Ehrlich Ascites Tumor Model Research Articles

Magnetic Lipid-Based hybrid nanosystems: A combined stimuli- responsive nanocarriers for enriched chemotherapeutic potential of L-carnosine in induced breast Ehrlich ascites tumor model

Magnetic Lipid-Based Hybrid Nanosystems (M-LCNPs) is a novel nanoplatform that can respond to magnetic stimulus and are designed for delivering L-carnosine (CN), a challenging dipeptide employed in the treatment of breast cancer. CN exhibits considerable water solubility and undergoes in-vivo degradation, hence restricting its application. Consequently, it is anticipated that the developed M-LCNPs will enhance the effectiveness of CN. To ensure the physical stability of MNPs, they were initially coated with a mixture of oleic acid and oleylamine before being included in pegylated liquid crystalline nanoparticles (PLCNPs). The proposed M-LCNPs exhibited promising in-vitro characteristics, notably a small particle size (143.5 nm ± 1.25) and a high zeta potential (-39.5 mV ± 1.54), together with superparamagnetic behavior. The in-vitro release profile exhibited a prolonged release pattern. The IC50 values of M-LCNPs were 1.57 and 1.59 times lower than these of the CN solution after 24 and 48 hours, respectively. Female BALB/C female mice with an induced breast cancer (Ehrlich Ascites tumor [EAT] model) were used to study the influence of an external magnetic field on the chemotherapeutic activity and toxicity of CN loaded in the developed M-LCNPs.Stimuli-responsive M-LCNPs exhibited no apparent systemic toxicity in addition to enhanced chemotherapeutic efficacy compared to nontargeted M-LCNPs and CN solution, as evidenced by a reduction of % tumor growth (11.7%), VEGF levels (22.95 pg/g tissue), and cyclin D1 levels (27.61 ng/g tissue), and an increase in caspase-3 level (28.9 ng/g tissue). Ultimately, the developed stimuli-responsive CN loaded M-LCNPs presented a promising nanoplatform for breast cancer therapy.

Switching indication of PEGylated lipid nanocapsules-loaded with rolapitant and deferasirox against breast cancer: Enhanced in-vitro and in-vivo cytotoxicity

Breast cancer (BC) is considered the leading cause of mortality and morbidity among adult women worldwide, and it is associated with many genetic or hormonal factors. Despite the advanced therapeutic and theranostic strategies for BC treatment, cancer metastasis and relapse are often observed among patients which lead to therapeutic failure. Accordingly, among the repositioned medication against BC proliferation is neurokinin receptor antagonists and iron chelating agents especially rolapitant HCl (RP) and deferasirox (DFO), respectively. However, RP and DFO are classified as class II with low aqueous solubility. Both drugs were nanoformulated into PEGylated lipid nanocapsules (LNCs) for enhancing their aqueous solubility and augmenting their efficacy. RP-LNCs, DFO-LNCs and their combinations were evaluated according to particle size (PS), zeta potential, polydispersity index (PDI) and surface morphology. Importantly, the antitumor effect of these novel molecules and their nanoforms was evaluated against the suppression of Ehrlich Ascites tumor model using female mice. Results revealed that RP-LNCs, DFO-LNCs and RP/DFO-LNCs exerted PS from 45.23 ± 3.54 to 60.1 ± 3.32 nm with PDI around 0.20 which indicates homogenous particles distribution. Also, RP-LNCs, DFO-LNCs and RP/DFO-LNCs displayed surface charges of +16.6 ± 6.9, −13.3 ± 5.82 and − 20.2 ± 5.40 mV, respectively. The obtained LNCs conferred a high potent cytotoxic effect against MCF7 cancer cells as compared to parent drugs, with IC50 of 10.86 ± 0.89, 3.34 ± 0.99 and 2.24 ± 0.97 μg/mL for RP-LNCs, DFO-LNCs and RP/DFO-LNCs, respectively. The in-vivo pharmacodynamics effect of the developed nano-formulations showed superior antitumor effect for the individual drugs rather than their combinations as compared to the control group. The current study confirmed the potential of RP and DFO nanoforms as promising therapeutic agents for BC treatment.

Elucidation of anti-proliferative and anti-angiogenic potential ofnovel imidazo[2,1-b][1,3,4]thiadiazole derivatives in Ehrlich ascites tumor model

Introduction and Aim:Synthesis of antineoplastic drugs is challenging and shrouded with possibilities of multidrug resistance and numerous side effects. Imidazo[2,1-b][1,3,4]thiadiazole moieties exhibit tremendous scope as novel anti-cancer molecules. In the present study, we synthesize and characterize a series of 5(a-e) Imidazo[2,l-b][1, 3,4]thiadiazole derivatives andevaluate them for antiproliferative properties using in vivo, in vitro , andin silicoapproach. Materials and Methods:The in vivostudies conducted using murine Ehrlich Ascites Cancer (EAC) cell model establishes that treatment with 5c reduces the tumorigenesisby promoting apoptosis inEAC-bearing mice. The cells retrieved from the control andtreatment arms of EAC cell bearing mice were used for nuclear and Giemsa staining, DNA fragmentation, RT-PCR and chorioallantoic membrane evaluations. Results:5cinduces apoptosis, plasma membrane degradation, up-regulation of apoptotic genes and anti-angiogenic characteristics. In vitro evaluation of 5cusing,various cancer cell linesagainst normal fibroblast 3T3 L1 cells confirm 5c sensitivity to MCF-7 with IC50value of 8?M. 5c exudes marked reduction in cell viability, dual nuclear staining,and long-term colony formationassays in thesecells. Conclusion:5c inhibits the growth and proliferation of cancer cells. The results of our molecular docking predictions further substantiate our claim. This study is valuable as 5c exhibitsapromising approach for the treatment of cancer and itsanti-proliferative potential can be exploited for designing novel anticancer drugs in the near future. Keywords:Imidazo[2,1-b][1,3,4]thiadiazole derivatives;NMRcytotoxicity, EAC cell;apoptosis;anti-angiogenesis.

Cornus Mas L improves Antioxidant Status in the Liver, Lung, Kidney, Testis and Brain of Ehrlich Ascites Tumor Bearing Mice.

Cornelian Cherry (Cornus Mas L) has widespread use due to its anti-inflammatory, anti-carcinogenic and anti-oxidant properties. In this study, the effects of Cornus Mas L (C. mas L) in different dosages on the biochemical values of mice organs were investigated in the Ehrlich Ascites tumor model, which originated from mice breast adenocarcinoma and developed in Balb/C mice. In our study, 32 Balb/C type male mice were used. Ehrlich Ascites Tumor (EAT) cells (1x106 EAT cell) from the stock animal were injected into all the mice in an intraperitoneal way. Experimental groups were given 100 and 200mg/kg C. mas L extract intraperitoneally for 9 days. The weights of the animals were recorded every day and were sacrificed on the 9th day. To estimate tumor proliferation of the lung, brain, kidney, liver, and testis, antioxidant parameters were recorded including, the reduced glutathione (GSH), lipid peroxidation, glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT). Treatments of different doses of C. mas L. meaningfully (p < 0.05) modulated the lung, brain, kidney, liver and testis tissues antioxidant parameters as compared to the control. Our study showed the anti-tumor effect of C. mas L. in assisted tumor development with EAT cells, conceivably moderated by the enhancement of oxidative stress due to numerous mechanisms.

Design of expert guided investigation of native L-asparaginase encapsulated long-acting cross-linker-free poly (lactic-co-glycolic) acid nanoformulation in an Ehrlich ascites tumor model

Present study explores native L-asparaginase encapsulated long-acting cross-linker-free PLGA-nanoformulation in an Ehrlich ascites tumor model. L-asparaginase-PLGA nanoparticles for tumor were prepared using a double emulsion solvent evaporation technique, optimized and validated by Box-Behnken Design. L-ASN-PNs showed a particle size of 195 nm ± 0.2 nm and a PDI of 0.2. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) techniques revealed its smooth morphology and elicited an in-vitro release of 80% of the drug, following the Higuchi drug release model. In-vivo studies of L-ASN-PNs on an Ehrlich ascites tumor (EAT) model were completed and compared with the standard medication of 5-fluorouracil (5-FU) treatment. L-ASN-PN treated mice showed a 51.15% decrease in tumor volume and 100% survival rate with no reduction in body weight, no haemotoxicity and no hepatotoxicity, as evident from the hematological parameters, and liver enzyme parameters that were well within the prescribed limits. Chemotherapy has severe side effects and restricted therapeutic success. Henceforth, the purported L-Asparaginase PLGA nanoparticles are a suitable entity for better tumor regression, intra-tumor accumulation and no hematological side-effects.

Chemotherapeutic potential of L-carnosine from stimuli-responsive magnetic nanoparticles against breast cancer model.

Aim: L-carnosine-coated magnetic nanoparticles (CCMNPs) were developed to enhance chemotherapeutic activity of carnosine-dipeptide. Materials & methods: Surface grafting of MNPs with carnosine was contended by differential scanning calorimetry, infrared spectroscopy and x-ray diffraction. Physicochemical characterization and in vitro cytotoxicity on MCF-7 cell line was carried out. In vivo chemotherapeutic activity and toxicity was assessed by an Ehrlich Ascites tumor model. Results: CCMNPs possessed monodispersed size (120nm), ζ(-27.3mV), magnetization (51.52emu/g) and entrapment efficiency (88.3%) with sustained release rate. CCMNPs showed 2.3-folds lower IC50 values compared with carnosine solution after 48h. Targeted CCMNPs were specifically accumulated in tumor showing significant reduction in tumor size with no systemic toxicity. Significant reduction in VEGF and cyclin D1 levels were observed. Conclusion: The developed system endowed with responsiveness to an external stimulus can represent a promising magnetically targeted delivery system for carnosine site specific delivery.

Fuzzy delay differential equations under granular differentiability with applications

In this paper, we consider a new setting of fuzzy delay differential equations by employing the concepts of granular differentiability. Firstly, we establish some basic properties of complete granular metric space. Then we study the local and global existence and uniqueness of integral fuzzy solution. For the first task, we use successive approximation technique combined with Gronwall’s lemma. The second task will be solved by Banach contraction principle in weighted metric space defined by granular distance. Additionally, we demonstrate the theoretical results by solving some real-world models in both analytical method and numerical method. The first model is often referred to the exponential growth, namely time-delay growth Malthusian model. The second model is one type of dynamical systems, which is used for studies involving large amounts of tissues, called Ehrlich ascites tumor model with delay. Furthermore, we introduce the Mackey–Glass model which is considered as a useful tool for times series prediction in the neutral network and fuzzy logic fields. Finally, we represent the surface of fuzzy solution for visible identification mark-on.

Examining the antitumoral effect of cornelian cherry (Cornus mas) in ehrlich ascites tumor-induced mice

Introduction: Different doses of C. Mas concentrated syrup on ascitic tumors was investigated in the Ehrlich Ascites Tumor model (EAT). Material and Methods: A total of 46 Balb/C mice were used in our study, 6 of which were stock animals and the other were in ascitic tumor groups. EAT cells (1×106 EAT cells) were injected intraperitoneally into all of the mice. Mice in the treatment groups with ascitic tumors received 100 mg/kg and 200 mg/kg Cornus Mas extract intraperitoneally for 9 days. Results: Counts after the 3 and 24-hour incubations in the EAT cell line that the average number of the dead cells was less in the group to which 100μg/ml C. Mas was administered when compared with the control group, and that this difference was significant at a statistical level (P<0.05). The purpose was also to determine the in vitro cytotoxic effects of Cornus Mas on EAT cells, to define the alive and dead cell rates, and to compare the 3-hour and 24-hour incubation in groups to which Cornus Mas (syrup) extract were given at different concentrations (50, 100, 250μg/ml). Discussion and Conclusion: EAT model is one of the animal tumors induced empirically, it has been the subject matter of many other studies. In the group in which EAT was applied together with high-dose C. mas fruit syrup, it was observed that the EAT cells were not as intense as they were in the tumor control group. Our study showed the anti-tumor effect of C. Mas in assisted tumor development with EAT cells.

The effects of gilaburu (Viburnum opulus) juice on experimentally induced Ehrlich ascites tumor in mice.

The aim of study was to investigate anticancer effect of Viburnum opulus (VO) on Ehrlich ascites carcinoma (EAC) bearing mice that treated with different concentrations of VO. For tumor transplantation; mice were inoculated with 1 × 106 EAC cells intraperitoneally and than divided into five groups (n = 9). Two hours after inoculation; experimental groups were treated daily with VO extract at doses of 1000 mg/kg, 2000 mg/kg, 4000 mg/kg. Extracts obtained from gilaburu juice can have hinder effect on tumor cell growth. As far as we known, this is the first study about in vivo antitumoral activity of VOon Ehrlich ascites tumor model, and consequently VO extract exhibited anticancer activity against EAC-bearing mice.

A pyrrole-based natural small molecule mitigates HSP90 expression in MDA-MB-231 cells and inhibits tumor angiogenesis in mice by inactivating HSF-1.

Heat shock proteins (HSPs), molecular chaperones, are crucial for the cancer cells to facilitate proper functioning of various oncoproteins involved in cell survival, proliferation, migration, and tumor angiogenesis. Tumor cells are said to be "addicted" to HSPs. HSPs are overexpressed in many cancers due to upregulation of transcription factor Heat-shock factor 1 (HSF-1), the multifaceted master regulator of heat shock response. Therefore, pharmacological targeting of HSPs via HSF-1 is an effective strategy to treat malignant cancers like triple negative breast cancer. In the current study, we evaluated the efficacy of a pyrrole derivative [bis(2-ethylhexyl)1H-pyrrole-3,4-dicarboxylate], TCCP, purified from leaves of Tinospora cordifolia for its ability to suppress heat shock response and angiogenesis using MDA-MB-231 cells and the murine mammary carcinoma: Ehrlich ascites tumor model. HSP90 was downregulated by TCCP by inactivation of HSF-1 resulting in inhibition of tumor cell proliferation, VEGF-induced cell migration, and concomitant decrease in tumor burden and neo-angiogenesis in vivo. The mechanism of suppression of HSPs involves inactivation of PI3K/Akt and phosphorylation on serine 307 of HSF-1 by the activation of ERK1. HSF-1 and HSP90 and 70 localization and expression were ascertained by immunolocalization, immunoblotting, and qPCR experiments. The anti-angiogenic effect of TCCP was studied in vivo in tumor-bearing mice and ex vivo using rat corneal micro-pocket assay. All the results thus corroborate the logic behind inactivating HSF-1 using TCCP as an alternative approach for cancer therapy.

In vitro and in vivo efficacy of doxorubicin loaded biodegradable semi-interpenetrating hydrogel implants of poly (acrylic acid)/gelatin for post surgical tumor treatment

The paper describes the preparation and evaluation of doxorubicin loaded semi-interpenetrating polymeric hydrogel network of polyacrylic acid (PAc) and gelatin (G). Post surgical antitumor efficacy and biodistribution of doxorubicin from the implanted degradable hydrogels was investigated on Ehrlich's ascites tumor model using albino mice. Polycaprolactone diacrylate (PCL-DAr) was employed as a crosslinking agent for PAc chains whereas G was kept free. The effect of crosslinking concentration on various physico-chemical properties such as thermal behavior, swelling, degradation behavior, drug release and polymer–polymer interactions was investigated by various physico-chemical tools. Semi-interpenetrating polymeric networks (IPNs) with 0.2 mol% crosslinking concentration showed degradation within 20 days in phosphate buffer (pH 6.5). To determine the in vivo anticancer efficacy, placebo and drug laden cylindrical implants (65 ± 5 µg/implant of 10 mg) were implanted in tumor cavity post tumor excision. After predetermined time intervals (day 7, 11, 14, 20 and 25), drug biodistribution was assessed in tumor, tumor periphery, residual hydrogel and all vital organs i.e. liver, spleen, kidney, heart, lung and blood (spectrofluorimetrically). The drug distribution study showed the concentration of drug in the tumor, tumor periphery and residual hydrogel decreased with increasing time; on the 7th day, drug concentration was highest while, on the 25th day, it was negligible; however, insignificant quantities of the drug was found in vital organs. Histological examination revealed no sign of tumor recurrence until the 25th day with 100% necrosis and slight inflammation in treated the group. In vivo results established that these biodegradable implants can be utilized as post surgical therapy for solid tumors.

Cytotoxicity and antitumoral activity of dichloromethane extract and its fractions from Pothomorphe umbellata

The cytotoxicity of the dichloromethane crude extract (DCE), obtained from the aerial parts of Pothomorphe umbellata (L.) Miq (Piperaceae), was evaluated against nine human cancer cell lines (MCF-7, NCI-ADR/RES, OVCAR-3, PC-3, HT-29, NCI-H460, 786-O, UACC-62, K-562). The DCE presented antiproliferative activity with good potency against all cell lines at low concentrations (between 4.0 and 9.5 microg/mL) and with selectivity (1.55 microg/mL) for the leukemia cell line (K-652). DCE (100, 200, 300 and 400 mg/kg, ip) was also evaluated in the Ehrlich ascites tumor model. Both the survival number and the life span of the animals that died increased by at least 45 and 50%, respectively (8 animals per group), demonstrating P. umbellata extract potential anticancer activity. The results of the in vivo antitumor activity prompted the fractionation of the crude extract. The crude extract was submitted to dry column chromatography with dichloromethane-methanol (99:1). The column effluent fractions were extracted with methanol, dried under vacuum yielding fractions FR1 (less polar), FR2 (medium polarity), and FR3 (polar), which were analyzed for their growth inhibition or cytotoxic properties by a 48-h sulforhodamine B cell viability assay by measuring the total protein content. FR1 demonstrated high potency and cytotoxicity, a result compatible with the high toxicity of oxalic acid; FR2, containing 4-nerolidylcathecol, presented the lowest cytotoxic activity compared to the other two fractions but with selectivity for prostate cancer cell line; FR3, containing a mixture of steroids described in the literature as possessing various biological activities, also presented potent anticancer in vitro activity. These results suggest that P. umbellata DCE in vivo antitumor activity may be a consequence of the activity of different active principles.

Chemotherapeutic potential of the volatile oils from Zanthoxylum rhoifolium Lam leaves

In this work, the anti-tumor properties of the volatile oil from Zanthoxylum rhoifolium Lam leaves and some terpenes (α-humulene, β-caryophyllene, α-pinene and β-pinene) were investigated in vitro and in vivo using the Ehrlich ascites tumor model. Treatment of Ehrlich ascites tumor-bearing mice with 20 mg/kg of the volatile oil and β-caryophyllene for 4 days has significantly increased survival, whereas administration of α-humulene, α-pinene and β-pinene were ineffective in affording protection. Volatile oil and β-caryophyllene exhibited little direct activity against Ehrlich tumor cells in vitro, while α-humulene, α-pinene and β-pinene did not such activity. Investigation of the effects of the volatile oil (and terpenes) treatment on total natural killer cells (NK cell) activity from tumor-bearing mice as a possible mechanism of these compounds in vivo revealed that volatile oil and β-caryophyllene significantly improved NK cell cytotoxicity against YAC-1, a Moloney virus-induced mouse T-cell lymphoma of A/SN origin and Ehrlich ascites cells. As expected, tumor growth in non-treated mice markedly suppressed NK cell cytolysis while the volatile oil and β-caryophyllene reversed this effect when mice were treated with 20-mg/kg dosages of these compounds for 4 days. Summing up, volatile oil exhibits anti-tumor efficacy and significative immunomodulatory action in vivo, which may be related to β-caryophyllene associated to the synergism of other natural compounds presented in volatile oil from Z. rhoifolium Lam leaves.

ISOLATION, PURIFICATION, AND N-TERMINAL PARTIAL SEQUENCE OF AN ANTITUMOR PEPTIDE FROM THE VENOM OF THE CHINESE SCORPION BUTHUS MARTENSII KARSCH

ABSTRACT An antitumor peptide (ANTP) was isolated and purified from the venom of the Chinese scorpion Buthus martensii Karsch. The purification procedure included gel filtration on Sephadex G-50 and Superdex 30 high resolution chromatography, Phenyl Sepharose 6 Fast Flow chromatography, and SP-Sepharose Fast Flow chromatography. Its homogeneity was demonstrated by size exclusion HPLC on TSK G2000 SW. The isoelectric point is more than 10 by pH 3–10 range isoelectric focusing. ANTP has a relative molecular mass of 6280, calculated from the measurement of 16.5% SDS-PAGE. The pharmacological tests showed that ANTP has antitumoral effects in the mouse S-180 fibro sarcoma model and Ehrlich ascites tumor model. Amino acid analysis suggested the ANTP is rich in glycine and does not have histidine and threonine. The sequence of the first 25 N-terminal residues is as follows: Val-Arg-Asp-Gly-Tyr-Ile-Ala-Asp-Asp-Lys-Asn-Cys-Ala-Tyr-Phe-Cys-Gly-Arg-Asn-Ala-Tyr-Cys-Asp-Asp-Glu.

Optimization of tumor radiotherapy. Part VI: Modification of tumor glucose metabolism for increasing the bioavailability of 2-deoxy-D-glucose (2-DG) in a murine tumor model.

Differential radiomodification induced by 2-deoxy-D-glucose (2-DG) is proving to be a feasible modality for optimizing tumor radiotherapy. Our earlier work on Ehrlich ascites tumor cells has shown that pretreatment with hematoporphyrin derivatives increases the uptake and phosphorylation of 2-DG. Moreover, the alteration induced in bioenergetic profile was more drastic and less reversible. The promising combination of hematoporphyrin derivatives and 2-DG has been further evaluated in the Ehrlich ascites tumor bearing mice for determining the effects on radiotherapeutic response. Solid tumors (average volume = 0.9 +/- 0.1 cm3) implanted in Swiss-albino strain "A" mice were focally irradiated (10 Gy) using 60Co teletherapy. Drugs were administered intravenously. Tumor bioenergetics was assessed by 31P MR spectroscopy. The uptake and phosphorylation of 2-DG was observed to be increased following pretreatment with hematoporphyrin derivatives. Upon hematoporphyrin derivatives + 2-DG treatment followed by irradiation, the intracellular pH reduced and a remarkable increase in glycerophosphorylcholine and inorganic phosphate levels was observed. The present study demonstrates the potential of hematoporphyrin derivative pretreatment in increasing the bioavailability of 2-DG in a mice Ehrlich ascites tumor model. The finding may have interesting clinical implications in the form of increased manifestation of the radiation-induced damage in the case of use of these drugs as a potential adjuvant in radiotherapy of tumors.