Ehrlich Carcinoma-bearing Mice Research Articles

Euphorbia grantii Oliv. standardized extract and its fraction ameliorate doxorubicin-induced cardiomyopathy in Ehrlich carcinoma bearing mice

Ethnopharmacological relevanceEuphorbia plants have long been used as traditional medicine in China, Europe, America, Turkey, India, Africa, Iran, and Pakistan because of its high medicinal value and health advantages especially as a remedy for several types of cancer. Aim of the studyDoxorubicin (DOX) is one of the most frequently prescribed drugs in cancer chemotherapy, with dose-limiting cardiotoxicity. The development of medicinal approaches to attenuate drug's toxicity represents an area of great concern in cancer research. Because research on this topic is still disputed and limited, we aim to investigate the potential of supplementation with Euphorbia grantii Oliv. on DOX-induced cardiomyopathy in Ehrlich carcinoma bearing mice. Materials and methodsThe high-performance thin layer chromatography (HPTLC) analysis of total methanolic extract (TE), and its bioactive dichloromethane fraction (DCMF) was applied for the determination of friedelin. Male BALB/c mice were used to keep the Ehrlich ascites tumor cells. The experiment was performed for a 2-weeks period. ResultsA good linearity relationship was found to be with correlation coefficient (r2) value of 0.9924 for the isolated friedelin. Limit of detection (LOD) and limit of quantitation (LOQ) was found to be 0.00179, and 0.000537 ng/band respectively for friedelin. The amount of friedelin in the TE and DCMF were determined by using calibration curve of standard as 106.32 ± 5.69 μg, and 159.2 ± 4.24 μg friedelin/mg extract, respectively. DOX-induced cardiomyopathy by decreasing the ejection fraction (EF) compared to the Ehrlich and negative control groups. It resulted in a decrease in the EF by 30 and 39% compared to the other groups. High and low doses of the TE and DCMF did not result in significantly different ejection fractions compared to the Ehrlich group. Co-administration of DCMF with DOX ameliorated the alteration in the serum CKMB and LDH levels. As revealed from histopathological study, DOX impairs viability of cardiac myocytes and DCMF could effectively and extensively counteract this action of DOX and potentially protect the heart from severe toxicity of DOX. ConclusionsFinally, our results indicated that Euphorbia grantii Oliv. would be the best option to reduce DOX adverse effects.

L-carvone decreases breast cancer cells adhesion, migration, and invasion by suppressing FAK activation

Breast cancer is one of the most common types of cancer in the world and current therapeutic strategies present severe drawbacks. l-carvone (CRV), a monoterpene found in Mentha spicata (spearmint), has been reported to have potent anti-inflammatory activity. Here, we examined the role of CRV in breast cancer cell adhesion, migration and invasion in vitro and how this component could suppress the growth of Ehrlich carcinoma-bearing mice. In vivo, treatment with CRV significantly decreased tumor growth, increased tumor necrosis area, and reduced the expression of VEGF and HIF-1α in Ehrlich carcinoma-bearing mice. Furthermore, the anticancer efficacy of CRV was similar to currently used chemotherapy (Methotrexate), and the combination of CRV with MTX potentiated the chemotherapy effects. Further mechanistic investigation in vitro revealed that CRV modulates the interaction of breast cancer cells with the extracellular matrix (ECM) by disrupting focal adhesion, which was shown by scanning electron microscopy (SEM) and immunofluorescence. Moreover, CRV caused a decrease in β1-integrin expression and inhibited focal adhesion kinase (FAK) activation. FAK is one of the most important downstream activators of several metastatic processes, including MMP-2 mediated invasion and HIF-1α/VEGF angiogenesis stimulus, both of which were found to be reduced in MDA-MB-231 cells exposed to CRV. Our results provide new insight about targeting β1-integrin/FAK signaling pathway with CRV, which could be a new potential agent in the treatment of breast cancer.

Potential cardioprotective and anticancer effects of carvedilol either free or as loaded nanoparticles with or without doxorubicin in solid Ehrlich carcinoma-bearing mice

AimThe aim of this study was to investigate the potential cardioprotective and anti-cancer effects of carvedilol (CAR) either free or as loaded nano-formulated with or without doxorubicin (DOX) in solid Ehrlich carcinoma (SEC)-bearing mice. It focused on assessment of cardiac damage, drug resistance, apoptosis, oxidative stress status, angiogenesis and proliferation. MethodsCAR was loaded into poly-D,L lactic-co-glycolic acid)PLGA(or Niosomes. SEC was induced in female albino mice as an experimental model of breast cancer. Seventy-two mice were randomly divided into 9 equal groups (Normal control, Untreated-SEC, SEC + DOX, SEC + CAR-free, SEC + CAR-PLGA, SEC + CAR-Niosomes, SEC + DOX + CAR-free, SEC + DOX + CAR-PLGA and SEC + DOX + CAR-Niosomes). Tumor volume and survival rate were recorded. On day 28 from tumor inoculation, mice were sacrificed, and blood samples were collected for determination of serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB). One part from tumor tissues was prepared for assessment of multidrug resistance protein-1 (MDR-1), caspase-3, reduced glutathione (GSH) and malondialdehyde (MDA), while the other part was processed for histopathological examination and immunohistochemical expression of vascular endothelial growth factor (VEGF) and Ki-67. ResultsThere was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both. ConclusionCAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.

Novel antitumor activity of the combined treatment of galloylquinic acid compounds with doxorubicin in solid Ehrlich carcinoma model via the Notch signaling pathway modulation

AimsThis study aims to investigate the potential synergistic effect of the combined treatment of galloylquinic acid compounds from Copaifera lucens with doxorubicin via the modulation of the Notch pathway in solid Ehrlich carcinoma-bearing mice model. Main methodsThe solid tumor model was induced by subcutaneous inoculation of Ehrlich carcinoma cells in the right hind limb of mice, after serial syngeneic cell passages in the peritoneal cavity. Sixty mice were allocated into five groups including treated groups with galloylquinic acid compounds, doxorubicin, and their combination. Normal and tumor control groups were also assigned. Tissue homogenates were collected to measure the levels of the Notch-1, Hes-1, Jagged-1, TNF-α, IL-6 and VEGF, as well as SOD, MDA, and GSH. Histopathological and immunohistochemical examinations of tumor or control tissues were also performed for the levels of NF-κB p65, cyclin D1 and caspase 3 activity. Key findingsOur results showed that the combined treatment of galloylquinic acid compounds with doxorubicin significantly decreased the levels of the Notch-1, Hes-1, Jagged-1, TNF-α, IL-6, VEGF, NF-κB p65, and cyclin D1 in tumor tissues. Moreover, the compounds induced cancer cell death as evidence by increasing the caspase 3 activity, and they possessed potent inhibitory effects on oxidative stress. SignificanceGalloylquinic acid compounds exhibited promising antineoplastic effects and promoted the chemosensitivity of doxorubicin, mainly by modulating the Notch signaling pathway and its downstream effectors. These compounds may be considered in solid tumors treatment for improving the efficacy and reducing the side effects of chemotherapeutic agents.

Immune Stimulating Outcome of Chrysin and γ-Irradiation via Apoptotic Activation Against Solid Ehrlich Carcinoma Bearing Mice.

The rising interest in innovative methods of cancer immunotherapy has prompted research into the immunomodulatory mechanisms of natural and synthetic substances. The goal of this study was to assess chrysin immune-stimulating and pro-apoptotic effects on tumor growth and cell susceptibility to ionizing radiation in order to improve cancer therapy. Chrysin (20 mg/kg/day) was intraperitoneally injected to mice bearing 1 cm3 solid tumor of Ehrlich ascites carcinoma (EAC) for 21 consecutive days. Mice were whole body exposed to 1 Gy of gamma radiation (2 fractionated dose 0.5 Gy each). Treatment with chrysin dramatically reduces tumor proliferation in EAC mice; furthermore, IFN-γ activity is significantly reduced when compared to EAC mice. When compared to EAC mice, the expression of TNF-α, free radicals, and nitric oxide (NO) levels were considerably reduced, along with improvements in apoptotic regulators (caspase-3 activity). Moreover, the histopathological investigation confirms the improvement exerted by chrysin even in the EAC mice group or the EAC + R group. What is more, exposure to gamma radiation sustained the modulatory effect of chrysin on tumor when compared with EAC + Ch mice. Hence, chrysin might represent a potential therapeutic strategy for increasing the radiation response of solid tumor.

Antibacterial and antitumor activities of a lectin-rich preparation from Microgramma vacciniifolia rhizome

The rhizome of Microgramma vacciniifolia contains a lectin (carbohydrate-binding protein) called MvRL. Studies demonstrated that a MvRL-rich fraction did not show in vivo genotoxicity and acute toxicity in mice. This study aimed to evaluate the MvRL-rich fraction from M. vacciniifolia rhizome for antibacterial activity in vitro and in vivo as well as antitumor effect in vivo using the Ehrlich carcinoma model in mice. The fraction showed antibacterial activity against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus with minimal inhibitory concentrations ranging from 31.2 to 125.0 ​μg/mL and minimal bactericidal concentrations from 62.5 to 200 ​μg/mL. The fraction was also effective in vivo against infection caused by these bacteria on Tenebrio molitor larvae considering the parameters evaluated. In regard to the antitumor activity, the treatments of Ehrlich carcinoma-bearing mice with the fraction at 100 and 200 ​mg/kg per os resulted in 62.58% and 75.43% of tumor inhibition, respectively. In conclusion, the MvRL-rich fraction showed in vivo antibacterial and antitumor activities and thus can be considered as an alternative of natural origin for the development of candidates for therapy.

Vochysia tucanorum Mart. butanol fraction presents antitumoral activity in vivo and prevents the installation of cachexia in solid Ehrlich tumor model

BackgroundCancer is a multifactorial disease caused by uncontrolled proliferation of cells. About 50–80% of cancer patients develop cachexia, a complex metabolic syndrome associated with an increase of mortality and morbidity. However, there are no effective therapies in medical clinic for cancer cachexia. Vochysia tucanorum Mart. is a common three of the Brazilian “Cerrado”. The butanolic fraction of V. tucanorum (Fr-BuVt), very rich in triterpenes with various biological activities, might be interesting in being tested in cancer cachexia syndrome. Hence, the present study was undertaken to investigate the antitumoral activity of Fr-BuVt and its potential against cachexia development.MethodsEhrlich tumor was used as model of cancer cachexia. Ascitic Ehrlich tumor cells were collected, processed and inoculated subcutaneously in saline solution (1 × 107/100 μl; ≥95% viability) for the obtention of solid Ehrlich carcinoma. After inoculation, solid Ehrlich carcinoma-bearing mice were treated by 14 consecutive days by gavage with Fr-BuVt (200 mg/kg). Body weight and tumor volume were measure during the treatment period. Tumors were removed, weighed and properly processed to measure the content and phosphorylation levels of key-proteins involved to apoptotic and proliferation process by Western Blot. Muscles and adipose tissues were removed for weighed. Serum was collected to cytokines levels and energetic blood markers measurements.ResultsThe treatment with the Fr-BuVt (200 mg/kg, 14 days) decreased the solid Ehrlich tumor volume and weight besides increased the expression of the pro-apoptotic proteins caspase-3 and BAX, but also decreased the expression of the proteins involved in proliferation NFκB, mTOR and ERK. In addition, our data shows that the administration of Fr-BuVt was able to prevent the installation of cancer cachexia in Ehrlich carcinoma-bearing mice, since prevented the loss of body weight, as well as the loss of muscle and adipose tissue. Moreover, an improvement in some blood parameters such as decrease in cytokines TNF-α and IL-6 levels is observed.ConclusionsThe study revealed that Fr-BuVt has antitumoral activity and prevent installation of cancer cachexia in Ehrlich model. Therefore, Fr-BuVt may represent an alternative treatment for cancer cachexia.

Antitumor impact of iron oxide nanoparticles in Ehrlich carcinoma-bearing mice

ABSTRACT Magnetic nanoparticles are promising approaches for cancer treatment. Iron oxide nanoparticles have been pre-formed by the co-precipitation method to investigate their antitumor activity on Ehrlich carcinoma in mice. The nanoparticles have been studied by UV spectrophotometer, transmission electron microscopy, dynamic light scattering, and zeta potential measurement. To determine the therapeutic impact of Iron oxide nanoparticles in tumor-bearing mice, in vivo experiments were carried out. Fourier Transform Infra-red (FTIR) spectroscopy and DNA comet assay were used to estimate the toxicity of nanoparticles of iron oxide. The tissue was analyzed using FTIR spectral parameters such as the area beneath the peak, peak position, and peak intensity. The results showed that iron oxide nanoparticles significantly led to antitumor activity against Ehrlich carcinoma. There was a low shift in position and intensity at the amide I band (1650 cm−1) in tissues of mice treated with iron oxide nanoparticles compared to the control group. Comet examination showed a decrease across all the parameters of the assay (tail moment, tail DNA percentage, and tail length) in the tumor + iron nanoparticles group, having values lower than the tumor group. According to the presented results, Iron oxide nanoparticles have exhibited therapeutic efficacy against cancer.

Antitumor and Radiosensitizing Effects of Zinc Oxide-Caffeic Acid Nanoparticles against Solid Ehrlich Carcinoma in Female Mice.

This study aimed to evaluate the anticancer and radio-sensitizing efficacy of Zinc Oxide-Caffeic Acid Nanoparticles (ZnO-CA NPs). ZnO-CA NPs were formulated by the conjugation of Zinc Oxide nanoparticles (ZnO NPs) with caffeic acid (CA) that were characterized by Fourier Transform Infrared Spectra (FT-IR), X-ray Diffractometer (XRD), and Transmission Electron Microscopy (TEM). In vitro anticancer potential of ZnO-CA NPs was evaluated by assessing cell viability in the human breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines. In vivo anticancer and radio-sensitizing effects of ZnO-CA NPs in solid Ehrlich carcinoma-bearing mice (EC mice) were also assessed. Treatment of EC mice with ZnO-CA NPs resulted in a considerable decline in tumor size and weight, down-regulation of B-cell lymphoma 2 (BCL2) and nuclear factor kappa B (NF-κB) gene expressions, decreased vascular cell adhesion molecule 1 (VCAM-1) level, downregulation of phosphorylated-extracellular-regulated kinase 1 and 2 (p-ERK1/2) protein expression, DNA fragmentation and a recognizable peak at sub-G0/G1 indicating dead cells’ population in cancer tissues. Combined treatment of ZnO-CA NPs with γ-irradiation improved these effects. In conclusion: ZnO-CA NPs exhibit in-vitro as well as in-vivo antitumor activity, which is augmented by exposure of mice to γ-irradiation. Further explorations are warranted previous to clinical application of ZnO-CA NPs.

Functions of tumor-associated macrophages and macrophages residing in remote anatomical niches in Ehrlich carcinoma bearing mice.

The impact of growing tumor on polarization and functions of tumor-associated macrophages is well known while its influence on residential macrophages occupying different anatomical niches reminds to be elucidated. To study changes in polarization and functions of macrophages isolated from discrete anatomical niches in tumor-bearing mice at different stages of tumor growth. Ehrlich carcinoma was transplanted intramuscularly to Balb/c male mice. On days 7, 14, 21and 28after tumor transplantation, macrophages from tumor tissue, peritoneal cavity and spleen were isolated and analyzed. Nitric oxide production was measured by standard Griess reaction, arginase activity was determined by the measurement of urea, reactive oxygen species production was checked using NBT dye reduction assay and electron paramagnetic resonance spectroscopy, cytotoxic activity was estimated in MTT-assay. Independently of their localization in different anatomic niches, macrophages in mice with transplanted Ehrlich carcinoma gradually lose their tumoricidal activities while arginase activity is upregulated. This indicates the shift of polarization from M1-like towards M2-like phenotype. Our findings demonstrated that growing tumor could be able to subvert functioning of macrophages at the systemic level.

Magnetic fields enhance the anti-tumor efficacy of low dose cisplatin and reduce the nephrotoxicity.

The present work was to examine a combination of therapy for a low dose of cisplatin and a magnetic field (MF) on Ehrlich carcinoma-bearing mice. In this study, a total of 50 BALB/C female mice were equally distributed into five groups. Mice from the control group did not receive MF or cisplatin. The low and high dose cisplatin groups were injected intraperitoneal (i.p.) with 3 and 6mg/kg cisplatin, respectively, on the experimental days (1, 4, and 8). Mice group of cisplatin + MF was injected with a low dose of cisplatin followed by MF exposure (50Hz, 50mT), and the MF group was exposed to MF only. The impact of MF and cisplatin on the tumor and kidney were evaluated by measuring superoxide dismutase (SOD) activity, malondialdehyde (MDA) and glutathione (GSH) levels, DNA injury (comet assay), histopathological investigation of tissues, and tumor progress. The results suggested that the combination of a low dose of cisplatin with MF was significantly elevated in MDA levels, reduced SOD activity, and GSH levels. Furthermore, it caused a rise in comet parameters and inhibition in tumor growth. These results showed that MF enhances the therapeutic efficacy of low cisplatin doses and reduces nephrotoxicity.

Enhanced anticancer activity of combined treatment of imatinib and dipyridamole in solid Ehrlich carcinoma-bearing mice.

The current study was designed to evaluate potential enhancement of the anticancer activity of imatinib mesylate (IM) with dipyridamole (DIP) and to investigate the underlying mechanisms of the combined therapy (IM/DIP) to reduce hepatotoxicity of IM in solid Ehrlich carcinoma (SEC)-bearing mice. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into seven groups (n = 10): SEC vehicle, IM50 (50mg/kg), IM100 (100mg/kg), DIP (35mg/kg), a combination of IM50/DIP and IM100/DIP. On day 28th, mice were sacrificed and blood samples were collected for hematological studies. Biochemical determination of liver markers was evaluated. Glutamic oxaloacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT) and alkaline phosphatase (ALP) levels were assessed. In addition, MDR-1 gene expression and immunohistochemical staining of BAX and BCL-2 was done. Also, in vitro experiment for determination of IC50 of different treatments and combination index (CI) were assessed in both MCF-7 and HCT-116 cell lines. IM- and/or DIP-treated groups showed a significant reduction in tumor volume, weight, and serum levels of SGOT, SGPT, and AIP compared to vehicle group. In addition, reduction of VEGF, Ki67, and adenosine contents was also reported by treated groups. Also, IM/DIP combination showed lower IC50 than monotherapy. Combination index is less than 1 for IM/DIP combination in both cell lines. DIP as an adjuvant therapy potentiated the cytotoxic effect of IM, ameliorated its hepatic toxicity, and showed synergistic effect with IM in vitro cell lines. Furthermore, the resistance against IM therapy may be overcome by the use of DIP independent on mdr-1 gene expression.

Preliminary biological evaluation of 99mTc-glucosamine as a potential radiotracer for tumor imaging

The development of novel specific radiolabeled probes as targeted imaging agents for a more accurate detection of cancer has gained considerable interest. Glucose analogue 18F-FDG is used worldwide for imaging of several cancer types. New glucose analogs radiolabeled with 99mTc could be a less-expensive and more accessible alternative for diagnosis using SPECT imaging. The complex of glucosamine and 99mTc were prepared, and its biodistribution was evaluated in solid Ehrlich carcinoma bearing mice. 99mTc-glucosamine was synthesized and radiolabeled with 99mTc with high yield and stability. Biodistribution studies showed that tumor uptake of 99mTc-glucosamine increased from 0.44±0.06 %ID/g at 5 min postinjection (p.i.) to 0.54±0.06 %ID/g and 0.64±0.07 %ID/g at 1 h and 3 h p.i., respectively. The tumor/blood and tumor/muscle ratios also increased with time and reached 1.02±0.12 and 1.88±0.20 at 3 h p.i. 99mTc-glucosamine was rapidly removed from blood through the urinary system, so high amount of activity accumulated in kidneys. High uptake of 99mTc-glucosamine was also observed in two high-energy-dependent organs, heart and liver. In other organs such as lungs, spleen, stomach, small intestine and brain high uptake of 99mTc-glucosamine was only at 5 min after intravenous administration, but later the most part of activity was removed. In conclusion, we suggested that 99mTc-glucosamine would be a promising candidate for cancer SPECT imaging.

Role of Bee Venom and Melittin on Restraining Angiogenesis and Metastasis in γ-Irradiated Solid Ehrlich Carcinoma-Bearing Mice.

Pathological angiogenesis and apoptosis evasion are common hallmarks of cancer. The present work was an endeavor to evaluate the influence of bee venom (BV) or its major constituent melittin (MEL) as antiapoptotic and angiogenic regulator modifier on the tumor growth and the cell sensitivity to ionizing radiation targeting the improvement of cancer therapeutic protocols. BV (0.56 mg/kg/day) and MEL (500 µg/kg body weight/day) were injected intraperitoneally to mice bearing 1 cm3 solid tumor of Ehrlich ascites carcinoma (EAC) for 21 consecutive days. Mice were whole-body exposed to 1 Gray (Gy) of γ-radiation (2 fractionated doses). Treatment with BV or MEL markedly suppresses the proliferation of tumor in EAC mice. The concentrations of m-RNA for angiogenic factors (TNF-α, VEGF) as well as MMPs 2 and 9 activities and NO concentration were significantly decreased, combined with improvements in apoptotic regulators (caspase-3 activity) and normal cells redox tone (catalase and free radicals content) compared with EAC mice. Moreover, the histopathological investigation confirms the improvement exerted by BV or MEL in the EAC mice group or EAC + R group. Exposure to γ-radiation sustained the modulatory effect of BV on tumor when compared with EAC + BV mice. Convincingly, the role of BV or MEL as a natural antiangiogenic in the biological sequelae after radiation exposure is verified. Hence, BV and its major constituent MEL might represent a potential therapeutic strategy for increasing the radiation response of solid tumors.

Dual-targeted therapeutic strategy combining CSC-DC-based vaccine and cisplatin overcomes chemo-resistance in experimental mice model.

Emerging evidence suggests that one of the main reasons of chemotherapy treatment failure is the development of multi-drug resistance (MDR) associated with cancer stem cells (CSCs). Our aim is to identify a therapeutic strategy based on MDR-reversing agents. CSC-enriched Ehrlich carcinoma (EC) cell cultures were prepared by drug-resistant selection method using different concentrations of cisplatin (CIS). Cell cultures following drug exposure were analyzed by flow cytometry for CSC surface markers CD44+/CD24-. We isolated murine bone marrow-derived dendritic cells (DCs) and then used them to prepare CSC-DC vaccine by pulsation with CSC-enriched lysate. DCs were examined by flow cytometry for phenotypic markers. Solid Ehrlich carcinoma bearing mice were injected with the CSC-DC vaccine in conjunction with repeated low doses of CIS. Tumor growth inhibition was evaluated and tumor tissues were excised and analyzed by real-time PCR to determine the relative gene expression levels of MDR and Bcl-2. Histopathological features of tumor tissues excised were examined. Co-treatment with CSC-DC and CIS resulted in a significant tumor growth inhibition. Furthermore, the greatest response of downregulation of MDR and Bcl-2 relative gene expression were achieved in the same group. In parallel, the histopathological observations demonstrated enhanced apoptosis and absence of mitotic figures in tumor tissues of the co-treatment group. Dual targeting of resistant cancer cells using CSC-DC vaccine along with cisplatin represents a promising therapeutic strategy that could suppress tumor growth, circumvent MDR, and increase the efficacy of conventional chemotherapies.

Magnetic Field Improves the Efficiency of Low Dose Cis-Platin by Alteration the Oxidative Stress in Ehrlich Carcinoma-Bearing Mice

50 Hz and 50 mT magnetic field (MF) with an exposure period of 30 min./day for 15 days was used to enhance the efficiency of a low dose of cisplatin on BALB/C mice. Tumor tissues were evaluated by oxidative stress parameters such as superoxide dismutase (SOD) enzyme activity, malondialdehyde (MDA) and glutathione (GSH) levels. The result shows that treatment with MF and cisplatin decreases the activity of SOD and GSH level and increases the MDA level compared to the treatment with MF or cisplatin alone. In conclusion, these results reveal that MF improves the therapeutic efficiency of cisplatin.

Novel Ran-RCC1 Inhibitory Peptide-Loaded Nanoparticles Have Anti-Cancer Efficacy In Vitro and In Vivo.

The delivery of anticancer agents to their subcellular sites of action is a significant challenge for effective cancer therapy. Peptides, which are integral to several oncogenic pathways, have significant potential to be utilised as cancer therapeutics due to their selectivity, high potency and lack of normal cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1 (Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic target in breast cancer, were delivered by entrapment into polyethylene glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A modified double emulsion solvent evaporation technique was used to optimise the physicochemical properties of these peptide-loaded biodegradable NPs. The anti-cancer activity of peptide-loaded NPs was studied in vitro using Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines, and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic activity of peptide-loaded NPs was investigated using migration, invasion and colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating N-terminal peptide showed a pronounced antitumor and anti-metastatic action in lung and breast cancer cells in vitro and caused a significant reduction of tumor volume and associated tumor growth inhibition of breast cancer model in vivo. These findings suggest that the novel inhibitory peptides encapsulated into PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This novel Ran-targeting peptide construct shows significant potential for therapy of breast cancer and other cancers mediated by Ran overexpression.

Antitumor activity of silver nanoparticles in Ehrlich carcinoma-bearing mice.

Silver nanoparticles (AgNPs) have a wide range of industrial and biomedical applications. The aim of the present study was to determine the cytotoxic and genotoxic effects of AgNPs on Ehrlich carcinoma-bearing mice. AgNPs were characterized by ultraviolet-visible absorption spectroscopy, dynamic light scattering, and transmission electron microscopy (TEM). Furthermore, the cytotoxicity and genotoxicity of AgNPs were evaluated using a series of assays: superoxide dismutase (SOD) enzyme activity, malondialdehyde (MDA) levels, DNA damage (comet assay), and histopathological examination of tissues and tumor size in Ehrlich carcinoma-bearing mice. Treatment of Ehrlich carcinoma-bearing mice with various concentrations of AgNPs (6, 24, and 48mg/kg) injected intra peritoneal (IP) and intra tumor (IT) revealed that AgNPs significantly elevated the levels (0.5- to 5-fold) of MDA and reduced the activity (32-64%) of SOD. Furthermore, AgNPs caused a 2- to 3-fold increase in comet parameters such as percent tail DNA. Additionally, AgNPs inhibit the promotion of Ehrlich carcinoma by masses of necrotic and fragmented tumor cells. Consequently, the volume of tumor reduced by about 31-95% compared to control one. The results indicate that AgNPs possess cytotoxic and genotoxic effects against Ehrlich tumor and confirm the antitumor properties of AgNPs.

Polymeric nano-encapsulation of 5-fluorouracil enhances anti-cancer activity and ameliorates side effects in solid Ehrlich Carcinoma-bearing mice.

Biodegradable PLGA nanoparticles, loaded with 5-fluorouracil (5FU), were prepared using a double emulsion method and characterised in terms of mean diameter, zeta potential, entrapment efficiency and in vitro release. Poly (vinyl alcohol) was used to modify both internal and external aqueous phases and shown have a significant effect on nanoparticulate size, encapsulation efficiency and the initial burst release. Addition of poly (ethylene glycol) to the particle matrix, as part of the polymeric backbone, improved significantly the encapsulation efficiency. 5FU-loaded NPs were spherical in shape and negatively charged with a size range of 185-350 nm. Biological evaluation was performed in vivo using a solid Ehrlich carcinoma (SEC) murine model. An optimised 5FU-loaded formulation containing PEG as part of a block copolymer induced a pronounced reduction in tumour volume and tumour weight, together with an improved percentage tumour growth inhibition. Drug-loaded nanoparticles showed no significant toxicity or associated changes on liver and kidney function in tested animals, whereas increased alanine aminotransferase, aspartate aminotransferase and serum creatinine were observed in animals treated with free 5FU. Histopathological examination demonstrated enhanced cytotoxic action of 5FU-loaded nanoparticles when compared to the free drug. Based on these findings, it was concluded that nano-encapsulation of 5FU using PEGylated PLGA improved encapsulation and sustained in vitro release. This leads to increased anti-tumour efficacy against SEC, with a reduction in adverse effects.

Antitumor and radiosensitizing synergistic effects of apigenin and cryptotanshinone against solid Ehrlich carcinoma in female mice.

Considerable attention has been paid to the introduction of novel naturally occurring plant-derived radiosensitizer compounds in order to augment the radiation efficacy and improve the treatment outcome of different tumors. This study was therefore undertaken to evaluate the antitumor, antiangiogeneic, and synergistic radiosensitizing effects of apigenin, a dietary flavonoid, and/or cryptotanshinone, a terpenoid isolated from the roots of Salvia miltiorrhiza, against the growth of solid Ehrlich carcinoma in female mice. Apigenin (50 mg/kg body weight) and/or cryptotanshinone (40 mg/kg body weight) was intraperitoneally (i.p.) injected into non-irradiated or γ-irradiated (6.5 Gy whole-body γ-irradiation) solid Ehrlich carcinoma-bearing mice for 30 consecutive days. Investigations included molecular targets involved in proliferation, inflammation, angiogenesis, and tumor invasiveness. Treatment with apigenin and/or cryptotanshinone significantly suppressed the growth of solid Ehrlich carcinoma tumors and demonstrated a synergistic radiosensitizing efficacy together with γ-irradiation. These effects were achieved through downregulating the expression of angiogenic and lymphangiogenic regulators, including signal transducer and activator of transcription 3, vascular endothelial growth factor C, and tumor necrosis factor alpha, suppressing matrix metalloproteinase-2 and -9 activities, which play a key role in tumor invasion and metastasis, and enhancing apoptosis via inducing cleaved caspase-3 and granzyme B levels. Histological findings of solid Ehrlich carcinoma tumors verified the recorded data. In conclusion, a synergistic radiosensitizing efficacy for apigenin and cryptotanshinone was demonstrated against Ehrlich carcinoma in the current in vivo murine model, representing therefore a potential therapeutic strategy for increasing the radiation response of solid tumors.