Dataset Information

Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer.

ABSTRACT: Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer.Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by vitamin D3 (VitD3), and AOM-treated by 5-FU?+?vitamin D3 (5-FU/D). The study duration was 15 weeks. AOM was injected subcutaneously for 2 weeks (15 mg/kg/week). 5-FU was injected intraperitoneally in the 9th and 10th weeks post AOM (8 total injections were given: 12 mg/kg/day for 4 successive days, then 6 mg/kg every other day for another 4 doses) and oral vitamin D3 (500 IU/rat/day; 3 days/week) was given from week 7 post AOM till the last week of the study. The colons were collected following euthanasia for gross and histopathological examination. The expression of ?-catenin, transforming growth factor-?1 (TGF-?1), TGF-? type 2 receptor (TGF-?R2), smad4, inducible nitric oxide synthase (iNOS), and heat shock protein-90 (HSP-90) proteins was measured by immunohistochemistry. In colonic tissue homogenates, quantitative RT-PCR was used to measure the mRNA expression of Wnt, ?-catenin, Dickkopf-1 (DKK-1) and cyclooxygenase-2 (COX-2) genes, while ELISA was used to measure the concentrations of TGF-?1, HSP-90 and COX-2 proteins.Monotherapy with 5-FU or vitamin D3 significantly decreased the number of grown tumours induced by AOM (P?

SUBMITTER: Refaat B

PROVIDER: S-EPMC4513788 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer.

Refaat Bassem B El-Shemi Adel Galal AG Kensara Osama Adnan OA Mohamed Amr Mohamed AM Idris Shakir S Ahmad Jawwad J Khojah Athar A

Journal of experimental & clinical cancer research : CR 20150725

<h4>Background</h4>Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer.<h4>Methods</h4>Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by ...[more]

PMID: 26205949

Similar Datasets

Project description:BackgroundAcanthus ilicifolius, a mangrove medicinal plant, is traditionally used to treat a variety of diseases. The aim of this research is to assess the chemoprotective outcomes of A. ilicifolius ethanolic extract against azoxymethane (AOM) induced colonic aberrant crypt foci (ACF) in rats.Methodology/principal findingsIn our study, rats were arranged in to five groups. Rats in the normal control group were given subcutaneous injections of normal saline once weekly for 2 weeks. The AOM control, reference and treatment groups were given subcutaneous injection of AOM, 15 mg/kg body weight, once weekly for 2 weeks each. The reference group was treated with 35 mg/kg 5-Fluorouracil via intraperitoneal injection once weekly for 8 weeks, and the treatment groups were administered by gavage with 250 and 500 mg/kg A. ilicifolius extract daily for 8 weeks. Both normal and AOM control groups received the vehicle; 10% Tween-20 only. Rats treated with 250 mg/kg and 500 mg/kg of A. ilicifolius extracts showed a decrease in the mean number of ACF by 65% and 53%, respectively. Those fed with A. ilicifolius showed significantly decreased multiplicity of ACF formations when compared with the results from the AOM control group. The 250 mg/kg A. ilicifolius treatment group showed significant decreases in lipid peroxidation MDA levels when compared with the AOM control group. In immunohistochemistry staining, the proliferating nuclear cell antigen (PCNA)-positive cells were significantly higher in the AOM control group than in the A. ilicifolius-treated groups. RT-PCR showed that A. ilicifolius caused a change in the regulation of apoptosis-related genes expression.Conclusion/significanceThe results of the current study show that AOM-treated rats receiving oral exposure to A. ilicifolius demonstrated a significant decrease in the number of ACF in the colon when compared to AOM-treated rats receiving vehicle only. A ilicifolius may be an effective herbal approach for the prevention of AOM-induced ACF in the rat colon.

Project description:Epidemiological evidence suggests that a diet abundant in fruits and vegetables may protect against colon cancer. Bioactive compounds, including flavonoids and limonoids, have been shown to possess antiproliferative and antitumorigenic effects in various cancer models. This experiment investigated the effects of four citrus flavonoids and one limonoid mixture at the promotion stage of chemically induced colon cancer in rats. Male Sprague-Dawley rats (n = 10 rats/group) were randomly allocated to one of six diets formulated to contain 0.1% apigenin, 0.02% naringenin, 0.1% hesperidin, 0.01% nobiletin, 0.035% limonin glucoside/obacunone glucoside mixture or a control diet (0% flavonoid/limonoid). Rats received experimental diets for 10 weeks and were injected with azoxymethane (15 mg/kg) at weeks 3 and 4. Excised colons were evaluated for aberrant crypt foci (ACF) formation, colonocyte proliferation (proliferating cell nuclear antigen assay), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay) and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) (immunoblotting). When compared with the control diet, apigenin lowered the number of high multiplicity ACF (HMACF >4 aberrant crypts/focus) by 57% (P < 0.05), while naringenin lowered both the number of HMACF by 51% (P < 0.05) and the proliferative index by 32% (P < 0.05). Both apigenin and naringenin increased apoptosis of luminal surface colonocytes (78% and 97%, respectively; P < 0.05) when compared with the control diet. Hesperidin, nobiletin and the limonin glucoside/obacunone glucoside mixture did not affect these variables. The colonic mucosal protein levels of iNOS or COX-2 were not different among the six diet groups. The ability of dietary apigenin and naringenin to reduce HMACF, lower proliferation (naringenin only) and increase apoptosis may contribute toward colon cancer prevention. However, these effects were not due to mitigation of iNOS and COX-2 protein levels at the ACF stage of colon cancer.

Project description:Background: 5-Fluorouracil (5-FU) represents one of the major constituents of chemotherapy combination regimens in colon cancer (CRC) treatments; however, this regimen is linked with severe adverse effects and chemoresistance. Thus, developing more efficient approaches for CRC is urgently needed to overcome these problems and improve the patient survival rate. Currently, 17β-estradiol (E2) has gained greater attention in colon carcinogenesis, significantly lowering the incidence of CRC in females at reproductive age compared with age-matched males. Aims: This study measured the effects of E2 and/or 5-FU single/dual therapies on cell cycle progression and apoptosis against human HT-29 female and SW480 male primary CRC cells versus their impact on SW620 male metastatic CRC cells. Methods: The HT-29, SW480, and SW620 cells were treated with IC50 of E2 (10 nM) and 5-FU (50 μM), alone or combined (E+F), for 48 h before cell cycle and apoptosis analyses using flow cytometry. Results: The data here showed that E2 monotherapy has great potential to arrest the cell cycle and induce apoptosis in all the investigated colon cancer cells, with the most remarkable effects on metastatic cells (SW620). Most importantly, the dual therapy (E+F) has exerted anti-cancer activities in female (HT-29) and male (SW480) primary CRC cells by inducing apoptosis, which was preferentially provoked in the sub-G1 phase. However, the dual treatment showed the smallest effect in SW620 metastatic cells. Conclusion: this is the first study that demonstrated that the anti-cancer actions of 17β-estradiol and 5-Fluorouracil dual therapy were superior to the monotherapies in female and male primary CRC cells; it is proposed that this treatment strategy could be promising for the early stages of CRC. At the same time, 17β-estradiol monotherapy could be a better approach for treating the metastatic forms of the disease. Nevertheless, additional investigations are still required to determine their precise therapeutic values in CRC.

Project description:In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a result of combined therapy. In HT-29 tumors and in cells from in vitro culture, we observed increased vitamin D receptor (VDR) expression after treatment with either PRI-2205 or 5-FU alone, or in combination. Moreover, PRI-2205 decreased the percentage of cells from intestinal tumors in G2/M and S stages and increased sub-G1. Increased VDR expression was also observed after combined treatment of mice with 5-FU and PRI-2191. Moreover, our docking studies showed that PRI-2205 has stronger affinity for VDR, DBP and CAR/RXR ligand binding domains than PRI-2191. PRI-2191 analog, used with 5-FU, increased the percentage of subcutaneous tumor cells in G0/G1 and decreased the percentage in G2/M, S and sub-G1 populations as compared to 5-FU alone. In in vitro studies, we observed increased expression of p21 and p-ERK1/2 diminution via use of both analogs as compared to use of 5-FU alone. Simultaneously, PRI-2191 antagonizes some pro-apoptotic activities of 5-FU in vitro. However, in spite of these disadvantageous effects in terms of apoptosis, the therapeutic effect expressed as tumor growth retardation by PRI-2191 is significant. Our results suggest that the mechanism of potentiation of 5-FU antitumor action by both analogs is realized via increased p21 expression and decreased p-ERK1/2 level which may lead to diminution of thymidylate synthase expression. Higher binding affinity for VDR, DBP, but also for CAR\RXR ligand binding domain of PRI-2205 may, in part, explain its very low toxicity with sustained anticancer activity.

Dataset Information

Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer.

Publications

Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets