Cancer Chemopreventive Effects Research Articles

Cancer Chemopreventive Effect of 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone on Diethylnitrosamine-Induced Early Stages of Hepatocarcinogenesis in Rats.

2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) is a major compound in Cleistocalyx nervosum seed extract (CSE), which has been reported to have various biological activities, including anti-cancer activity. Therefore, this study attempted to evaluate whether DMC is a chemopreventive compound in CSE. Moreover, the preventive mechanisms of CSE and DMC in the DEN-induced early stages of hepatocarcinogenesis in rats were investigated. Male Wistar rats were intraperitoneally injected with DEN 50 mg/kg bw once a week for 8 weeks. Rats received CSE and DMC orally throughout the experiment. The number of glutathione S-transferase placental form (GST-P)-positive foci in the liver was measured. Furthermore, the preventive mechanisms of CSE and DMC on DEN-induced HCC, including cell proliferation and apoptosis, were investigated. Administering CSE at a dosage of 400 mg/kg bw and DMC at a dosage of 10 mg/kg bw significantly decreased the number and size of GST-P-positive foci and GST-P expression. In addition, DMC inhibited the development of preneoplastic lesions by decreasing cell proliferation and causing cell apoptosis; however, CSE inhibited the development of preneoplastic lesions by inducing cell apoptosis. In conclusion, DMC exhibited a cancer chemopreventive effect on the early stages of hepatocarcinogenesis by increasing cell apoptosis and reducing cell proliferation.

Essential oil from Citrus depressa peel exhibits antimicrobial, antioxidant and cancer chemopreventive effects.

Many diseases may be caused by pathogens and oxidative stress resulting from carcinogens. Earlier studies have highlighted the antimicrobial and antioxidant effects of plant essential oils (EO). It is crucial to effectively utilize agricultural waste to achieve a sustainable agricultural economy and protect the environment. The present study aimed to evaluate the potential benefits of EO extracted from the discarded peels of Citrus depressa Hayata (CD) and Citrus microcarpa Bunge (CM), synonyms of Citrus deliciosa Ten and Citrus japonica Thunb, respectively. Gas chromatography-mass spectrometry analysis revealed that the main compounds in CD-EO were (R)-(+)-limonene (38.97%), γ-terpinene (24.39%) and linalool (6.22%), whereas, in CM-EO, the main compounds were (R)-(+)-limonene (48.00%), β-pinene (13.60%) and γ-terpinene (12.07%). CD-EO exhibited inhibitory effects on the growth of common microorganisms, including Candida albicans, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. However, CM-EO showed only inhibitory effects on E. coli. Furthermore, CD-EO exhibited superior antioxidant potential, as demonstrated by its ability to eliminate 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azinobis-3-ethylbenzthiazoline-6-sulfonate free radicals. Furthermore, CD-EO at a concentration of 100 μg mL-1 significantly inhibited 12-O-tetradecanoylphorbol-13-acetate-induced cancer transformation in mouse epidermal JB6 P+ cells (P < 0.05), possibly by up-regulating protein expression of nuclear factor erythroid 2-related factor 2 and its downstream antioxidant enzymes, such as NAD(P)H:quinone oxidoreductase 1, heme oxygenase-1 and UGT1A. These findings suggest that CD-EO exhibits inhibitory effects on pathogenic microorganisms, possesses antioxidant properties and has cancer chemopreventive potential. © 2024 Society of Chemical Industry.

Breast cancer cell growth arrest and chemopreventive effects of Passiflora edulis Sims (Passifloraceae) ethanolic leaves extract on a rat model of mammary carcinoma.

Despite various prevention and treatment measures, the incidence and mortality due to breast cancer has been increasing globally. Passiflora edulis Sims is a plant used for the treatment of various diseases in traditional medicine, including cancers. To assess the anti-breast cancer activity of the ethanolic extract of P. edulis leaves in vitro and in vivo. In vitro, the cell growth and proliferation were determined based on the MTT and BrdU assays. The flow cytometry was used to analyze the cell death mechanism while, cell migration, cell adhesion and chemotaxis were assayed for anti-metastatic potential. In vivo, 56 female Wistar rats aged 45-50 days (∼75g) were exposed to 7,12-dimethylbenz(a)anthracene-DMBA except the normal group. Negative control group (DMBA) received solvent dilution throughout the study; standards groups (tamoxifen - 3.3mg/kg BW and letrozole - 1mg/kg BW) as well as P. edulis leaves ethanolic extract groups (50, 100 and 200mg/kg) treated for 20 weeks. Tumor incidence, tumor burden and volume, CA 15-3 serum' level, antioxidant, inflammatory status and histopathology were assessed. P. edulis extract showed a significant and concentration-dependent inhibition of MCF-7 and MDA-MB 231cells growth at 100μg/mL. It inhibited cell proliferation and clones' formation and induced apoptosis in MDA-MB 231cells. The migration of cell into the zone freed of cells and the number of invading cells after the 48 and 72h were significantly diminished while, it increased their adherence to collagen and fibronectin extracellular matrix as does Doxorubicin. In vivo, all rats in the DMBA group exhibited a significant (p < 0.001) increase in tumor volume, tumor burden and grade (adenocarcinoma of SBR III) and pro-inflammatory cytokine levels (TNF-α, INF-γ, IL-6 and IL-12). P. edulis extract at all tested doses significantly inhibited the DMBA-induced increase in tumor incidence, tumor burden and grade (SBR I) as well as pro-inflammatory cytokines. Moreover, it increased enzymatic and non-enzymatic antioxidants (SOD, catalase, and GSH) and decreased MDA levels although a greater effect was observed with Tamoxifen and Letrozole. P. edulis has medium content on polyphenols, flavonoids and tannins. P. edulis has chemo-preventive effects against DMBA-induced breast cancer in rats probably through its antioxidative, anti-inflammatory and apoptosis-inducing potentials.

Sesame Extract Promotes Chemopreventive Effect of Hesperidin on Early Phase of Diethylnitrosamine-Initiated Hepatocarcinogenesis in Rats.

The combination of natural products is an alternative approach to achieving chemopreventive potential. Accordingly, citrus hesperidin exhibits numerous biological activities, including anticarcinogenic activities, while the sesamin in sesame exhibits potent anticancer activities and lipid-lowering effects. We investigated the cancer chemopreventive effects of mixed sesame and orange seed extract (MSO) containing hesperidin and sesamin in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Rats were injected with DEN once a week for 3 weeks to induce hepatocarcinogenesis. Rats were fed with MSO and various compositions that included sesame extract (SE) and hesperidin. The 10-week administration of MSO more effectively inhibited the number and size of hepatic GST-P-positive foci than hesperidin in DEN-initiated rats. MSO and hesperidin decreased the number of PCNA-positive hepatocytes but increased the apoptotic cells in DEN-induced rats. Furthermore, MSO and its constituents suppressed hepatic triglyceride content concurrently along with the expression of fatty acid synthase. Although the 5-week administration of MSO or hesperidin did not alter hepatic, preneoplastic lesion formation in DEN-initiated rats, it alleviated DEN-induced hepatotoxicity. MSO and its applied compositions did not impact upon the cytochrome P450 system. In conclusion, sesame extract promoted the chemopreventive effect of hesperidin on DEN-induced early stage of hepatocarcinogenesis in rats. The inhibitory mechanisms are likely involved with the induction of cell apoptosis, suppression of cell proliferation and modulation of hepatic lipogenesis. This study may provide revelations in the development of alternative treatments against hepatocellular carcinoma.

Can Cost-effectiveness Analysis Inform Genotype-Guided Aspirin Use for Primary Colorectal Cancer Prevention?

Inherited genetic variants can modify the cancer-chemopreventive effect of aspirin. We evaluated the clinical and economic value of genotype-guided aspirin use for colorectal cancer chemoprevention in average-risk individuals. A decision analytical model compared genotype-guided aspirin use versus no genetic testing, no aspirin. The model simulated 100,000 adults ≥50 years of age with average colorectal cancer and cardiovascular disease risk. Low-dose aspirin daily starting at age 50 years was recommended only for those with a genetic test result indicating a greater reduction in colorectal cancer risk with aspirin use. The primary outcomes were quality-adjusted life-years (QALY), costs, and incremental cost-effectiveness ratio (ICER). The mean cost of using genotype-guided aspirin was $187,109 with 19.922 mean QALYs compared with $186,464 with 19.912 QALYs for no genetic testing, no aspirin. Genotype-guided aspirin yielded an ICER of $66,243 per QALY gained, and was cost-effective in 58% of simulations at the $100,000 willingness-to-pay threshold. Genotype-guided aspirin was associated with 1,461 fewer polyps developed, 510 fewer colorectal cancer cases, and 181 fewer colorectal cancer-related deaths. This strategy prevented 1,078 myocardial infarctions with 1,430 gastrointestinal bleeding events, and 323 intracranial hemorrhage cases compared with no genetic testing, no aspirin. Genotype-guided aspirin use for colorectal cancer chemoprevention may offer a cost-effective approach for the future management of average-risk individuals. A genotype-guided aspirin strategy may prevent colorectal cancer, colorectal cancer-related deaths, and myocardial infarctions, while minimizing bleeding adverse events. This model establishes a framework for genetically-guided aspirin use for targeted chemoprevention of colorectal cancer with application toward commercial testing in this population.

Neoisoliquiritin exerts tumor suppressive effects on prostate cancer by repressing androgen receptor activity

BackgroundProstate cancer (PCa) is a major cause of morbidity and mortality in men in both developed and developing countries. Androgens and the androgen receptor (AR) play predominant roles in the progression of PCa. Neoisoliquiritin (NEO) belongs to the class of licorice (Glycyrrhiza) flavonoids, which have a variety of biological activities including anti-depressant, anti-tumor-promoting, and anti-inflammation properties. Licorice root has cancer chemopreventive effects and has been given to PCa patients as an ingredient of PC-SPES, a commercially available combination of eight herbs. Therefore, we determined if NEO can suppress the proliferation of PCa cells. PurposeWe investigated whether and how NEO exerts its anti-neoplastic activity against PCa. MethodsThe Cell Counting Kit 8 and flow cytometry were used to evaluate the effects of NEO on the proliferation and cell cycle progression of AR-dependent (LNCaP) and AR-independent (PC3) PCa cells. RNA sequencing was employed to examine the genome-wide changes in responsiveness to NEO in LNCaP cells. Quantitative PCR, Western blotting, docking, chromatin immunoprecipitation, and dual-luciferase reporter assays were conducted to determine the mechanism of action of NEO and its potential cross-talk with AR. A LNCaP xenograft nude mouse model was used to determine the inhibitory effects of NEO on AR-dependent PCa tumors in vivo. ResultsNEO inhibited LNCaP cell proliferation in vitro by inducing G0/G1 phase cell cycle arrest. Conversely, NEO treatment had no effect on PC3 cells. Transcriptomic analysis indicated that AR signaling might be the key target of NEO in preventing PCa. NEO regulated AR-mediated cell growth suppression and AR-sensitized cell cycle arrest in LNCaP cells. NEO also blocked several key steps in the AR signaling pathway, including proposed targeting to the ligand binding pocket of AR by computer modeling, modulating AR–androgen response element DNA-binding activity, inhibiting the expression and transcriptional activity of AR, and suppressing downstream AR signaling. ConclusionsNEO negatively regulates AR expression and activity, thus supporting the tumor suppressive role for NEO in AR-dependent PCa.

Inhibitory Effect of Thai Purple Rice Husk Extract on Chemically Induced Carcinogenesis in Rats.

This study investigated the cancer chemopreventive effects of an acidic methanol extract of purple rice husk on chemically induced carcinogenesis in rats. This purple rice husk extract (PRHE) had high polyphenol contents. Vanillic acid was a major phenolic compound in PRHE. Three major anthocyanins found in PRHE were malvidin-3-glucoside, peonidin-3-glucoside and cyanidin-3-glucoside. PRHE was not toxic and clastogenic in rats. The LD50 of PRHE was greater than 2000 mg kg−1 body weight (BW). The oral administration of 300 or 1000 mg kg−1 BW of PRHE for 28 days significantly decreased the number of micronucleated hepatocytes in diethylnitrosamine-initiated rats. The inhibitory mechanisms were associated with the reduction of cytochrome P450 2E1 expression and induction of some detoxifying enzymes in the liver. In addition, treatment with 500 mg kg−1 BW of PRHE for eight weeks did not induce preneoplastic lesions in the liver and colon. It significantly inhibited hepatic glutathione-S-transferase positive foci formation induced by diethylnitrosamine and 1,2-dimethylhydrazine by suppression of hepatocyte proliferation and induction of apoptosis. In conclusion, PRHE did not present toxicity, clastogenicity or carcinogenicity in rats. It exhibited cancer chemopreventive properties against chemically induced early stages rat hepatocarcinogenesis. Anthocyanins and vanillic acid might be candidate anticarcinogenic compounds in purple rice husk.

Alteration of fecal microbiota by fucoxanthin results in prevention of colorectal cancer in AOM/DSS mice.

Fucoxanthin (Fx), a marine carotenoid found in edible brown algae, is well known for having anticancer properties. The gut microbiota has been demonstrated as a hallmark for colorectal cancer progression in both humans and rodents. However, it remains unclear whether the gut microbiota is associated with the anticancer effect of Fx. We investigated the chemopreventive potency of Fx and its effect on gut microbiota in a mouse model of inflammation-associated colorectal cancer (by azoxymethane/dextran sulfate sodium treatment). Fx administration (30 mg/kg bw) during a 14 week period significantly inhibited the multiplicity of colorectal adenocarcinoma in mice. The number of apoptosis-like cleaved caspase-3high cells increased significantly in both colonic adenocarcinoma and mucosal crypts. Fx administration significantly suppressed Bacteroidlales (f_uc; g_uc) (0.3-fold) and Rikenellaceae (g_uc) (0.6-fold) and increased Lachnospiraceae (g_uc) (2.2-fold), compared with those of control mice. Oral administration of a fecal suspension obtained from Fx-treated mice, aimed to enhance Lachnospiraceae, suppress the number of colorectal adenocarcinomas in azoxymethane/dextran sulfate sodium-treated mice with a successful increase in Lachnospiraceae in the gut. Our findings suggested that an alteration in gut microbiota by dietary Fx might be an essential factor in the cancer chemopreventive effect of Fx in azoxymethane/dextran sulfate sodium-treated mice.

Effects and Mechanisms of Acylated Flavonoid on Cancer Chemopreventive Activity

Many studies have shown that flavonoids have various physiological activities such as anti-inflammatory, antibacterial, anti-cancer, and hepatoprotective activities. Meanwhile, its hydrophilic nature has led to low absorption into the body and the limitations of its bioactivity. Many acylated flavonoids and their bioactivities, including those obtained as natural compounds and those synthesized biochemically or chemically, have been reported to improve their bioavailability. This review focuses on the recent developments of the cancer chemopreventive activity of acylated flavonoids. Novel acylated flavonoids have been identified from nature since 2015, and many of them have shown high cytoprotective and anti-inflammatory effects by acylation of glycosyl residues. A large number of acylated flavonoids have been synthesized by enzyme-catalyzed and chemical methods, and their bioactivity has been evaluated. The introduction of acyl groups in the sugar residues showed higher antioxidant activity with increased lipophilicity and improved anti-inflammatory and cytoprotective effects and the ability of apoptosis induction in cancer cells. In contrast, introducing acyl groups into the hydroxy groups of aglycones resulted in less antioxidant activity but improved cancer proliferation inhibition and anti-inflammatory effects. Acylation of flavonoids tends to increase their bioactivity over the parent compound. The increased bioactivity by acylation can be attributed to increased lipophilicity and improved membrane permeability. Acylated flavonoids are one of a group of promising compounds that have cancer chemopreventive effects. However, the study of ADME (Absorption, Distribution, Metabolism, Excretion) will be essential to elucidate the relationship between acylation of flavonoids and the improvement of their bioactivity.

A Comprehensive Review and Perspective on Anticancer Mechanisms of Withaferin A in Breast Cancer.

Withaferin A (hereafter abbreviated as WA) is a promising anticancer steroidal lactone abundant in a medicinal plant (Withania somnifera) native to Asia. The root/leaf extract of Withania somnifera, which belongs to the Solanaceae family, continues to be included in the Ayurvedic medicine formulations of alternative medicine practice. Numerous chemicals are detectable in the root/leaf extract of Withania somnifera [e.g., withanolides (WA, withanone, withanolide A, etc.), alkaloids, sitoindosides, etc.], but the anticancer effect of this medicinal plant is largely attributed to WA. Anticancer effect of WA was initially reported in the early 70s in the Ehrlich ascites tumor cell model in vitro Since then, numerous preclinical studies have been performed using cellular and animal models of different cancers including breast cancer to determine cancer therapeutic and chemopreventive effects of WA. Chemoprevention, a word first introduced by Dr. Michael B. Sporn, was intended to impede, arrest, or reverse carcinogenesis at its earliest stages with pharmacologic agents. This review succinctly summarizes the published findings on anticancer pharmacology of WA in breast cancer focusing on pharmacokinetic behavior, in vivo efficacy data in preclinical models in a therapeutic and chemoprevention settings, and its known effects on cancer-relevant cellular processes (e.g., growth arrest, apoptosis induction, autophagy, metabolic adaptation, immune function, etc.) and molecular targets (e.g., suppression of oncogenes such as estrogen receptor-α, STAT3, etc.). Potential gaps in knowledge as well as future research directions essential for clinical development of WA for chemoprevention and/or treatment of breast cancer are also discussed.

Abstract 3828: Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that mutation of the gene encoding this transcription factor causes its overactivation in various types of human malignancies. The aberrant activation of NRF2 is considered to accelerate the proliferation and progression of cancer cells. However, the exact function of NRF2 in the stage of pre-malignancy remains still largely unresolved. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. In the present study, a well-known NRF2 activating chemopreventive phytochemical, sulforaphane (SFN), was daily injected intraperitonally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The relative fold changes of liver weight, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than that in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1 (NQO1), and the cell proliferation marker proliferating cell nuclear antigen (PCNA) and the DNA damage marker gamma-histone 2A family member X (γH2AX) was markedly elevated in SFN-treated mice compared with that in vehicle-treated mice as assessed by the Western blot assay. Immunohistochemistry and Immunofluorescence staining data further verified higher expression of NRF2 and PCNA in SFN-treated mice. These results suggest that once HCC is initiated, SFN stimulates the progression of DEN-induced HCC via activation of NRF2, rather than exerting a cancer chemopreventive effect. RNA sequencing analysis with liver tumors from DEN-treated mice revealed the B-raf V637E mutation (4/7). We speculate that mutation of B-raf proto-oncogene may contribute, at least in part, to activation of oncogenic NRF2 in DEN-induced murine carcinogenesis. The effects of SFN on DEN-induced mutation spectrum is under investigation. This study was supported by the Global Core Research Center (GCRC) Grant (No. 2011-003-0001) from the National Research Foundation (NRF) of Republic of Korea. Citation Format: Jie Zheng, Do-Hee Kim, Xi Zhu Fang, Seong Hoon Kim, Soma Saeidi, Su-Jung Kim, Young-Joon Surh. Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3828.

Licochalcone A reverses NNK-induced ectopic miRNA expression to elicit in vitro and in vivo chemopreventive effects

BackgroundChemoprevention is the best cost-effective way regarding cancers. MicroRNAs (miRNAs) have been reported to be differentially expressed during the development of lung cancer. However, if lung cancer prevention can be achieved through modulating miRNAs expression so far remains unknown. PurposeTo discover ectopically expressed miRNAs in NNK-induced lung cancer and clarify whether Licochalcone A (lico A) can prevent NNK-induced lung cancer by modulating miRNA expression. Study design and methodsA/J mice were used to construct a lung cancer model by intraperitoneal injection with physiological saline NNK (100 mg/kg). Chemopreventive effects of lico A against lung cancer at 2 mg/kg and 20 mg/kg doses were evaluated in vivo. MicroRNA array and RT-qPCR were used to assess the expression levels of miRNAs. MLE-12 cells were treated with 0.1 mg/ml NNK, stimulating the ectopic expression pattern of miR-144-3p, miR-20a-5p, miR-29c-3p, let-7d-3p, and miR-328-3p. miR-144-3p mimics and inhibitors were used to manipulate miR-144-3p levels. The effects of lico A (10 μM) on cell cycle distribution, apoptosis, and the expression of CK19, RASA1, miR-144-3p, miR-20a-5p, miR-29c-3p, let-7d-3p, and miR-328-3p in NNK-treated MLE-12 cells were studied. ResultsThe expression levels of miR-144-3p, miR-20a-5p, and miR-29c-3p increased, while those of let-7d-3p and miR-328-3p decreased in both NNK-induced A/J mice and MLE-12 cells. Lico A could reverse the NNK-induced ectopic miRNA (miR-144-3p, miR-20a-5p, miR-29c-3p, let-7d-3p, and miR-328-3p) expression both in vivo and in vitro and elicit in vivo lung cancer chemopreventive effect against NNK. In MLE-12 cells, the overexpression of miR-144-3p elicited the same effect as NNK regarding the expression of lung cancer biomarker CK19; the silencing of miR-144-3p reversed the effect of NNK on cell cycle distribution and apoptosis. Lico A could reverse the effect of NNK on the expression of miR-144-3p, CK19, and RASA1 (predicted target of miR-144-3p). ConclusionThe present study suggests that miR-144-3p, miR-20a-5p, miR-29c-3p, let-7d-3p, and miR-328-3p were involved in the in vivo pathogenesis of NNK-induced lung cancer, and lico A could reverse the effect of NNK both in vivo and in vitro to elicit lung cancer chemopreventive effects through, at least partially, these five ectopically expressed miRNAs, especially miR-144-3p.

Lycopene prevents carcinogen-induced cutaneous tumor by enhancing activation of the Nrf2 pathway through p62-triggered autophagic Keap1 degradation.

Biologically active natural products have been used for the chemoprevention of cutaneous tumors. Lycopene is the main active phytochemical in tomatoes. We herein aimed to assess the cancer preventive effects of lycopene and to find potential molecular targets. In chemically-induced cutaneous tumor mice and cell models, lycopene attenuated cutaneous tumor incidence and multiplicity as well as the tumorigenesis of normal cutaneous cells in phase-selectivity (only in the promotion phase) manners. By utilizing a comprehensive approach combining bioinformatics with network pharmacology, we predicted that intracellular autophagy and redox status were associated with lycopene’s preventive effect on cutaneous tumors. Lycopene stimulated the activation of antioxidant enzymes and the translocation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) that predominantly maintained intracellular redox equilibrium. The cancer chemopreventive effects were mediated by Nrf2. Further, lycopene enhanced the expression of autophagy protein p62. Therefore this led to the degradation of Keap1(Kelch ECH associating protein 1), the main protein locking Nrf2 in cytoplasm. In conclusion, our study provides preclinical evidence of the chemopreventive effects of lycopene on cutaneous tumors and reveals the mechanistic link between lycopene’s stimulation of Nrf2 signaling pathway and p62-mediated degradation of Keap1 via the autophagy-lysosomal pathway.

&lt;p&gt;Miconazole Contributes to NRF2 Activation by Noncanonical P62-KEAP1 Pathway in Bladder Cancer Cells&lt;/p&gt;

PurposeNuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, a transcription factor capable of upregulating antioxidant response element (ARE)-mediated expression and cytoprotective proteins, plays critical roles in chemoprevention, inflammation and aging. NRF2 has recently been proposed as a novel target for cancer chemoprevention. The fungicide miconazole has shown promising antiproliferative effects in cancer cells.Materials and MethodsAfter miconazole treatment, the p62-KEAP1-NRF2 activation was analyzed by qPCR and Western blot. The nuclear translocation indicating NRF2 activation was further confirmed by immunofluorescence. Finally, the ROS production was detected by CM-H2DCFDA staining.ResultsWe demonstrate in this study that miconazole dramatically increases NRF2 activation in bladder cancer cells, in a dose- and time-dependent manner. Interestingly, levels of expression of p62, a noncanonical pathway that mediates NRF2 activation, appeared to increase in accordance with NRF2. We also investigated levels of the negative regulator kelch-like ECH-associated protein 1 (KEAP1), which is involved in NRF2 activation. As expected, a decrease in KEAP1 expression was found after miconazole exposure. Confirmation of NRF2 nuclear translocation was monitored by immunofluorescence. Miconazole-induced generation of reactive oxygen species (ROS) promoted NRF2 activation. Pretreatment of bladder cancer cells with ROS scavengers abolished NRF2 expression and nuclear translocation, indicating that miconazole activates the noncanonical p62-KEAP1-NRF2 pathway, which is regulated by ROS production.ConclusionOur study elucidates the mechanisms through which miconazole stimulates NRF2 which may contribute to cancer chemopreventive effects.

Cancer Chemopreventive effect of Rodent Tuber (Typhonium flagelliforme (Lood) Bl) against DMBA-Induced Rats Breast Tumor

Cancer Chemopreventive effect of Rodent Tuber (Typhonium flagelliforme (Lood) Bl) against DMBA-Induced Rats Breast Tumor

Continuity of Tumor Microenvironmental Suppression in AOM/DSS Mice by Fucoxanthin May Be Able to Track With Salivary Glycine.

Fucoxanthin (Fx) is a potent anticancer carotenoid, demonstrated by mouse cancer models. We recently showed the decrease of salivary glycine could represent an attenuation of tumor microenvironment (TME) formation in an azoxymethane/dextran sodium sulfate (AOM/DSS) colon cancer mouse model. However, it remains unclear whether the salivary glycine is an indicator for continuous TME suppression of Fx in the mice. In the present study, we time-dependently analyzed salivary metabolites in AOM/DSS mice, and investigated candidate markers to evaluate the continuous inhibition of colonic TME formation and carcinogenesis in the mice with and without Fx. Fx attenuated the incidence and/or multiplicity of colonic lesions developed in AOM/DSS mice. The number of apoptosis-like cleaved caspase-3high cells was significantly increased, and colonic cancer stem cell-like CD44high/EpCAMhigh cells and cancer-associated fibroblast-like αSMAhigh cells were significantly decreased in colon mucosal tissue by Fx administration. Salivary glycine at 4, 11 and 14 weeks after the final DSS exposure in the Fx-treated mice showed successful and consecutive decreases of 0.5-, 0.4- and 0.7-fold respectively compared to that of control mice. Salivary glycine is a valuable indicator that could evaluate sustained efficacy of cancer chemopreventive effects of Fx in AOM/DSS mice.

Metabolite Storage in Theobroma cacao L. Seed: Cyto-Histological and Phytochemical Analyses.

Cocoa (Theobroma cacao L.), an economically important tropical-fruit crop as source of chocolate, has recently gained a considerable attention; its seeds contain a large amount of different bioactive compounds that have attracted interest because may be beneficial to humans by improving cardiovascular health, by cancer chemo-preventive effects and also through neuroprotective activities. The morphological and anatomical characteristics of cocoa seeds are closely related to the aroma and to the nutritional properties. This study aimed to provide more information about the storage of some metabolites in the various components of cocoa seed by microscopical and phytochemical analyses. Polyphenols, sterols, tocopherols and fatty acids were detected in different portions of the seeds (teguments, cotyledons, embryo axis and pulp). Quali and quantitative differences were observed and a characteristic polyphenol pattern was detected in the different portions of the seed; cytological analysis demonstrated the presence of these compounds in big vacuolated polyphenolic cells. Among the analyzed fatty acids, the stearic and oleic acids were the most abundant in all the seed components (teguments, cotyledons and embryo axis). Fatty acids, usually found in the form of esters, thioesters and amides, represent one of the storage substances of cocoa seed probably localized in lipid globules, which in our observations occupied almost the entire volume of small isodiametric cells of cotyledon mesophyll. In the cocoa seeds we observed also a different distribution of sterols: β-sitosterol and Δ5-avenasterol were the most abundant, above all in the embryo axis; stigmasterol and campesterol were less present in embryo axis and more abundant in teguments; campestanol level was again higher in teguments but lower in cotyledons. The specific localization of different kind of sterols was probably related to a peculiar function. Our experiments demonstrated that all seed components contribute to the metabolites storage, but with interesting differences in the localization and amount of each metabolite.

Therapeutic Activities and Phytochemistry of Physalis Species Based on Traditional and Modern Medicine

Physalis, the fifth largest genus of the Solanaceae family, consists many species which are used as food and natural remedies. Phytochemical investigations on Physalis species have led to characterization of important secondary metabolites such as withaphysalins, physalins and phytosterols which are responsible for wide range of pharmacological effects such as potent cytotoxic activity against various type of human cancer cell lines, immunomodulatory and cancer chemopreventive effects. Theyare widely used in the indigenous system of medicine for treatment of kidney and urinary disorders, leishmaniasis, inflammations, skin infections and etc. Based on Iranian traditional medicine texts, Physalis is effective for treatment of several disorders such as asthma, liver, kidney and bladder dysfunctions, wounds, hemorrhoids, and helminthic diseases. Based on recent surveys, many of the above properties have not been investigated so far except the for the healing effects on liver dysfunction. This review might be a starting point for the development of the new therapeutic applications and more investigations on Physalis species in the future.

Inhibitory effect of purple rice husk extract on AFB1-induced micronucleus formation in rat liver through modulation of xenobiotic metabolizing enzymes

BackgroundRice husk, a waste material produced during milling, contains numerous phytochemicals that may be sources of cancer chemopreventive agents. Various biological activities of white and colored rice husk have been reported. However, there are few comparative studies of the cancer chemopreventive effects of white and colored rice husk.MethodsThis study investigated the cancer chemopreventive activities of two different colors of rice husk using in vitro and in vivo models. A bacterial mutation assay using Salmonella typhimurium strains TA98 and TA100 was performed; enzyme induction activity in murine hepatoma cells was measured, and a liver micronucleus test was performed in male Wistar rats.ResultsThe white rice husk (WRHE) and purple rice husk (PRHE) extracts were not mutagenic in Salmonella typhimurium TA98 or TA100 in the presence or absence of metabolic activation. However, the extracts exhibited antimutagenicity against aflatoxin B1 (AFB1) and 2-amino-3,4 dimethylimidazo[4,5-f]quinolone (MeIQ) in a Salmonella mutation assay. The extracts also induced anticarcinogenic enzyme activity in a murine Hepa1c1c7 hepatoma cell line. Interestingly, PRHE but not WRHE exhibited antigenotoxicity in the rat liver micronucleus test. PRHE significantly decreased the number of micronucleated hepatocytes in AFB1-initiated rats. PRHE contained higher amounts of phenolic compounds and vitamin E than WRHE in both tocopherols and tocotrienols as well as polyphenol such as cyanidin-3-glucoside, protocatechuic acid and vanillic acid. Furthermore, PRHE increased CYP1A1 and 1A2 activities while decreasing CYP3A2 activity in the livers of AFB1-treated rats. PRHE also enhanced various detoxifying enzyme activities, including glutathione S-transferase, NAD(P)H quinone oxidoreductase and heme oxygenase.ConclusionsPRHE showed potent cancer chemopreventive activity in a rat liver micronucleus assay through modulation of phase I and II xenobiotic metabolizing enzymes involved in AFB1 metabolism. Vitamin E and phenolic compounds may be candidate antimutagens in purple rice husk.

Protective Effects of Defatted Sticky Rice Bran Extracts on the Early Stages of Hepatocarcinogenesis in Rats.

Use of natural products is one strategy to lessen cancer incidence. Rice bran, especially from colored rice, contains high antioxidant activity. Cancer chemopreventive effects of hydrophilic purple rice bran extract (PRBE) and white rice bran extract (WRBE) on carcinogen-induced preneoplastic lesion formation in livers of rats were investigated. A 15-week administration of PRBE and WRBE did not induce hepatic glutathione S-transferase placental form (GST-P) positive foci formation as the biomarker of rat hepatocarcinogenesis. PRBE and WRBE at 500 mg/kg body weight significantly decreased number and size of GST-P positive foci in diethylnitrosamine (DEN)-initiated rats. The number of proliferating nuclear antigen positive hepatocytes were also reduced in preneoplastic lesions in both PRBE and WRBE fed DEN-treated rats. Notably, the inhibitory effect on GST-P positive foci formation induced by DEN during the initiation stage was found only in rats treated by PRBE for five weeks. Furthermore, PRBE attenuated the expression of proinflammatory cytokines involving genes including TNF-α, iNOS, and NF-κB. PBRE contained a higher number of anthocyanins and other phenolic compounds and vitamin E. PRBE might protect DEN-induced hepatocarcinogenesis in rats via attenuation of cellular inflammation and cell proliferation. Anthocyanins and other phenolic compounds, as well as vitamin E, might play a role in cancer chemopreventive activity in rice bran extract.