Anticancer activity of Pseudomonas aeruginosa derived peptide with iRGD in colon cancer therapy.

Objectives: Colon cancer is well-known as a life-threatening disease. Since the current treatment modalities for this type of cancer are powerful yet face some limitations, finding novel treatments is required to achieve better outcomes with fewer side effects. Here we investigated the therapeutic potential of Azurin-p28 alone or along with iRGD (Ac-CRGDKGPDC-amide) as a tumor-penetrating peptide and 5-fluorouracil (5-FU) for colon cancer. Materials and Methods: Inhibitory effect of p28 with or without iRGD/5-FU was studied in CT26 and HT29, as well as the xenograft animal model of cancer. The effect of p28 alone or along with iRGD/5-FU on cell migration, apoptotic activity, and cell cycle of the cell lines was assessed. Level of the BAX and BCL2 genes, tumor suppressor genes [(p53 and collagen type-Iα1 (COL1A1), collagen type-Iα2 (COL1A2)] were assessed by quantitative RT-PCR. Results: These findings show that using p28 with or without iRGD and 5-FU raised the level of p53 and BAX but decreased BCL2, compared with control and 5-FU groups in tissues of the tumor, which result in raising the apoptosis. Conclusion: It seems that p28 may be used as a new therapeutic approach in colon cancer therapy that can enhance the anti-tumor effect of 5-FU.

Angiotensin II Receptor Antagonist, Valsartan, Has Beneficial Effect in Lung Metastasis of Colorectal Cancer Treated with Fluorouracil.

PURPOSE: Lung metastasis is the main cause of death in patients with colorectal carcinoma (CRC). Angiotensin II has been confirmed to facilitate cancer cell progression and metastasis. In this study, the possible anti-metastatic effects of an angiotensin II receptor type 1 (AT1R) antagonist, valsartan, have been investigated in an experimental CRC lung metastasis model. METHODS: An animal CRC lung metastasis model was used, involving intravenous injection of CRC cells. The experimental groups included (1) control group; (2) 5-FU (5-fluorouracil) group (5 mg/kg/every other day; ip); (3) valsartan group (40 mg/kg/day; po); and (4) valsartan + 5-FU group (combination group; valsartan 40 mg/kg/day, oral gavage, and 5-FU 5 mg/kg/every other day; ip). After 11 days, macroscopic and histological evaluations of lung tissues have been done for evaluation of lung metastatic nodules. In addition, inflammatory and angiogenic markers and oxidative stress index were measured in lung tissue. RESULTS: Our results showed that administration of valsartan especially in combination with 5-FU significantly reduced lung metastatic nodule and metastatic area (p < 0.05) in macroscopic and histological evaluations stained by hematoxylin-eosin. Measurement of inflammatory, angiogenic, and oxidative/antioxidative markers in lung tissue indicated that the level of IL-6, angiogenic markers (VEGF and VEGFR-1), and antioxidative markers significantly reduced in combination group (p < 0.05) while the MDA as a marker of oxidative stress increased (p < 0.05). CONCLUSION: These results suggest that valsartan in combination with standard chemotherapeutic agents can have a synergistic effect in treatment of lung metastasis of CRC.

The photocatalytic, cytotoxicity, and antibacterial properties of zinc oxide nanoparticles synthesized using Trigonella foenum-graecum L extract.

In this study, the manufacture of zinc oxide nanoparticles (ZnO-NPs) was completed via the sol-gel method with Trigonella foenum-graecum L extract for the first time to function as the stabilizing and reducing agent. The obtained product was investigated by various analyzing procedures such as TGA/DTG, FT-IR, UV-Vis, XRD, and EDX/FESEM. The calcination of our product was conducted at temperatures of 400, 500, and 600 °C. In conformity to the XRD pattern, heightening the temperature of calcination caused an enlargement in the size of nanoparticles. The photocatalytic performance of ZnO-NPs was evaluated to degrade methylene blue and Eriochrome black T (EBT) dyes under UV light, which resulted in a degradation percentage of about 96% and 94%, after 90 min, respectively. There has been some evidence suggesting that the green synthesis of ZnO-NPs has increased their use in medicine. The outcomes of examining the cytotoxicity effect of this product against the Huh-7 cell line by the performance of the MTT assay were indicative of an IC50 of around 62.5 µg/mL. Finally, according to the results of the broth microdilution method, which was performed to assess the antibacterial activity of ZnO-NPs towards gram-positive and gram-negative bacteria, the value of MIC was in the range of 31 to 125 µg/mL. The obtained results from biological studies confirm the antibacterial and anticancer properties of ZnO-NPs, which are promising for applying NPs in medical fields.

Facile green synthesis of Ag-doped ZnO/CaO nanocomposites with Caccinia macranthera seed extract and assessment of their cytotoxicity, antibacterial, and photocatalytic activity.

The current paper exhibited a green method for the manufacture of Ag-doped ZnO/CaO nanocomposites (NCPs) by the usage of Caccinia macranthera seed extract, zinc, calcium, and silver salts solution, for the first time. The chemical structure of NCPs was studied by the FT-IR technique. The XRD pattern shows a crystallite structure with an Fm3m group space and particle size of about 23 nm. The FESEM/PSA images displayed that NCPs have uniform distribution with spherical morphology. Also, the cytotoxicity of synthesized NCPs was examined on Huh-7 cells by MTT test and the IC50 value was 250 ppm. Additionally, the photocatalytic activity of NCPs was investigated to the methylene blue MB dye degradation, which resulted in a removal of about 90% after 100 min. According to the results of the broth microdilution process, which was done to evaluate the antibacterial activity of NCPs towards gram-positive and gram-negative bacteria, the MIC values were in the range of 0.97-125 ppm.

Inhibition of angiotensin pathway via valsartan reduces tumor growth in models of colorectal cancer.

BACKGROUND: Overexpression of the angiotensin-II receptor and renin-angiotensin system (RAS) has been reported in several malignancies, including colorectal-cancer (CRC), indicating its potential value as a therapeutic target. Here we explored the impact of targeting the RAS using an angiotensin II receptor blocker, valsartan, alone and its combination with Fluorouracil (5-FU) in in vitro and in vivo models of CRC. METHODS: Anti-proliferative activity of valsartan was evaluated in 2-/3-dimensional in vitro and in vivo CRC mouse models. The anti-migratory effects of this agent was assessed by wound-healing assay, while apoptosis was studied using 4',6-diamidino-2-phenylindole or DAPI staining, and staining with Annexin-V-fluorescein isothiocyanate with analysis using FACS. Gene-expression was determined at mRNA and protein levels. We further evaluated the anti-inflammatory properties of valsartan by histological analysis and the measurement of oxidative/antioxidant markers. Gelatin zymography was used to measure matrix metalloproteinase-2 and -9 activity (MMP-2 and 9). RESULTS: Valsartan suppressed CRC cell-growth and synergistically enhanced the anti-tumor-activities of 5-FU by induction of apoptosis, BAX, BCL2, P53 and modulation of the cell cycle. Valsartan inhibited the cell migration by perturbation of MMP2/9. Furthermore, valsartan inhibited tumor-growth, and this was more pronounced when using the valsartan/5-FU combination. The plausible mechanism for this is via the induction of ROS and down-regulation of SOD, thiol/catalase as well as VEGF. Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory factors including interleukins and Col1A1 expression. CONCLUSIONS: Our findings demonstrated that targeting RAS pathway using Valsartan interferes with cell-proliferation, induces apoptosis, reduces migration and synergistically interacts with 5-FU, supporting further studies on this new therapeutic approach for colorectal cancer.

The therapeutic potential of γ-Al2O3 nanoparticle containing 5-fluorouracil in the treatment of colorectal cancer.

5-Fluorouracil (5-FU) is being used in the treatment of several malignancies, but side effects are often reported and include: diarrhea, vomiting, nausea, poor appetite, watery eyes, and photophobia. We have developed and tested the cytotoxic activity of nanocrystalline powder of γ-alumina (γ-Al2O3) containing 5-FU in two-dimensional and three-dimensional (3D) CRC cell culture. γ-Al2O3 was prepared using a facile sol-gel method. The physicochemical properties of nanoparticles were investigated by Fourier Transform Infrared (FTIR) analysis, Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive X-ray Analysis (EDXA). Moreover, the particle size was monitored by Transmission Electron Microscopy (TEM). We used MTT and a scratch assay to assess the antiproliferative and anti-migratory of this agent. The effect of γ-Al2O3-5-FU on SOD, MDA, and total-thiols levels were evaluated. We assessed the expression of apoptotic markers in mRNA or proteins by RT-PCR and ELISA respectively. γ-Al2O3-5-FU inhibited cell growth in two-dimensional (2D) and three-dimensional (3D) cell culture and increased apoptosis as detected by DAPI stainning via modulation of caspases, BAx, BCl2 and cyclinD1. γ-Al2O3-5-FU also reduced the migratory activity of CRC cells relative to untreated controls. γ-Al2O3-5-FU increased the level of MDA, while reducing the level of SOD and total-thiols as well as inflamatory markers (e.g., TNF-s and IL-6). Our study demonstrated that γ-Al2O3-5-FU inhibited cell growth and migration, indicating its potential value in the treatment of colorectal cancer.

Hydrogen-rich water exerts anti-tumor effects comparable to 5-fluorouracil in a colorectal cancer xenograft model.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the world. Tumor removal remains the preferred frontline treatment; however, effective non-surgical interventions remain a high priority. 5-fluorouracil (5-FU) is a widely used chemotherapy agent, and molecular hydrogen (H2) has been recognized for its antioxidant and anti-inflammatory effects, with research also suggesting its potential anti-tumor effects. Therefore, H2 dissolved in water [hydrogen-rich water (HRW)], with or without 5-FU, may present itself as a novel therapeutic for CRC. AIM: To investigate the effects of HRW, with or without 5-FU, as a novel therapeutic for CRC. METHODS: CRC was induced in the left flank of inbred Balb/c mice. A total of 24 mice bearing tumors were randomly divided into four groups (n = 6 per group) and treated as follows: (1) Control group; (2) 5-FU group that received intraperitoneal injection of 5-FU (5 mg/kg) every other day; (3) H2 group that received HRW, created and delivered via dissolving the H2-generating tablet in the animals' drinking water, with 200 µL also delivered by oral gavage; and (4) The combination group, H2 (administered in same way as for group three) combined with 5-FU administered same way as group two. RESULTS: Administration of HRW + 5-FU significantly improved tumor weight, tumor size, collagen content and fibrosis as compared to the CRC control group. Specifically, HRW attenuated oxidative stress (OS) and potentiated antioxidant activity (AA), whereas 5-FU treatment exacerbated OS and blunted AA. The combination of HRW + 5-FU significantly reduced tumor weight and size, as well as reduced collagen deposition and the degree of fibrosis, while further increasing OS and decreasing AA compared to administration of 5-FU alone. CONCLUSION: Administration of HRW, with or without 5-FU, may serve as a therapeutic for treating CRC.

Inhibition of angiotensin II type 1 receptor by candesartan reduces tumor growth and ameliorates fibrosis in colorectal cancer.

Colorectal cancer (CRC) is an important cause of cancer-related mortality. Aberrant activation of the renin-angiotensin system (RAS) is reported to be associated with poor clinical outcomes in patients with CRC. This study was designed to explore the anti-tumor effects of the angiotensin receptor blocker Candesartan either alone or in combination with 5-FU in in vitro and in vivo models of CRC. The cytotoxic effects of Candesartan were assessed using the MTT assay in two colorectal cancer cell lines (CT-26 and SW-480). To investigate the potential regulatory role of Candesartan on tumor growth, apoptosis, and migration, the expression levels of Cyclin D1, Survivin, MMP3, MMP9, and E-cadherin mRNAs were evaluated. The oxidant/antioxidant balance was also examined by determining the levels of MDA, thiols, SOD, and CAT. We used a xenograft model of colon cancer to investigate the effects of Candesartan alone, or in combination with 5-FU, on tumor growth following histological staining (Hematoxylin & Eosin and Masson trichrome staining) and biochemical studies as well as gene expression analyses by RT-PCR and western blotting. Candesartan suppressed tumor cell proliferation and migration by modulating Cyclin D1, MMP3/9, and E-cadherin. Treatment with Candesartan either alone, or in combination with 5-FU decreased tumor size in the mouse model, and also increased the level of oxidative markers MDA and reduced CAT, SOD, and thiols. Histological evaluation showed that Candesartan increased tumor necrosis, reduced tumor density and attenuated collagen deposition reducing tumor fibrosis in tumor xenograft. Candesartan, an inhibitor of the RAS, when used in combination with 5-FU reduced tumor growth by inhibiting fibrosis and inducing ROS production, supporting further clinical studies on this therapeutic approach for treatment of CRC.

The therapeutic potential of losartan in lung metastasis of colorectal cancer.

Colorectal cancer (CRC) is a common cancer with a high incidence rate. Components of the renin-angiotensin system (RAS) have been reported to be dysregulated in several malignancies including CRC. Here, we have explored the potential anti-metastatic effects of a RAS inhibitor, losartan, in an experimental model of lung metastasis in CRC. A murine model of lung metastasis of CRC was used, which involved the intravenous injection of CT26 cells via a tail vein. Four experimental groups comprised: an untreated group; a group that received 5-FU which was administered intraperitoneally; a losartan group that received a combination group that received 5-FU plus losartan . We evaluated the anti-inflammatory effects of losartan by histopathological method, and the measurement of oxidative or antioxidant markers including malondialdehyde (MDA) and total-thiols (T-SH) tissue levels, superoxide-dismutase (SOD) and catalase activity. We found that losartan inhibited lung metastasis of CRC and there was a reduction of the IL-6 expression level in the tissue sample. It was also associated with reduced levels of the anti-angiogenic factor Vascular endothelial growth factor (VEGF). Furthermore, we found that losartan induced oxidative stress as assessed by an elevation of MDA level, reduction of T-SH, SOD and catalase activities in lung tissue. Our findings demonstrated that losartan ameliorates angiogenesis, inflammation and the induction of oxidative stress via Angiotensin II type I receptor (AT1R). This may shine some lights on targeting the RAS pathway as a potential therapeutic approach in the treatment of metastatic CRC patients.

The Esophageal Cancer and the PI3K/AKT/mTOR Signaling Regulatory microRNAs: a Novel Marker for Prognosis, and a Possible Target for Immunotherapy.

The Phosphatidylinositol 3-kinase/AKT/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) pathway has a critical regulatory role in cell biology including translation, transcription, and autophagy. Dysregulation of this pathway is involved in the pathogenesis, development, and prognosis of esophageal cancer that has been assessed in the recent years and its potential as a target in therapy. This report summarizes the current knowledge about PI3K/AKT/mTOR pathway and its cross-talk with a focus on the value of targeting this pathway as a potential therapeutic target in the treatment of esophageal cancer.

Apoptosis inducing capacity of Holothuria arenicola in CT26 colon carcinoma cells in vitro and in vivo.

OBJECTIVES: Sea cucumber is one of the classes of echinoderms, which is considered as a health marine product and possess various biological characteristics with therapeutic application. The present investigation attempted to evaluate the potential of anti-cancer Persian Gulf sea cucumber species Holothuria arenicola (H. arenicola) aqueous extract on mice colon carcinoma cells in vitro and in vivo. MATERIALS AND METHODS: The CT26 carcinoma cells were treated with various concentrations of extract in 24 and 48 hr, and then its anti-proliferative effect was measured by MTT assay and morphological observations. The apoptotic effect was examined by fluorescence microscopy (DNA fragmentation assay), Flow cytometry, caspase-3 and -9 colorimetric assays. The in vivo anti-tumor efficacy of sea cucumber extract on CT26 tumor cells transplanted in BALB/c mice was also investigated. RESULTS: The results showed that the water extract of sea cucumber revealed remarkable anti-proliferative effect on CT26 tumor cells with IC50= 31 µg/ml with recruitment of intrinsic apoptotic pathway in vitro. In addition, the colon tumor volume in treated groups remarkably reduced in homozygous mice. Histopathological examination elucidated that sea cucumber extract attenuated tumor size and volume along with apoptosis characteristics. Moreover, RT-PCR analysis revealed that sea cucumber extract induced intrinsic apoptosis in vivo through suppression of Bcl-2 expression. CONCLUSION: Our data confirmed this notion that sea cucumber administrates anti-cancer effect that can be used as complementary in preclinical experiments, so further characterization are recommended for detection sea cucumber metabolites and clinical application.