rosmarinic-acid and Colonic-Neoplasms

Previously, we found that rosmarinic acid (RA) exerted anti-inflammatory activities in a dextran sulfate sodium (DSS)-induced colitis model. Here, we investigated the anti-tumor effects of RA on colitis-associated colon cancer (CAC) and the underlying molecular mechanisms. We established an azoxymethane (AOM)/DSS-induced CAC murine model for in vivo studies and used a conditioned media (CM) culture system in vitro. H&E staining, immunohistochemistry, western blot assay, enzyme-linked immunosorbent assay, molecular docking, co-immunoprecipitation, and immunofluorescence assay were utilized to investigate how RA prevented colorectal cancer. In the AOM/DSS-induced CAC murine model, RA significantly reduced colitis severity, inflammation-related protein expression, tumor incidence, and colorectal adenoma development. It significantly modulated toll-like receptor-4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, thus attenuating the expression of anti-apoptotic factors, which mediate transcription factor-dependent tumor growth. In vitro, RA inhibited CM-induced TLR4 overexpression and competitively inhibited TLR4-myeloid differentiation factor 2 complex in an inflammatory microenvironment. Thus, RA suppressed NF-κB and STAT3 activation in colon cancer cells in an inflammatory microenvironment. Therefore, RA suppressed colitis-associated tumorigenesis in the AOM/DSS-induced CAC murine model and abrogated human colon cancer progression in an inflammatory microenvironment by propitiating TLR4-mediated NF-κB and STAT3 activation, pleiotropically.

Topics: Animals; Biomarkers; Cell Line, Tumor; Cinnamates; Colitis-Associated Neoplasms; Colonic Neoplasms; Depsides; Disease Models, Animal; Humans; Immunohistochemistry; Male; Mice; Models, Molecular; NF-kappa B; Rosmarinic Acid; Signal Transduction; STAT3 Transcription Factor; Structure-Activity Relationship; Toll-Like Receptor 4; Xenograft Model Antitumor Assays

To shed light on colon cancer chemoprevention, natural phytochemicals attract researchers by virtue of their beneficial biological effects. The chemopreventive potential of rosmarinic acid (RA) was tested by using the colon carcinogen, 1,2-dimethylhydrazine (DMH) by evaluating the Aberrant crypt foci (ACF), tumour incidence, lipid peroxidative byproducts, phase I & II drug metabolizing enzymes, cell proliferative and apoptotic proteins. Rats were divided into six groups and received modified pellet diet. Group 1 served as control rats, group 2 rats received RA (5mg/kg b.w. p.o.), rats in groups 3-6 received DMH (20mg/kg b.w., s.c.) for the first fifteen weeks. In addition to DMH, groups 4-6 received RA at the dose of 5mg/kg b.w. during initiation, post initiation stages and also for the entire study period. DMH treated rats showed an increase in the development of ACF, tumour formation and multiplicity and decrease in lipid peroxidative byproducts. Moreover, it modulates xenobiotic enzymes and reduces the expressions of proapoptotic proteins; increases expressions of anti apoptotic proteins at the end of the study. Supplementation with RA to carcinogen treated rats protected them from the above deleterious effects caused by DMH and thus RA may be used as a potent chemopreventive agent.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Body Weight; Carcinogenesis; Carcinogens; Cinnamates; Colonic Neoplasms; Depsides; Feces; Gene Expression Regulation, Neoplastic; Intestinal Mucosa; Lipid Peroxidation; Rats; RNA, Messenger; Rosmarinic Acid; Tumor Suppressor Protein p53; Xenobiotics

Rosmarinic acid (RA) is a polyphenolic compound that shows a number of interesting biological activities, such as antiapoptotic, antifibrotic, antioxidant, hepatoprotective, antineurodegenerative, and anti-inflammatory properties. The aim of this study was to investigate the ability of RA to prevent 1,2-dimethylhydrazine (DMH)-induced primary DNA damage and aberrant crypt foci (ACF) in Wistar rat colon. The animals were treated by gavage with doses of 4, 8, and 16 mg/kg body weight/day. Next, the animals received a single subcutaneous injection of 40 mg/kg DMH and were killed 4 h later for the evaluation of DNA damage using the comet assay. In addition, two doses of 40 mg/kg DMH were administered weekly for 2 weeks and the animals were killed 2 weeks after the last injection for the evaluation of ACF formation in rat colon. The results showed that RA exerted no genotoxic/carcinogenic effects. Treatment with different doses of RA combined with DMH led to a significant reduction in the extent of DNA damage and in the frequency of ACF compared with animals treated with DMH alone. These findings suggest that RA reduces DNA damage and suppresses the formation of ACF.

Topics: 1,2-Dimethylhydrazine; Aberrant Crypt Foci; Adenocarcinoma; Animals; Antioxidants; Carcinogenesis; Carcinogens; Cinnamates; Colon; Colonic Neoplasms; Depsides; DNA Damage; Male; Rats; Rats, Wistar; Rosmarinic Acid

Colon cancer is one of the most common cancers in both men and women. The present study is an effort to unravel the anticarcinogenic effects of rosmarinic acid (RA) in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Administration of DMH induces multiple tumors in the rat colon, which mimics human colon cancer.. Male Wistar rats were divided into six groups and fed a high-fat diet. Group 1 served as control, group 2 rats were given RA [5 mg/kg body weight (b.w.)] orally every day for a total period of 30 weeks, and groups 3-6 were given weekly injections of DMH (20 mg/kg b.w. subcutaneous) once a week in the groin for the first 15 weeks. In addition to DMH, groups 4-6 received RA at a dose of 5 mg/kg b.w. during the initiation and postinitiation stages, and also throughout the entire study period. Colon tissues were examined histologically; further, the extent of oxidative stress was assessed by measuring lipid peroxidation and antioxidant levels in the colonic mucosa of rats.. Macroscopic and microscopic tumors were identified in all the groups that received DMH. The results revealed that supplementation with RA significantly inhibited the tumor formation and tumor multiplicity in DMH-treated rats. RA supplementation to DMH-administered rats significantly reduced the cell proliferation markers, namely, argyrophilic nucleolar organizing regions as well as proliferative cell nuclear antigen labeling index. In addition, RA supplementation reduces the expressions of tumor necrosis factor-α, interlukin-6, and cyclooxygenase-2, and modulates the expression of p65.. The above findings clearly underline the chemopreventive efficacy of RA against DMH-induced colon carcinogenesis.

Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; Antioxidants; Cell Proliferation; Cinnamates; Colonic Neoplasms; Depsides; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar; Rosmarinic Acid

Based on the Wnt inhibitors as potential targets in the development of anticancer agents, natural compounds were evaluated for β-catenin-mediated transcriptional activity. A natural lignan hydnocarpin isolated from Lonicera japonica was considered a potential inhibitor for Wnt/β-catenin signalings. The anti-proliferative activity of hydnocarpin was also found to be associated with the suppression of Wnt/β-catenin-mediated signaling pathway in human colon cancer cells. These data suggest that hydnocarpin might be a novel Wnt inhibitor and has a potential of signaling regulator in β-catenin-mediated signaling pathways.

Topics: Antineoplastic Agents, Phytogenic; Axin Protein; beta Catenin; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Flavonolignans; Humans; Lignans; Lonicera; RNA Interference; RNA, Small Interfering; Wnt Proteins; Wnt Signaling Pathway

This study was carried out to investigate the chemopreventive potential of rosmarinic acid (RA) against 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the effect of RA on tumour formation, antioxidant enzymes, cytochrome P450 content, p-nitrophenol hydroxylase and GST activities. Rats were divided into six groups and fed modified pellet diet for the entire experimental period. Group 1 served as control, group 2 received RA (10 mg/kgb.w.). Groups 3-6 were induced colon cancer by injecting DMH (20 mg/kgb.w.) subcutaneously once a week for the first four weeks (groups 3-6). In addition, RA was administered at the doses of 2.5, 5 and 10 mg/kgb.w. to groups 4-6 respectively. DMH treated rats showed large number of colonic tumours; decreased lipid peroxidation; decreased antioxidant status; elevated CYP450 content and PNPH activities; and decreased GST activity in the liver and colon. Supplementation with RA (5 mgkg/b.w.) to DMH treated rats significantly decreased the number of polyps (50%); reversed the markers of oxidative stress (21.0%); antioxidant status (38.55%); CYP450 content (29.41%); and PNPH activities (21.9%). RA at the dose of 5 mg/kgb.w. showed a most pronounced effect and could be used as a possible chemopreventive agent against colon cancer.

Topics: 1,2-Dimethylhydrazine; Animals; Antineoplastic Agents; Antioxidants; Carcinogens; Cinnamates; Colonic Neoplasms; Depsides; Dietary Supplements; Disease Models, Animal; Male; Oxidative Stress; Rats; Rats, Wistar; Rosmarinic Acid

Colorectal cancer is one of the leading causes of cancer related deaths in Western countries and is becoming increasingly common in Asia. Rosmarinic acid (RA), one of the major components of polyphenol possesses attractive remedial features. The purpose of this study is to investigate the possible chemopreventive mechanism of action of RA against 1,2-dimethylhydrazine (DMH) induced rat colon carcinogenesis by evaluating the circulatory antioxidant status and colonic bacterial enzymes activities. Additionally, we analyzed the aberrant crypt foci (ACF) formation and multiplicity in the colon of experimental groups. Wistar male rats were divided into six groups. Group 1 was control rats, group 2 rats received RA (10 mg/kg b.w., p.o. everyday), rats in groups 3-6 received DMH (20 mg/kg b.w., s.c.) for the first 4 weeks. In addition to DMH, groups 4-6 received 2.5, 5, and 10 mg/kg b.w. RA respectively. The results revealed that supplementation with RA significantly reduced the formation of ACF and ACF multiplicity in DMH treated rats. Moreover RA supplementation prevented the alterations in circulatory antioxidant enzymes and colonic bacterial enzymes activities. Overall, our results showed that all three doses of RA inhibited carcinogenesis, though the effect of the intermediary dose of 5 mg/kg b.w. was more pronounced.

Topics: 1,2-Dimethylhydrazine; Aberrant Crypt Foci; Animals; Anticarcinogenic Agents; Antioxidants; Carcinogens; Cinnamates; Colonic Neoplasms; Depsides; Male; Precancerous Conditions; Rats; Rats, Wistar; Rosmarinic Acid

Rosmarinic acid is a major phenylpropanoid isolated from Prunella vulgaris L., which is a composition of herbal tea for centuries in China. However, the anti-invasion activity on Ls174-T human colon carcinoma cells has not been studied. In this study, we investigated the anti-metastasis functions according to wound healing assay, adhesion assay, and Transwell assay and found that rosmarinic acid could inhibit migration, adhesion, and invasion dose-dependently. Rosmarinic acid also could decrease the level of reactive oxygen species by enhancing the level of reduced glutathione hormone. In addition, rosmarinic acid repressed the activity and expression of matrix metalloproteinase-2,9. According to Western blot and quantitative real-time PCR assay, rosmarinic acid may inhibit metastasis from colorectal carcinoma mainly via the pathway of extracellular signal-regulated kinase. In animal experiment, intraperitoneal administration of 2 mg of rosmarinic acid reduced weight of tumors and the number of lung nodules significantly compared with those of control group. Therefore, these results demonstrated that rosmarinic acid can effectively inhibit tumor metastasis in vitro and in vivo.

Topics: Animals; Antioxidants; Cell Line, Tumor; Cinnamates; Colonic Neoplasms; Depsides; Extracellular Signal-Regulated MAP Kinases; Glutathione; Humans; Lung Neoplasms; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Oxidation-Reduction; Reactive Oxygen Species; Rosmarinic Acid; Tumor Burden