Anticarcinogenic Efficacy Research Articles

Antioxidant, Anti-Inflammatory, and Anticarcinogenic Efficacy of an Ayurvedic Formulation: Amritotharanam Kashyam

Amritotharanam Kashyam, a specific Ayurvedic drug, was the focus of the current inquiry to evaluate its efficacy. For liver and digestive-related issues, this medication is suggested. This was obtained from a standard Ayurvedic vendor in Chennai (India), and GC-MS analysis was carried out according to the standard procedure. A few critical biomolecules include benzoic acid, hexadecanoic acid, 6,9-octadecadienoic acid, 9-octadecenoic acid, methyl ester (E)-, heptadecanoic acid, 16-methyl, methyl ester, methyl 18-methylnonadecanoate, tetracosanoic acid, distearin, hexadecanoic acid, and 1-(hydroxymethyl)-1,2-ethanediol ester. The obtained biomolecules exhibited some significant therapeutic functions, including acidification, inhibition of arachidonic acid formation, increase in the aromatic amino acid decarboxylase, suppression of uric acid generation, inhibitors of catechol-O-methyltransferase, urine acidifiers, etc. The anticancer and antiviral potential of these phytocompounds were investigated using molecular docking and dynamics. The phytocompounds pharmacokinetic characteristics were investigated using ADME analysis. Through docking and dynamics simulation, in silico tests demonstrated the phytocompounds' inhibitory efficiency against the target proteins. These functions reasonably relate to the medicinal function of Amritotharanam Kashyam. The MTT assay findings demonstrated this medication’s anticancer effects. The ability to be an effective drug is demonstrated by its antioxidant, anti-inflammatory, and membrane-stabilizing properties.

Anticarcinogenic Efficacy of Fucoxanthin on HepG2 Cell Lines

Introduction: Hepatocellular Carcinoma (HCC) is considered one of the deadliest cancers which grow rapidly worldwide. Fucoxanthin can be acquired from edible brown seaweeds, reported that fucoxanthin has numerous physiological functions and biological abilities, and various medicinal properties. Aim: To evaluate the anti-carcinogenic efficiency of fucoxanthin against the Human Hepatoma Cell Line (HepG2). Materials and Methods: This in-vitro examination and research was carried from June 2018 to August 2018, at Alagappa University, Karaikudi, Tamil Nadu, India. Fucoxanthin at different concentrations was taken to demonstrate its antiproliferative potential and its cytotoxic effect. In this present examination, based on the outcome of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl2H-tetrazolium bromide (MTT) assay, 80 µM and 100µM were chosen for further in-vitro studies. It was noted that remarkable leakage of Lactate Dehydrogenase (LDH) and a noteworthy decrease in the Glutathione (GSH) content of 80µ M and 100µM of fucoxanthin treated HepG2 cells. Under light and fluorescence microscopic examination, there was a significant reduction in cell growth and cell proliferation in the fucoxanthin-treated HepG2 cells. Data were presented as the mean±standard deviation. The one-way analysis of variance (ANOVA) and Tukey’s multiple comparison method were used to find the level of significance. Results: The human HepG2 to be studied and analysed were divided into group I: control group; group II: comprising those cells treated with fucoxanthin in concentration of 80 µM; group III: comprising those cells treated with fucoxanthine in concentration of 100 µM. The results of the MTT assay put forward that fucoxanthin has the cytotoxic and anti-proliferative potential against HepG2 further fucoxanthin significantly alter the marker enzymes level (p-value <0.05). The therapeutic efficiency of fucoxanthin might be due to the antioxidant effect of the bioactive compound. In this present investigation, the results of in-vitro studies, fucoxanthin strongly put forward that it has potential anticarcinogenic efficacy against the hepatic tumour (p-value <0.05). Conclusion: The results of this analysis undoubtedly symbolise that fucoxanthin has anti-oxidant activity and anti-carcinogenic efficacy against primary liver cancer HCC. Due to their therapeutic efficacy, may be considered as an excellent candidate against HCC.

Mechanistic anticarcinogenic efficacy of phytofabricated gold nanoparticles on human lung adenocarcinoma cells

The present study deals with Plectranthus amboinicus (Lour.), multiple potential herbs perceived as a medicinal and culinary adjunct has been used to fabricate gold (Au) nanoparticles (NPs) in an eco-benign fashion. We have primly reported the antioxidant and anticarcinogenic effects of phytofabricated Au NPs towards lung adenocarcinoma (LAC) cells (A549 cell line) in vitro. The herbal concentrate, size and dosage of Au NPs were the key variables that determined the anticarcinogenic efficacy. Results indicated that the herbal concentrate encompassing flavonoids, alkaloids and polyphenolics aided reduction and stabilisation of Au NPs supported by spectral (λ max @ 550 nm) and quantitative analyses. The Fourier transform-infrared spectra anticipated distinct phenolics and protein frequencies involved in Au NPs capping in the course of fabrication. The manipulated Au NPs of 15 nm size has significantly influenced the radical scavenging (48.1 μg) and proliferation pattern of LAC cells (A549) associated with cytotoxic characteristics and IC50 (Au NPs concentration linked with 50% mortality) defined at 16.3 μg/mL in 48 h. This nanotoxicological prospect on the use of nanomaterials as an anticancer agent would be an alternative for the emerging intrinsic resistance of cells to the drug; a great challenge pertaining to safer environmental and biological outcomes.

Folic acid-conjugated magnetic mesoporous silica nanoparticles loaded with quercetin: a theranostic approach for cancer management

The development of drug carriers based on nanomaterials that can selectively carry chemotherapeutic agents to cancer cells has become a major focus in biomedical research. A novel pH-sensitive multifunctional envelope-type mesoporous silica nanoparticle (SBA-15) was fabricated for targeted drug delivery to human colorectal carcinoma cells (HCT-116). SBA-15 was functionalized with folic acid (FA), and the material was loaded with the water-insoluble flavonoid, quercetin (QN). Additionally, acid-labile magnetite Fe3O4 nanoparticles were embedded over the FA-functionalized QN-loaded monodisperse SBA-15 to prepare the highly orchestrated material FA-FE-SBA15QN. The in vitro and in vivo anti-carcinogenic efficacy of FA-FE-SBA15QN was carried out to explore the pH-sensitive QN release with putative mechanistic aspects. FA-FE-SBA15QN caused a marked tumor suppression, and triggered mitochondrial-dependent apoptosis through a redox-regulated cellular signaling system. Furthermore, FA-IO-SBA-15-QN initiated the c-Jun N-terminal Kinase (JNK)-guided H2AX phosphorylation, which relayed the downstream apoptotic signal to the phosphorylate tumor suppressor protein, p53. On the other hand, the selective inhibition of heat shock protein-27 (HSP-27) by FA-FE-SBA15QN augmented the apoptotic fate through JNK/H2AX/p53 axis. The in vitro and in vivo magnetic resonance imaging (MRI) studies have indicated the theranostic perspective of the composite. Thus, the result suggested that the newly synthesized FA-FE-SBA15QN could be used as a promising chemo theranostic material for the management of carcinoma.

Комбинация низких доз глюкозамина и 2-DG усиливает цитотоксический эффект в опухолевых клетках человека в культуре

Химиотерапия опухолей традиционно направлена на ингибирование пролиферации раковых клеток и активацию апоптоза. В данной работе на клетках карциномы (линия HeLaG63) и эндотелиоцитах (линия ECV304) человека проведено сравнительное исследование эффектов низких концентраций (1,5-10мМ) двух аналогов глюкозы: 2-DG и глюкозамина D. Оценка эффективности действия этих агентов проводилась по следующим параметрам: снижение жизнеспособности по МТТ-тесту, изменение проницаемости клеточной мембраны, изменение прогрессии по клеточному циклу, выраженность апоптотической гибели при культивировании клеток в питательной среде с различным содержанием глюкозы. Показано, что 48 часовая обработка 2-DG в исследованных концентрациях приводила к снижению доли клеток в G1 и S-фазах и аккумуляции их в G2\M фазах. Глюкозамин D, в отличие от 2-DG при тех же концентрациях блокировал эти же клетки в G1\S фазе клеточного цикла. При обработке клеток HeLaG63 глюкозамин D оказывал более токсичное действие, чем 2-DG. При сочетанном воздействии 2-DG и глюкозамина D регистрировали существенное увеличение суб- G1-популяции по сравнению с раздельным воздействием. Эффективность обработки увеличивалась при снижении концентрации глюкозы в питательной среде и/или с увеличением дозы агентов. Эндотелиоциты (ECV304) были менее чувствительны, как к действию глюкозамина D, так и 2-DG, и сочетанное воздействие даже при концентрациях 10мМ не отличалось от раздельного воздействия. Обработка клеток 10мМ 2-DG и глюкозамина D приводила к увеличению проницаемости клеточных мембран для флуоресцентного красителя пропидиум йодида, при этом наибольшую эффективность регистрировали для клеток HeLaG63. Chemotherapy for tumors has traditionally been aimed at inhibiting proliferation and activating apoptosis of cancer cells. Aim. To perform a comparative study of effects of two glucose analogues, 2-deoxy-D-glucose (2-DG) and glucosamine D, at low concentrations (1.5-10 mM) on carcinoma cells (HeLaG63 line) and endotheliocytes (ECV304 line). Methods. Efficacy of these agents was evaluated by decreased cell viability (MTT test), permeability of the cell membrane, changes in progression by the cell cycle, and apoptosis (cytometric method) of cells cultured in mediums with different glucose concentrations. Results. The 48-h 2-DG treatment of cells in the studied concentrations reduced the proportion of cells in G1 and S-phases and their accumulation in G2\M phases. The same concentrations of glucosamine D, as distinct from 2-D, blocked the same cells in the G1\S phase of the cell cycle. The same concentrations of glucosamine D were more toxic to carcinoma cells than 2-DG. A combination of 2-DG and glucosamine D significantly greater increased the sub-G1 population of HeLaG63 cells than either agent alone. The treatment effectiveness increased with a decrease in the glucose concentration in the medium and/or with an increase in the agent dose. Endotheliocytes (ECV304) were less sensitive to both glucosamine D and 2-DG, and the effect of their combination did not differ from the effect of either agent alone, even at concentrations of 10 mM. Treatment of cells with 10 mM 2-DG and glucosamine D increased the cell membrane permeability for the fluorescent dye, propidium iodide, with the greatest effect recorded for HeLaG63 cells. Conclusion. Therefore, the anticarcinogenic efficacy of glycolysis inhibitors can be enhanced, which would allow to considerably reduce their doses and avoid potential side effects induced by therapeutically effective drug concentrations.

Celecoxib alleviates AKT/c-Met-triggered rapid hepatocarcinogenesis by suppressing a novel COX-2/AKT/FASN cascade.

Previous studies have demonstrated that the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib shows efficacy against multiple cancers, including hepatocellular carcinoma. However, whether celecoxib is effective in alleviating steatosis during hepatocarcinogenesis is unknown. In a rapid hepatocellular carcinoma (HCC) mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes, we investigated the antisteatotic and anticarcinogenic efficacy of celecoxib in vivo. Multiple HCC cell lines were employed for in vitro evaluation. Additionally, immunoblotting, immunohistochemistry, hematoxylin and eosin staining and Oil Red O staining were applied for mechanistic investigation. The results revealed that if celecoxib was administered in the early stage of AKT/c-Met-induced HCC, it resulted in disease stabilization. Moreover, celecoxib could alleviate lipid accumulation in the HCC mice and in an oleic acid-induced in vitro hepatic steatosis model. Further evidence at the molecular level indicated that celecoxib down-regulated the expression of phospho-ERK (Thr202/Tyr204) and proliferating cell nuclear antigen (PCNA) in the HCC mice. In addition, celecoxib efficiently repressed the phosphor-Akt (Thr308)/fatty acid synthase (FASN) axis both in vivo and in vitro. Altogether, this study suggests that celecoxib exerts its antilipogenic efficacy by targeting a COX-2/AKT/FASN cascade, which contributes to its ability to delay hepatocarcinogenesis.

Anti-proliferative, anti-inflammatory and pro-apoptotic effects ofDunaliella salinaon human KB oral carcinoma cells

This study was aimed to evaluate the antiproliferative, anti-inflammatory, and proapoptotic effects of Dunaliella salina (DS) on KB human oral squamous carcinoma cells. Phytochemical analysis of DS by HPLC revealed the presence of different types of carotenoids like α-carotene, lutein, zeaxanthin, and higher contents of all trans-β-carotene and 9-cis-β-carotene. Antioxidative indexes like reducing capacity, chelating activity, DPPH and superoxide anion scavenging activities were significantly enhanced by treating with DS in dose-depended fashion. Whereas, the in vitro studies with KB cell line showed antiproliferative/cytotoxic effects of DS by suppressing the KB cell count. Meanwhile, the anti-inflammatory property of DS was confirmed by downregulating the protein expression of COX-2 in DS treated group. Also, DS extract would trigger apoptosis of KB cell in a dose-depended manner. Based on the above results, it clearly displays its anticarcinogenic efficacy, however, further studies are needed to explore the in-depth mechanism behind its chemotherapeutic property. Practical applications DS is a type of microalgae found in salty lakes and considered as the richest source of β-carotene than any other plant-based products. DS exhibit various biological properties like antioxidant, anti-inflammatory, immunomodulatory, and therefore used as a nutraceutical agent by several pharmaceutical companies. Also, DS has been utilized by the tradition medicine practitioners in Asian countries like China, and Japan to treat various ailments like wound healing, vomiting, and ulcer. Modern researchers also hinted that DS are effective against many metabolic syndromes as well as several types of cancer. However, till date, no studies exist on the anticancer effect of DS (carotenoids) related to oral cancer. The present study indicates that DS could exert antioxidative, antiproliferative, anti-inflammatory, and proapoptotic effects and thus endorse its anticarcinogenic effect. Hence, in future, it might be used for treating oral cancer as an adjuvant therapy along with standard chemotherapeutic agents.

Stathmin overexpression is associated with growth, invasion and metastasis of lung adenocarcinoma.

Stathmin has been investigated as a tumor biomarker because it appear to be associated with tumorigenesis; however, the effect of stathmin in lung adenocarcinoma (LAC) remains poorly understood. The purpose of this study was to examine the expression of stathmin in lung adenocarcinoma, and to disclose the relationship between them. The expression of stathmin was examined by RT-PCR, IHC and Western blot. Furthermore, small interfering RNA (shRNA)-mediated silencing of stathmin was employed in LAC cells to investigate cell proliferation, invasion and apoptosis. In this study, we showed that overexpression of stathmin was significantly associated with poorly differentiated, lymph node metastasis and advance TNM stages of lung adenocarcinoma. And silencing of stathmin expression inhibited the proliferation, migration and invasion of lung adenocarcinoma PC-9 cells, and retarded the growth of PC-9 cells xenografts in nude mice. Additionally, the anticarcinogenic efficacy of stathmin silencing might be involved in P38 and MMP2 signaling pathways. In conclusion, these results showed that stathmin expression was significantly up-regulated in LAC, which may act as a biomarker for LAC. Furthermore, silence of stathmin inhibiting LAC cell growth indicated that stathmin may be a promising molecular target for LAC therapy.

Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer.

The establishment of docetaxel-based chemotherapeutic treatments has improved the survival of castration-resistant prostate cancer (CRPC) patients. However, most patients develop resistance supporting the development of therapy. The current study was undertaken to establish the therapeutic benefit to target hedgehog signaling cascade using GDC-0449 to improve the efficacy of chemotherapeutic drug, docetaxel. Here, we show that the combination of GDC-0449 plus docetaxel inhibited the proliferation of WPE1-NB26 cells and PC3 cells via a blockade of G1 and G2M phases. The combined treatment significantly inhibited PC cell migration in vitro. Moreover, the apoptotic effect induced by GDC-0449 plus docetaxel on PC3 cells was mediated, at least partly, via the mitochondrial membrane depolarization, H2O2 production and caspase cascade activation. Interestingly, GDC-0449 was effective at inhibiting the prostasphere formation, inducing the prostasphere disintegration and apoptotic death of side population (SP) from PC3 cells and reversing the resistance of SP cells to docetaxel. In addition, GDC-0449 plus docetaxel also have shown a greater anti-tumoral growth inhibitory effect on PC3 cell xenografts. These findings support the use of the hedgehog inhibitor GDC-0449, which is currently in clinical trials, for improving the anticarcinogenic efficacy of docetaxel-based chemotherapeutic treatments against locally advanced, AI and metastatic PC.

Novel Lignan and Stilbenoid Mixture Shows Anticarcinogenic Efficacy in Preclinical PC-3M-luc2 Prostate Cancer Model

Prostate cancer is the most common cancer of men in the Western world, and novel approaches for prostate cancer risk reduction are needed. Plant-derived phenolic compounds attenuate prostate cancer growth in preclinical models by several mechanisms, which is in line with epidemiological findings suggesting that consumption of plant-based diets is associated with low risk of prostate cancer. The objective of this study was to assess the effects of a novel lignan-stilbenoid mixture in PC-3M-luc2 human prostate cancer cells in vitro and in orthotopic xenografts. Lignan and stilbenoid –rich extract was obtained from Scots pine (Pinus sylvestris) knots. Pine knot extract as well as stilbenoids (methyl pinosylvin and pinosylvin), and lignans (matairesinol and nortrachelogenin) present in pine knot extract showed antiproliferative and proapoptotic efficacy at ≥40 μM concentration in vitro. Furthermore, pine knot extract derived stilbenoids enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis already at ≥10 μM concentrations. In orthotopic PC-3M-luc2 xenograft bearing immunocompromized mice, three-week peroral exposure to pine knot extract (52 mg of lignans and stilbenoids per kg of body weight) was well tolerated and showed anti-tumorigenic efficacy, demonstrated by multivariate analysis combining essential markers of tumor growth (i.e. tumor volume, vascularization, and cell proliferation). Methyl pinosylvin, pinosylvin, matairesinol, nortrachelogenin, as well as resveratrol, a metabolite of pinosylvin, were detected in serum at total concentration of 7−73 μM, confirming the bioavailability of pine knot extract derived lignans and stilbenoids. In summary, our data indicates that pine knot extract is a novel and cost-effective source of resveratrol, methyl pinosylvin and other bioactive lignans and stilbenoids. Pine knot extract shows anticarcinogenic efficacy in preclinical prostate cancer model, and our in vitro data suggests that compounds derived from the extract may have potential as novel chemosensitizers to TRAIL. These findings promote further research on health-related applications of wood biochemicals.

Synergistic and individual effects of umbelliferone with 5-flurouracil on the status of lipid peroxidation and antioxidant defense against 1, 2-dimethylhydrazine induced rat colon carcinogenesis

5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers including colon cancer, but its chemoresistance remains as a major obstacle in clinical settings. Towards this goal, we evaluated the in vivo efficacy of umbelliferone (UMB) with 5-flurouracil (5-fu) against 1, 2-dimethylhydrazine (DMH) induced colon carcinogenesis in rats. Rats were divided into seven groups of six rats each. Rats in group 1 received high fat diet and served as control, group 2 rats received high fat diet with DMH (20mg/kg body weight) once a week subcutaneously for the first 15weeks which represent the colon cancer bearing rats. Group 3 rats received umbelliferone via intragastric injection at a daily dose of 30mg/kg body weight for 30weeks every day. Groups 4–7 rats received high fat diet with DMH (20mg/kg body weight) as in group 2. In addition group 4 rats (initiation) received UMB starting 1week before 1st DMH injection and continued till the end of last DMH injection, group 5 rats (post-initiation) received UMB after 1 week of last DMH injection and continued till the end of the experimental period, group 6 rats (Entire period) received UMB throughout the experimental period. Group 7 cancer bearing rats received 5-flurouracil (100mg/kg body weight) once a week intravenously for first 4weeks and UMB was given as in group 6 throughout the experimental period of 30 weeks Levels of glutathione-s-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), glutathione reductase (GR) and reduced glutathione (GSH) decreased following DMH treatment, and also the levels of lipid peroxidation end products like thiobarbituric acid substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dines (CD) were significantly decreased in DMH-treated rats. Administration of UMB alone and combined effect of UMB with 5-Fu significantly reversed these activities to near normal, which concludes the anti-carcinogenic efficacy of UMB. This effect was further confirmed by histopathological studies and finally proved that UMB as an effective and potential chemotherapeutic agent against DMH-induced colon carcinogenesis.

Potential applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy

Curcumin has attracted great attention in the therapeutic arsenal in clinical oncology due to its chemopreventive, antitumoral, radiosensibilizing and chemosensibilizing activities against various types of aggressive and recurrent cancers. These malignancies include leukemias, lymphomas, multiple myeloma, brain cancer, melanoma and skin, lung, prostate, breast, ovarian, liver, gastrointestinal, pancreatic and colorectal epithelial cancers. Curcumin mediates its anti-proliferative, anti-invasive and apoptotic effects on cancer cells, including cancer stem/progenitor cells and their progenies, through multiple molecular mechanisms. The oncogenic pathways inhibited by curcumin encompass the members of epidermal growth factor receptors (EGFR and erbB2), sonic hedgehog (SHH)/GLIs and Wnt/β-catenin and downstream signaling elements such as Akt, nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription (STATs). In counterbalance, the high metabolic instability and poor systemic bioavailability of curcumin limit its therapeutic efficacy in human. Of great therapeutic interest, the selective delivery of synthetic analogs or nanotechnology-based formulations of curcumin to tumors, alone or in combination with other anticancer drugs, may improve their chemopreventive and chemotherapeutic efficacies against cancer progression and relapse. Novel curcumin formulations may also be used to reverse drug resistance, eradicate the total cancer cell mass and improve the anticarcinogenic efficacy of the current anti-hormonal and chemotherapeutic treatments for patients with various aggressive and lethal cancers.

Chemomodulation of the antioxidative enzymes and peroxidative damage in the colon of 1,2‐dimethyl hydrazine‐induced rats by ellagicacid

Prevention of cancer remains a primary need and new chemopreventive agents must be developed for this purpose. Toward this goal, a chemopreventive study was conducted to evaluate the potential effect of ellagic acid (EA) against 1,2-dimethylhydrazine (DMH-) induced colon carcinogenesis in experimental rats. Rats were administered with DMH (20mg/kg body weight) subcutaneous injection once a week for 15 weeks and were supplemented with EA (60 mg/kg body weight/day orally). In the present study, the efficacy of EA on the formation of aberrant crypt foci (ACF), levels of lipid peroxidation (LPO) and activities of enzymic and non-enzymic antioxidants in DMH-induced colon-cancer-bearing rats were assessed. After the experimental period, frequency of ACF, levels of LPO were found to be increased, whereas a significant decrease in the activities of enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase) and non-enzymic antioxidants (reduced glutathione, vitamin C and vitamin E) were observed in DMH-induced rats. Supplementation of EA attenuated all these alterations to near normal levels, which indicates the anti-carcinogenic efficacy of EA. This effect was further confirmed by histopathological studies. The results obtained in the present study suggest EA as an effective chemopreventive agent on colon carcinogenesis induced by DMH.

Chemopreventive effects of 13α,14α-epoxy-3β-methoxyserratan-21β-ol (PJJ-34), a serratane-type triterpenoid, in a rat multi-organ carcinogenesis bioassay

A novel serratane-type triterpenoid, 13α,14α-epoxy-3β-methoxyserratan-21β-ol (PJJ-34) derived from cuticles of Picea jezoensis Carr. var. jezoensis, has proved to be highly effective at suppressing carcinogenesis both in vitro and in vivo. To investigate possible anti-carcinogenic efficacy at the whole-body level, male Fischer 344 rats were subjected to an established rat multi-organ carcinogenesis bioassay (DMBDD model). After initiation with five carcinogens, groups 1–3 (20 in each) were intragastrically (i.g.) administered PJJ-34 dissolved in 1 ml of 0.5% CMC (5 times/week) at doses of 0, 5 and 10 mg/kg body weight (b.w.), respectively, until the end of week 30. PJJ-34 did not show apparent toxicity. Incidences of adenomas (100 → 75%) and carcinomas (63 → 30%) in the lung were significantly decreased in the 5 mg/kg b.w. group, and multiplicity of alveolar hyperplasias and total lung tumors (adenomas + carcinomas) were significantly reduced by both 5 and 10 mg/kg. The incidence of colorectal tumors was also significantly decreased in the 10 mg/kg group (63 → 28%) along with the multiplicity. Rat liver pre-neoplastic lesions, glutathione S-transferase placental form (GST-P) foci, and tumor development in the other organs were not affected. Immunohistochemical indices for proliferating cell nuclear antigen (PCNA) and cyclin D1 in normal alveolar epithelium of the lung were significantly suppressed at both doses. In conclusion, PJJ-34 is chemopreventive against lung and colon carcinogenesis without exerting apparent toxicity, and suppression of cell proliferation could play a key role in the underlying mechanisms.

Anticarcinogenic efficacy of phytic acid extracted from rice bran on azoxymethane-induced colon carcinogenesis in rats

This study is carried out to determine the potential of phytic acid extracted from rice bran in the suppression of colon carcinogenesis induced by azoxymethane (AOM) in rats. Seventy-two male Sprague-Dawley rats were divided into 6 groups with 12 rats in each group. The intended rats for cancer treatment received two intraperitoneal injections of AOM in saline (15mg/kg bodyweight) over a 2-week period. The treatments of phytic acid were given in two concentrations: 0.2% (w/v) and 0.5% (w/v) during the post-initiation phase of carcinogenesis phase via drinking water. The colons of the animals were analyzed for detection and quantification of aberrant crypt foci (ACF) after 8 weeks of treatment. The finding showed treatment with 0.2% (w/v) extract phytic acid (EPA) gave the greatest reduction in the formation of ACF. In addition, phytic acid significantly suppressed the number of ACF in the distal, middle and proximal colon as compared to AOM alone (p<0.05). For the histological classification of ACF, treatment with 0.5% (w/v) commercial phytic acid (CPA) had the highest percentage (71%) of non-dysplastic ACF followed by treatment with 0.2% (w/v) EPA (61%). Administration of phytic acid also reduced the incidence and multiplicity of total tumors even though there were no significant differences between groups. In conclusion, this study found the potential value of phytic acid extracted from rice bran in reducing colon cancer risk in rats.

Protection Against Photoaging in the Hairless Mouse by the Isoflavone Equol

Topical application of the isoflavone equol immediately following solar-simulated UV (SSUV) radiation exposure has previously been demonstrated to have significant photoprotective effects. Equol reduced both the inflammatory edema and the systemic suppression of the contact hypersensitivity reaction in hairless mice. Furthermore, daily topical equol application immediately following irradiation during a 10-week chronic SSUV exposure regime also reduced photocarcinogenesis severity in the mouse. This study examines the potential for topical equol to prevent photoaging in response to chronic SSUV irradiation for up to 30 weeks. We did not find consistent expression of the characteristic markers of photoaging until 30 weeks, although moderate epidermal hyperplasia and a transient increase in dermal mast cell numbers were evident after 1 week. Daily application of 10 muM equol lotion significantly reduced these early changes. However after 30 weeks of SSUV exposure, photoaging was well developed, as shown histologically by markedly increased epidermal hyperplasia, increased dermal mast cell number, pronounced focal elastotic deposits, degraded dermal collagen and deposition of glycosaminoglycans in the lower dermis. Topical equol treatment protected significantly from each of these impairments, as demonstrated histologically and quantitatively. Additionally, equol was found to have strong antioxidant action against acute UVA (320-400 nm)-induced lipid peroxidation of mouse skin, this property accounting for its antiphotoaging mechanism. The evidence for equol's antiphotoaging activity, taken together with its anti-inflammatory, immunoprotective and anticarcinogenic efficacy against SSUV irradiation in the mouse, suggests that equol could be developed as a helpful topical photoprotective agent for daily use by humans.

Molecular and biochemical characterization of the selenocysteine Se-methyltransferase gene and Se-methylselenocysteine synthesis in broccoli.

Selenium (Se) plays an indispensable role in human nutrition and has been implicated to have important health benefits, including being a cancer preventative agent. While different forms of Se vary in their anticarcinogenic efficacy, Se-methylselenocysteine (SeMSC) has been demonstrated to be one of the most effective chemopreventative compounds. Broccoli (Brassica oleracea var. italica) is known for its ability to accumulate high levels of Se with the majority of the selenoamino acids in the form of Se-methylselenocysteine. Therefore, it serves as a good model to study the regulation of SeMSC accumulation in plants. A cDNA encoding selenocysteine Se-methyltransferase, the key enzyme responsible for SeMSC formation, was cloned from broccoli using a homocysteine S-methyltransferase gene probe from Arabidopsis (Arabidopsis thaliana). This clone, designated as BoSMT, was functionally expressed in Escherichia coli, and its identity was confirmed by its substrate specificity in the methylation of selenocysteine. The BoSMT gene represents a single copy sequence in the broccoli genome. Examination of BoSMT gene expression and SeMSC accumulation in response to selenate, selenite, and sulfate treatments showed that the BoSMT transcript and SeMSC synthesis were significantly up-regulated in plants exposed to selenate but were low in plants supplied with selenite. Simultaneous treatment of selenate with selenite significantly reduced SeMSC production. In addition, high levels of sulfate suppressed selenate uptake, resulting in a dramatic reduction of BoSMT mRNA level and SeMSC accumulation. Our results reveal that SeMSC accumulation closely correlated with the BoSMT gene expression and the total Se status in tissues and provide important information for maximizing the SeMSC production in this beneficial vegetable plant.

The metabolism of sulindac enhances its scavenging activity against reactive oxygen and nitrogen species.

Sulindac is a sulfoxide prodrug that, in vivo, is converted to the metabolites sulindac sulfide and sulindac sulfone. It is therapeutically used as an anti-inflammatory and analgesic in the symptomatic treatment of acute and chronic rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. In addition to its anti-inflammatory properties, sulindac and its metabolites have been shown to have an important role in the prevention of colonic carcinogenesis. Although the inhibition of prostaglandin synthesis constitutes the primary mechanism of action of sulindac, it is well known that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are implicated in the pathophysiology of inflammation and cancer. Thus, the aim of this study was to evaluate the scavenging activity of sulindac and its sulfone and sulfide metabolites for an array of ROS (HO*, O2(*-), and HOCl) and RNS (*NO and ONOO-) using in vitro systems. The results we obtained demonstrate that the metabolism of sulindac increases its scavenging activity for all RNS and ROS studied, notably with regard to the scavenging of HOCl. These effects may strongly contribute to the anti-inflammatory and anticarcinogenic efficacy that has been shown for sulindac.

Anticarcinogenic Properties of a Daidzein-Rich Fraction Isolated from Soybean

In a previous study, we demonstrated that the methanol extract of soybean powder contains an active component(s) that promotes the differentiation of HL-60 cells. Partial purification of the extract, using solvent fractionation and silica gel chromatography, produced an active fraction rich in daidzein. The daidzein-rich fraction (DRF) was evaluated for its cancer preventive potential by assessing its cytotoxic activity and effect on the expression of the transforming growth factor beta (TGF-beta) family of cytokines and their receptors. DRF appeared to exert cytotoxic activity via an apoptotic pathway as evaluated by a DNA fragmentation assay and caspase-3 induction. DRF also increased the expression of TGF-beta2, but had little effect on the expression of other members of the TGF-beta family of cytokines and their receptors, or on the expression of the vascular endothelial growth factor gene. In conclusion, the DRF isolated from the methanol extract of soybean may have the potential to prevent tumorigenesis and, therefore, deserves to undergo further evaluation of its active component(s) and in vivo evaluation for anticarcinogenic efficacy.

The Cancer Preventive Flavonoid Silibinin Causes Hypophosphorylation of Rb/p107 and Rb2/p130 Via Modulation of Cell Cycle Regulators in Human Prostate Carcinoma DU145 Cells

Phosphorylation status of retinoblastoma (Rb) and related proteins is important to drive cell cycle progression. In hyperphosphorylated state, they are growth stimulatory, but their hypophosphorylation is growth inhibitory. Here we assessed whether silibinin causes hypophosphorylation of Rb-related proteins as its growth inhibitory response in human prostate cancer (PCA) DU145 cells. Silibinin treatment of cells resulted in a strong increase (up to 2.3-and 5.4-fold) in the levels of hypophosphorylated Rb/p107 and Rb2/p130, respectively, but a strong decrease (91, 78 and 45%) in protein levels of transcription factors E2F3, E2F4 and E2F5, respectively. In the studies analyzing whether this effect of silibinin is via modulation of cell cycle regulators, silibinin-treated cells showed a strong increase (up to 13- and 6-fold) in Cip1/p21 and Kip1/p27 levels, respectively. Silibinin treatment also resulted in 90 and 70% decrease in CDK4 and CDK2 levels, respectively, but did not alter the protein levels of cyclin D1 and cyclin E. Consistent with its effect on G1 cell cycle regulators, silibinin treated cells exhibited a strong G1 arrest, almost complete growth inhibition, and morphological changes suggestive of differentiation. Together, these results suggest that silibinin caused hypophosphorylation of Rb-related proteins may in part be responsible for its cancer preventive and anti-carcinogenic efficacy in different cancer models including PCA. Key Words:Silibinin, Retinoblastoma, Cell cycle, CDKI, CDK, Cyclin