M. , von Lintig Johannes , Wang Xiang-Dong
Published: March 2024

Abstract
Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10′-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9′,10′-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)–promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress–mediated unfolded protein response (ERUPR), through decreasing ERUPR-mediated protein kinase RNA-activated like kinase–eukaryotic initiation factor 2α activation, and inositol requiring 1α–X-box–binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, β-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression. Cancer Prev Res; 7(12); 1219–27. ©2014 AACR.
Data from A Randomized, Placebo-Controlled, Preoperative Trial of Allopurinol in Subjects with Colorectal Adenoma
Authors: Puntoni Matteo , Branchi Daniela , Argusti Alessandra , Zanardi Silvia , Crosta Cristiano , Meroni Emanuele , Munizzi Francesco , Michetti Paolo , Coccia Gianni , De Roberto Giuseppe , Bandelloni Roberto , Turbino Laura , Minetti Egle , Mori Marco , Salvi Sandra , Boccardo Simona , Gatteschi Beatrice , Benelli Roberto , Sonzogni Angelica , DeCensi Andrea
Published: March 2024

Abstract
Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis.

After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue.

Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of −10.6%, 95% confidence interval (CI), −20.5 to −0.7, and −8.1%, 95% CI, −22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (−16.4%; 95% CI, −29.0 to −3.8). No dose–response relationship was noted, except for NF-κB expression in normal tissue.

Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity. Cancer Prev Res; 6(2); 74–81. ©2012 AACR.
Data from Prospective Multicenter Randomized Intermediate Biomarker Study of Oral Contraceptive versus Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome
Authors: Lu Karen H. , Loose David S. , Yates Melinda S. , Nogueras-Gonzalez Graciela M. , Munsell Mark F. , Chen Lee-may , Lynch Henry , Cornelison Terri , Boyd-Rogers Stephanie , Rubin Mary , Daniels Molly S. , Conrad Peggy , Milbourne Andrea , Gershenson David M. , Broaddus Russell R.
Published: March 2024

Abstract
Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population. Cancer Prev Res; 6(8); 774–81. ©2013 AACR.
Data from Cardiovascular Risk Markers and Mechanisms in Targeting the COX Pathway for Colorectal Cancer Prevention
Authors: Oates John A.
Published: March 2024

Abstract
COX-2 inhibition reduces the incidence of colorectal neoplasia. The increased risk of thrombotic cardiovascular events produced by selective or nonselective COX-2 inhibitors, however, has confounded the consideration of employing them in cancer prevention. Developing a strategy for preventing colorectal cancer by inhibiting COX-2 depends on research advances in several key areas, including predictive biomarkers to identify people at the lowest risk for cardiovascular events, the molecular mechanisms whereby interdicting the COX-2 pathway produces thrombotic events, and the pharmacology of the widely divergent agents that act on COX-2 and its downstream pathway. Cancer Prev Res; 4(8); 1145–8. ©2011 AACR.
Data from Benzyl Isothiocyanate Inhibits Epithelial-Mesenchymal Transition in Cultured and Xenografted Human Breast Cancer Cells
Authors: Sehrawat Anuradha , Singh Shivendra V.
Published: March 2024

Abstract
We showed previously that cruciferous vegetable constituent benzyl isothiocyanate (BITC) inhibits growth of cultured and xenografted human breast cancer cells and suppresses mammary cancer development in a transgenic mouse model. We now show, for the first time, that BITC inhibits epithelial-mesenchymal transition (EMT) in human breast cancer cells. Exposure of estrogen-independent MDA-MB-231 and estrogen-responsive MCF-7 human breast cancer cell lines and a pancreatic cancer cell line (PL-45) to BITC resulted in upregulation of epithelial markers (e.g., E-cadherin and/or occludin) with a concomitant decrease in protein levels of mesenchymal markers, including vimentin, fibronectin, snail, and/or c-Met. The BITC-mediated induction of E-cadherin protein was accompanied by an increase in its transcription, whereas BITC-treated MDA-MB-231 cells exhibited suppression of vimentin, snail, and slug mRNA levels. Experimental EMT induced by exposure to TGFβ and TNFα or Rb knockdown in a spontaneously immortalized nontumorigenic human mammary epithelial cell line (MCF-10A) was also partially reversed by BITC treatment. The TGFβ-/TNFα-induced migration of MCF-10A cells was inhibited in the presence of BITC, which was partially attenuated by RNA interference of E-cadherin. Inhibition of MDA-MB-231 xenograft growth in vivo in female athymic mice by BITC administration was associated with an increase in protein level of E-cadherin and suppression of vimentin and fibronectin protein expression. In conclusion, this study reports a novel anticancer effect of BITC involving inhibition of EMT, a process triggered during progression of cancer to invasive state. Cancer Prev Res; 4(7); 1107–17. ©2011 AACR.
Data from Clinical Trial of Acolbifene in Premenopausal Women at High Risk for Breast Cancer
Authors: Fabian Carol J. , Kimler Bruce F. , Zalles Carola M. , Phillips Teresa A. , Metheny Trina , Petroff Brian K. , Havighurst Thomas C. , Kim KyungMann , Bailey Howard H. , Heckman-Stoddard Brandy M.
Published: March 2024

Abstract
The purpose of this study was to assess the feasibility of using the selective estrogen receptor modulator (SERM) acolbifene as a breast cancer prevention agent in premenopausal women. To do so, we assessed change in proliferation in benign breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) as a primary endpoint, along with changes in other risk biomarkers and objective and subjective side effects as secondary endpoints. Twenty-five women with cytologic hyperplasia ± atypia and ≥2% of breast epithelial cells staining positive for Ki-67, received 20 mg acolbifene daily for 6–8 months, and then had benign breast tissue and blood risk biomarkers reassessed. Ki-67 decreased from a median of 4.6% [interquartile range (IQR), 3.1%–8.5%] at baseline to 1.4% (IQR, 0.6%–3.5%) after acolbifene (P < 0.001; Wilcoxon signed-rank test), despite increases in bioavailable estradiol. There were also significant decreases in expression (RT-qPCR) of estrogen-inducible genes that code for pS2, ERα, and progesterone receptor (P ≤ 0.026). There was no significant change in serum IGF1, IGFBP3, IGF1:IGFBP3 ratio, or mammographic breast density. Subjective side effects were minimal with no significant increase in hot flashes, muscle cramps, arthralgias, or fatigue. Objective measures showed a clinically insignificant decrease in lumbar spine bone density (DEXA) and an increase in ovarian cysts but no change in endometrial thickness (sonography). In summary, acolbifene was associated with favorable changes in benign breast epithelial cell proliferation and estrogen-inducible gene expression but minimal side effects, suggesting a phase IIB placebo-controlled trial evaluating it further for breast cancer prevention. Cancer Prev Res; 8(12); 1146–55. ©2015 AACR.
Data from Comparative Effects of Two Different Forms of Selenium on Oxidative Stress Biomarkers in Healthy Men: A Randomized Clinical Trial
Authors: Richie John P. , Das Arun , Calcagnotto Ana M. , Sinha Raghu , Neidig Wanda , Liao Jiangang , Lengerich Eugene J. , Berg Arthur , Hartman Terryl J. , Ciccarella Amy , Baker Aaron , Kaag Matthew G. , Goodin Susan , DiPaola Robert S. , El-Bayoumy Karam
Published: March 2024

Abstract
Epidemiologic and laboratory studies indicate that dietary selenium protects against prostate cancer. Results from clinical trials suggest that selenium-enriched yeast (SY) but not selenomethionine (SeMet) may be effective at reducing prostate cancer risk. Our objectives were to directly compare for the first time the effects of SeMet and SY on prostate cancer relevant biomarkers in men. We performed a randomized double blind, placebo-controlled trial of SY (200 or 285 μg/day) and SeMet (200 μg/day) administered for 9 months in 69 healthy men. Primary endpoints included blood levels of selenium-containing compounds and oxidative stress biomarkers [urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α) and blood glutathione (GSH)]. Secondary endpoints included plasma glucose and PSA levels. Compliance was high in all groups (>95%). Plasma selenium levels were increased 93%, 54%, and 86% after 9 months in SeMet and low- and high-dose SY groups, respectively, and returned to baseline levels after a 3-month washout (P < 0.05). Levels of 8-OHdG and 8-iso-PGF2α were decreased 34% and 28%, respectively, after 9 months in the high-dose SY group (P < 0.05). These decreases were greatest in individuals with low baseline plasma levels of selenium (<127 ng/mL). No changes in serum PSA or blood glucose and GSH were observed. Overall, we showed for the first time, reductions in biomarkers of oxidative stress following supplementation with SY but not SeMet in healthy men. These findings suggest that selenium-containing compounds other than SeMet may account for the decrease in oxidative stress. Cancer Prev Res; 7(8); 796–804. ©2014 AACR.
Data from Orally Active Vitamin D for Potential Chemoprevention of Posttransplant Malignancy
Authors: Obi Yoshitsugu , Ichimaru Naotsugu , Hamano Takayuki , Tomida Kodo , Matsui Isao , Fujii Naohiko , Okumi Masayoshi , Kaimori Jun-ya , Yazawa Koji , Kokado Yukito , Tsubakihara Yoshiharu , Nonomura Norio , Rakugi Hiromi , Takahara Shiro , Isaka Yoshitaka
Published: March 2024

Abstract
Posttransplant malignancy (PTM) is a limiting factor both for patient and allograft survival in kidney transplant recipients (KTRs). We hypothesized that active vitamin D compounds (AVD) could reduce PTM development in KTRs. Ambulatory KTRs in a Japanese prospective cohort were followed from August 2007 to November 2010. The outcome of interest was newly diagnosed PTM. A propensity score (PS) of having received AVDs was estimated using 26 clinically relevant factors. We used the Cox proportional hazards model with stratification by PS tertiles on the assumption that baseline hazard functions differ among tertiles. As sensitivity analyses, we used inverse probability weighting and PS matching. Among 218 participants, the median age was 50 (interquartile range [IQR], 40 to 59) years, 63.3% were male, median time since transplantation was 11.2 (IQR, 5.2 to 17.1) years, and mean estimated GFR was 41.3 (SD, 15.6) mL/min per 1.73 m2. At baseline, 42.2% had been treated with AVDs mainly for glucocorticoid-induced osteoporosis. AVDs used were calcitriol (58.7%) and alfacalcidol (41.3%). During follow-up, PTM developed in 5.4% of 92 AVD users and 8.7% of 126 nonusers. Poor vitamin D status was common in the participants, but the serum 25-hydroxyvitamin D level was not significantly associated with PTM in Cox regression analysis. After stratifying patients by PS tertiles, we found that AVDs were significantly associated with a lower risk of PTM (HR 0.25 [0.07 to 0.82]). Sensitivity analyses yielded similar results. AVDs are potential chemopreventive agents against PTM in KTRs. Cancer Prev Res; 5(10); 1229–35. ©2012 AACR.
Data from Enhanced Antitumor Activity of 3-Bromopyruvate in Combination with Rapamycin In Vivo and In Vitro
Authors: Zhang Qi , Pan Jing , Lubet Ronald A. , Komas Steven M. , Kalyanaraman Balaraman , Wang Yian , You Ming
Published: March 2024

Abstract
3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the serine/threonine protein kinase mTOR. Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single-agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non–small cell lung cancer (NSCLC) cell lines. 3-BrPA and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3-BrPA did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA–treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of GAPDH. Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-BrPA, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention. Cancer Prev Res; 8(4); 318–26. ©2015 AACR.
Data from Xanthohumol Prevents DNA Damage by Dietary Carcinogens: Results of a Human Intervention Trial
Authors: Pichler Christoph , Ferk Franziska , Al-Serori Halh , Huber Wolfgang , Jäger Walter , Waldherr Monika , Mišík Miroslav , Kundi Michael , Nersesyan Armen , Herbacek Irene , Knasmueller Siegfried
Published: March 2024

Abstract
Xanthohumol (XN) is a hop flavonoid contained in beers and soft drinks. In vitro and animal studies indicated that XN has DNA and cancer protective properties. To find out if it causes DNA protective effects in humans, an intervention trial was conducted in which the participants (n = 22) consumed a XN containing drink (12 mg XN/P/d). We monitored prevention of DNA damage induced by representatives of major groups of dietary carcinogens [i.e., nitrosodimethylamine (NDMA) benzo(a)pyrene (B(a)P) and the heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)]. Lymphocytes were collected before, during, and after the intervention and incubated with the carcinogens and with human liver homogenate (S9). We found substantial reduction of B(a)P and IQ (P < 0.001 for both substances) induced DNA damage after consumption of the beverage; also, with the nitrosamine a moderate, but significant protective effect was found. The results of a follow-up trial (n = 10) with XN pills showed that the effects are caused by the flavonoid and were confirmed in γH2AX experiments. To elucidate the underlying mechanisms we measured several parameters of glutathione related detoxification. We found clear induction of α-GST (by 42.8%, P < 0.05), but no alteration of π-GST. This observation provides a partial explanation for the DNA protective effects and indicates that the flavonoid also protects against other carcinogens that are detoxified by α-GST. Taken together, our findings support the assumption that XN has anticarcinogenic properties in humans. Cancer Prev Res; 10(2); 153–60. ©2016 AACR.
Data from Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden
Authors: Montrose David C. , Zhou Xi Kathy , McNally Erin M. , Sue Erika , Yantiss Rhonda K. , Gross Steven S. , Leve Nitai D. , Karoly Edward D. , Suen Chen S. , Ling Lilan , Benezra Robert , Pamer Eric G. , Dannenberg Andrew J.
Published: March 2024

Abstract
Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit antimicrobial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with those of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APCMin/+ mice. Treatment with celecoxib also altered select luminal bacterial populations in both APCMin/+ and wild-type mice, including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae. Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis, including glucose, amino acids, nucleotides, and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APCMin/+ mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. We hypothesize that these actions contribute to its chemopreventive activity. Cancer Prev Res; 9(9); 721–31. ©2016 AACR.
Data from A Randomized Double-Blind Placebo-Controlled Phase IIB Trial of Curcumin in Oral Leukoplakia
Authors: Kuriakose Moni Abraham , Ramdas Kunnambath , Dey Bindu , Iyer Subramanya , Rajan Gunaseelan , Elango Kalavathy K. , Suresh Amritha , Ravindran Divya , Kumar Rajneesh R. , R Prathiba , Ramachandran Surya , Kumar Nisha Asok , Thomas Gigi , Somanathan Thara , Ravindran Hiran K. , Ranganathan Kannan , Katakam Sudhakar Babu , Parashuram Shivashankar , Jayaprakash Vijayvel , Pillai M. Radhakrishna
Published: March 2024

Abstract
Oral leukoplakia is a potentially malignant lesion of the oral cavity, for which no effective treatment is available. We investigated the effectiveness of curcumin, a potent inhibitor of NF-κB/COX-2, molecules perturbed in oral carcinogenesis, to treat leukoplakia. Subjects with oral leukoplakia (n = 223) were randomized (1:1 ratio) to receive orally, either 3.6 g/day of curcumin (n = 111) or placebo (n = 112), for 6 months. The primary endpoint was clinical response obtained by bi-dimensional measurement of leukoplakia size at recruitment and 6 months. Histologic response, combined clinical and histologic response, durability and effect of long-term therapy for an additional six months in partial responders, safety and compliance were the secondary endpoints. Clinical response was observed in 75 (67.5%) subjects [95% confidence interval (CI), 58.4–75.6] in the curcumin and 62 (55.3%; 95% CI, 46.1–64.2) in placebo arm (P = 0.03). This response was durable, with 16 of the 18 (88.9%; 95% CI, 67.2–96.9) subjects with complete response in curcumin and 7 of 8 subjects (87.5%) in placebo arm, demonstrating no relapse after 6 months follow-up. Difference in histologic response between curcumin and placebo was not significant (HR, 0.88, 95% CI, 0.45–1.71; P = 0.71). Combined clinical and histologic response assessment indicated a significantly better response with curcumin (HR, 0.50; 95% CI, 0.27–0.92; P = 0.02). Continued therapy, in subjects with partial response at 6 months, did not yield additional benefit. The treatment did not raise any safety concerns. Treatment of oral leukoplakia with curcumin (3.6 g for six months), thus was well tolerated and demonstrated significant and durable clinical response for 6 months. Cancer Prev Res; 9(8); 683–91. ©2016 AACR.
Data from Serum Levels of Androgens, Estrogens, and Sex Hormone Binding Globulin and Risk of Primary Gastric Cancer in Chinese Men: A Nested Case–Control Study
Authors: Zhu Zhikai , Chen Yingxi , Ren Jiansong , Dawsey Sanford M. , Yin Jian , Freedman Neal D. , Fan Jin-Hu , Taylor Philip R. , Liu Yuanli , Qiao You-Lin , Abnet Christian C.
Published: March 2024

Abstract
Gastric cancer shows a strong male predominance, and sex steroid hormones have been hypothesized to explain this sex disparity. Previous studies examining the associations between sex hormones and sex hormone binding globulin (SHBG) and risk of gastric cancer come primarily from western populations and additional studies in diverse populations will help us better understand the association. We performed a nested case–control study in Linxian Nutrition Intervention Trials cohorts to evaluate the associations among Chinese men, where we had sufficient cases to perform a well-powered study. Using radioimmunoassays and immunoassays, we quantitated androgens, estrogens, and SHBG in baseline serum from 328 men that developed noncardia gastric cancer and matched controls. We used multivariable unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) and explored interactions with body mass index (BMI), age, alcohol drinking, smoking, and follow-up time. Subjects with SHBG in the highest quartile, as compared with those in the lowest quartile, had a significantly increased risk of gastric cancer (OR = 1.87; 95% CI, 1.01–3.44). We found some evidence for associations of sex steroid hormones in men with lower BMI. Our study found a novel association suggesting that higher serum concentrations of SHBG may be associated with risk of gastric cancer in men. We found no overall associations with sex hormones themselves, but future studies should expand the scope of these studies to include women and further explore whether BMI modifies a potential association.
Prevention Relevance:
It was the first study to investigate the association of gastric cancer with prediagnostic sex steroid hormones and SHBG in an Asian male population. Although there were no overall associations for sex steroid hormone concentrations, higher concentrations of SHBG was associated with increased risk of noncardia gastric cancer.
Data from Fluvastatin Inhibits HMG-CoA Reductase and Prevents Non–Small Cell Lung Carcinogenesis
Authors: Zhang Tianshun , Bai Ruihua , Wang Qiushi , Wang Keke , Li Xiang , Liu Kangdong , Ryu Joohyun , Wang Ting , Chang Xiaoyu , Ma Weiya , Bode Ann M. , Xia Qingxin , Song Yongping , Dong Zigang
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer-related death worldwide. However, promising agents for lung cancer prevention are still very limited. Identification of preventive targets and novel effective preventive agents is urgently needed for clinical applications. In this study, we found that fluvastatin targeted 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), which a rate-limiting enzyme in the mevalonate pathway, and inhibited non–small cell lung cancer (NSCLC) tumorigenesis. Initially, we demonstrated that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo. Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.
Data from Association of Aspirin, Metformin, and Statin Use with Gastric Cancer Incidence and Mortality: A Nationwide Cohort Study
Authors: Cho Mi Hee , Yoo Tae Gon , Jeong Su-Min , Shin Dong Wook
Published: March 2024

Abstract
Anticancer effects of aspirin, metformin, and statins against gastric cancer, one of the most common cancers in the world, have been reported. This retrospective cohort study aimed to investigate independent associations of aspirin, metformin, and statin use with gastric cancer incidence and mortality after adjustment for concomitant use of other drugs, using pooled cohort data extracted from the Korean National Health Insurance claim database. Follow-up started on January 1, 2004 and ended at the date of gastric cancer diagnosis, death, or December 31, 2013. Exposures to drugs were defined as cumulative duration of use for aspirin and cumulative defined daily dose for metformin and statin, and were entered as time-dependent variables in Cox analysis models to avoid immortal time bias. Use of aspirin for longer than 182.5 and 547.5 days during 2-year interval was associated with reduced risks of gastric cancer incidence and mortality, respectively. Patients with diabetes were at higher risk of gastric cancer incidence and mortality than nondiabetic people, regardless of metformin treatment. However, metformin use among patients with diabetes was associated with a reduction in gastric cancer mortality in a dose-response manner. Statin use was also associated with a reduction of gastric cancer mortality in the general population, but not with gastric cancer incidence. In conclusion, long-term use of aspirin was independently associated with reduced incidence and mortality of gastric cancer in the general population, but metformin or statin use was only associated with a reduction of gastric cancer mortality in patients with diabetes and in the general population, respectively.
Prevention Relevance:
Long-term use of aspirin was independently associated with reduced incidence and mortality of gastric cancer in the general population. Metformin or statin use, however, was only associated with a reduction of gastric cancer mortality in diabetic patients and in the general population in a dose-response manner, respectively.
Data from Association of IgG Glycosylation and Esophageal Precancerosis Beyond Inflammation
Authors: Wu Zhiyuan , Pan Huiying , Liu Di , Zhou Di , Tao Lixin , Zhang Jie , Wang Xiaonan , Wang Youxin , Wang Wei , Guo Xiuhua
Published: March 2024

Abstract
This study aimed to investigate the association of IgG glycosylation and esophageal precancerosis for squamous cell carcinoma and determine its role in inflammation. Primary glycans selected by the least absolute shrinkage and selection operator (LASSO) algorithm were validated using univariate and multivariate logistics models plus restricted cubic spline functions. In total, 24 direct glycans and 27 derived traits were detected, among which four glycans and three derived traits were primarily selected. Then, GP5 (adjusted OR: 0.805), GP17 (adjusted OR: 1.305), G12n (adjusted OR: 1.271), Gal_1 (adjusted OR: 0.776) and Fuc (adjusted OR: 0.737) were validated and significantly associated with esophageal precancerosis. In addition, there was a consistent positive association in GP17 and G12n and a negative association in GP5, Gal_1, and Fuc by restricted cubic spline function. Compared with esophageal inflammation, GP17, G12n, and Fuc were still independently associated with precancerosis. In brief, the IgG glycosylation profile was independently associated with esophageal precancerosis beyond inflammation, which could be an early biomarker for esophageal cancer.

Prevention Relevance: IgG glycosylation profile is associated with esophageal precancerosis and specific IgG glycans involves in the early stage of esophageal cancer, which is independent of inflammation.
Data from Obesity-Associated Alterations in Inflammation, Epigenetics, and Mammary Tumor Growth Persist in Formerly Obese Mice
Authors: Rossi Emily L. , de Angel Rebecca E. , Bowers Laura W. , Khatib Subreen A. , Smith Laura A. , Van Buren Eric , Bhardwaj Priya , Giri Dilip , Estecio Marcos R. , Troester Melissa A. , Hair Brionna Y. , Kirk Erin L. , Gong Ting , Shen Jianjun , Dannenberg Andrew J. , Hursting Stephen D.
Published: March 2024

Abstract
Using a murine model of basal-like breast cancer, we tested the hypothesis that chronic obesity, an established breast cancer risk and progression factor in women, induces mammary gland epigenetic reprogramming and increases mammary tumor growth. Moreover, we assessed whether the obesity-induced epigenetic and protumor effects are reversed by weight normalization. Ovariectomized female C57BL/6 mice were fed a control diet or diet-induced obesity (DIO) regimen for 17 weeks, resulting in a normal weight or obese phenotype, respectively. Mice on the DIO regimen were then randomized to continue the DIO diet or were switched to the control diet, resulting in formerly obese (FOb) mice with weights comparable with control mice. At week 24, all mice were orthotopically injected with MMTV-Wnt-1 mouse mammary tumor cells. Mean tumor volume, serum IL6 levels, expression of proinflammatory genes in the mammary fat pad, and mammary DNA methylation profiles were similar in DIO and FOb mice and higher than in controls. Many of the genes found to have obesity-associated hypermethylation in mice were also found to be hypermethylated in the normal breast tissue of obese versus nonobese human subjects, and nearly all of these concordant genes remained hypermethylated after significant weight loss in the FOb mice. Our findings suggest that weight normalization may not be sufficient to reverse the effects of chronic obesity on epigenetic reprogramming and inflammatory signals in the microenvironment that are associated with breast cancer progression. Cancer Prev Res; 9(5); 339–48. ©2016 AACR.
Data from Unmetabolized Folic Acid, Tetrahydrofolate, and Colorectal Adenoma Risk
Authors: Rees Judy R. , Morris Carolyn B. , Peacock Janet L. , Ueland Per M. , Barry Elizabeth L. , McKeown-Eyssen Gail E. , Figueiredo Jane C. , Snover Dale C. , Baron John A.
Published: March 2024

Abstract
In a randomized trial of folic acid supplementation for the prevention of colorectal adenomas, we previously found indications of increased risk during later treatment and follow-up. This could have been due to the unmetabolized folic acid (UFA) or natural reduced and methylated folates (mF) to which it is metabolized. In post hoc analyses, we measured mF (the sum of 5-methyl-tetrahydrofolate and 4-alfa-hydroxy-5-methyl-THF) and UFA concentrations in the serum of 924 participants. Using binomial regression models with a log link, we assessed the associations between plasma mF or UFA and adenoma occurrence. We found no association between plasma mF or UFA and overall adenoma risk. However, during later follow-up, the prespecified, composite endpoint of high-risk findings (advanced or multiple adenomas) was positively associated with plasma mF (Plinear trend = 0.009), with a 58% increased risk for participants in the upper versus lowest quartile. An irregular association was seen with plasma UFA, with suggestions of an inverse trend (Plinear trend=0.049). A modest, significant inverse association was also seen between mF and risk of serrated lesions, with a 39% lower risk for upper versus lower quartile participants (Plinear trend = 0.03). In conclusion, during the later follow-up period in which folic acid supplementation was previously seen to increase the risk of advanced and multiple adenomas, higher serum mF was associated with a higher risk of multiple and/or advanced adenomas, but no clear indication that UFA played a direct role. There were indications that higher mF was associated with reduced risk of serrated polyps. Cancer Prev Res; 10(8); 451–8. ©2017 AACR.
Data from Does Mutated K-RAS Oncogene Attenuate the Effect of Sulindac in Colon Cancer Chemoprevention?
Authors: Rice Photini F.S. , Ehrichs Kevin G. , Jones Mykella S. , Chen Hwudarw , Hsu Chiu-Hsieh , Abril Edward R. , Nagle Raymond B. , Besselsen David G. , Barton Jennifer K. , Ignatenko Natalia A.
Published: March 2024

Abstract
The NSAID sulindac has been successfully used alone or in combination with other agents to suppress colon tumorigenesis in patients with genetic predisposition and also showed its efficacy in prevention of sporadic colon adenomas. At the same time, some experimental and clinical reports suggest that a mutant K-RAS oncogene may negate sulindac antitumor efficacy. To directly assess sulindac activity at suppressing premalignant lesions carrying K-RAS mutation, we utilized a novel mouse model with an inducible colon-specific expression of the mutant K-ras oncogene (K-rasG12D). Tumor development and treatment effects were monitored by minimally invasive endoscopic Optical coherence tomography. Expression of the mutant K-ras allele accelerated azoxymethane (AOM)-induced colon carcinogenesis in C57BL/6 mice, a strain otherwise resistant to this carcinogen. Sulindac completely prevented AOM-induced tumor formation in K-ras wild-type (K-ras wt) animals. In K-rasG12D–mutant mice, a 38% reduction in tumor number, an 83% reduction in tumor volume (P ≤ 0.01) and an increase in the number of adenoma-free mice (P = 0.04) were observed. The partial response of K-RasG12D animals to sulindac treatment was evident by the decrease in mucosal thickness (P < 0.01) and delay in progression of the precancerous aberrant crypt foci to adenomas. Molecular analyses showed significant induction in cyclooxygenase 2 (COX-2), cleaved caspase-3 (CC3), and Ki-67 expression by AOM, but not sulindac treatment, in all genotypes. Our data underscore the importance of screening for K-RAS mutations in individuals with colon polyps to provide more personalized interventions targeting mutant K-RAS signaling pathways. Cancer Prev Res; 11(1); 16–26. ©2017 AACR.
Data from Vitamin D Signaling Suppresses Early Prostate Carcinogenesis in TgAPT121 Mice
Authors: Fleet James C. , Kovalenko Pavlo L. , Li Yan , Smolinski Justin , Spees Colleen , Yu Jun-Ge , Thomas-Ahner Jennifer M. , Cui Min , Neme Antonio , Carlberg Carsten , Clinton Steven K.
Published: March 2024

Abstract
We tested whether lifelong modification of vitamin D signaling can alter the progression of early prostate carcinogenesis in studies using mice that develop high-grade prostatic intraepithelial neoplasia that is similar to humans. Two tissue-limited models showed that prostate vitamin D receptor (VDR) loss increased prostate carcinogenesis. In another study, we fed diets with three vitamin D3 levels (inadequate = 25 IU/kg diet, adequate for bone health = 150 IU/kg, or high = 1,000 IU/kg) and two calcium levels (adequate for bone health = 0.5% and high = 1.5%). Dietary vitamin D caused a dose-dependent increase in serum 25-hydroxyvitamin D levels and a reduction in the percentage of mice with adenocarcinoma but did not improve bone mass. In contrast, high calcium suppressed serum 1,25-dihydroxyvitamin D levels and improved bone mass but increased the incidence of adenocarcinoma. Analysis of the VDR cistrome in RWPE1 prostate epithelial cells revealed vitamin D–mediated regulation of multiple cancer-relevant pathways. Our data support the hypothesis that the loss of vitamin D signaling accelerates the early stages of prostate carcinogenesis, and our results suggest that different dietary requirements may be needed to support prostate health or maximize bone mass.
Significance:
This work shows that disrupting vitamin D signaling through diet or genetic deletion increases early prostate carcinogenesis through multiple pathways. Higher-diet vitamin D levels are needed for cancer than bone.