ABSTRACT
The nucleic acids found in food play a crucial role in maintaining various bodily functions. This study investigated the potential anticancer effects of dietary nucleic acids, an area that is still not fully understood. By utilizing an in vivo mouse model and an in vitro cell model, we discovered an anti-proliferative impact of RNA in both systems. DNA exhibited anti-proliferative effects in the mouse model, while this phenomenon wasn't observed in the in vitro cell model using Ehrlich ascites tumor (EAT) cells. Conversely, DNA hydrolysate demonstrated distinct anti-proliferative effects in EAT cells, suggesting that nucleotides or nucleosides generated during nucleic acid digestion act as active constituents. Furthermore, we examined various nucleosides and two sodium-independent equilibrative nucleoside transporter inhibitors (ENTs), identifying guanosine and 2'-deoxyguanosine as pivotal in the anti-proliferative effect. We also found that the anti-proliferation activity with both nucleosides was suppressed by the treatment of dipyridamole, a non-selective inhibitor for ENT1 and ENT2, but not nitrobenzylthioinosine, a low inhibitor for ENT2. The uptake of these compounds into cells is likely facilitated by ENT2. These nucleotides impeded the progression of cancer cells from the G1 phase to the S phase in the cell cycle. Another significant finding is the increased expression of CCAAT/enhancer-binding protein (C/EBPß) induced by guanosine and 2'-deoxyguanosine. Furthermore, immunostaining revealed that C/EBPß diffuses into the nucleus, indicating its presence. This suggests that guanosine or 2-deoxyguanosine induces G1 arrest in cancer cells via the activation of C/EBPß. Encouraged by these promising results, guanosine and 2'-deoxyguanosine show potential applications in cancer prevention.
Subject(s)
Carcinoma, Ehrlich Tumor , Cell Proliferation , Nucleosides , Animals , Cell Proliferation/drug effects , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/pathology , Carcinoma, Ehrlich Tumor/metabolism , Mice , Nucleosides/pharmacology , Cell Line, Tumor , G1 Phase Cell Cycle Checkpoints/drug effects , Nucleic AcidsABSTRACT
AIM: To study the activity of antitumor immunity effectors and to analyze possible mechanisms of peritoneal Mph M1/M2 repolarization of Balb/c mice under the influence of lectin from B. subtilis IMV B-7724 in the dynamics of the model tumor growth. MATERIALS AND METHODS: Studies were performed on Balb/c mice; Ehrlich adenocarcinoma (ÐСÐ) was used as an experimental tumor. Lectin from B. subtilis IMV B-7724 was administered to ACE-bearing mice at a dose of 1 mg/kg of body weight, 10 times. Immunological testing was performed on days 21 and 28 after tumor grafting. The functional activity of peritoneal macrophages (Mph), natural killer (NK) cells, cytotoxic lymphocytes (CTL), and cytokine levels (IFN-γ, IL-4) were studied by the standard methods. mRNA expression levels of transcription factors STAT-1, STAT-6, IRF5, and IRF4 in Mph were evaluated. RESULTS: The administration of lectin from B. subtilis IMV B-7724 to mice with solid ACE led to the preservation of the initial functional state of peritoneal Mph M1 during the experiment. The bacterial lectin ensured the preservation of the cytotoxic activity of CD8+ T-lymphocytes and a significant (p < 0.05) increase in the NK activity (by 2.7 times compared to the intact animals and by 12.9 times compared to the untreated mice). A strong positive correlation was noted between the levels of the functional activity of Mph and CD8+ T-lymphocytes of animals with tumors and the indices of the antitumor effectiveness of bacterial lectin. The indirect polarization of Mph was evidenced by a strong positive correlation between the level of the NO/Arg ratio (which characterizes the direction of Mph polarization) and the cytotoxic activity of CD8+ T-lymphocytes, NK cells, and the expression of STAT1/STAT6 (the 21st day) and IRF5/IRF4 (the 28th day). CONCLUSION: In ACE-bearing mice, repolarization of the peritoneal Mph toward M1 can occur not only due to the direct action of bacterial lectin on the cellular receptors but also with the involvement of other effectors of antitumor immunity (NK cells, T-lymphocytes). The transcription factors of the STAT and IRF signaling pathways are involved in the polarization process.
Subject(s)
Killer Cells, Natural , Macrophages, Peritoneal , Mice, Inbred BALB C , Animals , Mice , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Macrophages, Peritoneal/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Carcinoma, Ehrlich Tumor/immunology , Carcinoma, Ehrlich Tumor/pathology , Carcinoma, Ehrlich Tumor/metabolism , Bacillus subtilis , Cytokines/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolismABSTRACT
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.
Subject(s)
Carcinoma, Ehrlich Tumor , Carnosine , Neoplasms , Mice , Animals , Female , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/metabolism , Vascular Endothelial Growth Factor A , Mice, Inbred BALB C , Lipids , Magnetic PhenomenaABSTRACT
BACKGROUND: The efficacy of chemotherapy continues to be limited due to associated toxicity and chemoresistance. Thus, synthesizing and investigating novel agents for cancer treatment that could potentially eliminate such limitations is imperative. OBJECTIVE: The current study aims to explore the anticancer potency of cryptolepine (CPE) analog on Ehrlich ascites carcinoma cells (EACs) in mice. METHODS: The effect of a CPE analog on EAC cell viability and ascites volume, as well as malonaldehyde, total antioxidant capacity, and catalase, were estimated. The concentration of caspase-8 and mTOR in EACs was also measured, and the expression levels of PTEN and Akt were determined. RESULTS: Results revealed that CPE analog exerts a cytotoxic effect on EAC cell viability and reduces the ascites volume. Moreover, this analog induces oxidative stress in EACs by increasing the level of malonaldehyde and decreasing the level of total antioxidant capacity and catalase activity. It also induces apoptosis by elevating the concentration of caspase-8 in EACs. Furthermore, it decreases the concentration of mTOR in EACs. Moreover, it upregulates the expression of PTEN and downregulates the expression of Akt in EACs. CONCLUSION: Our findings showed the anticancer activity of CPE analog against EACs in mice mediated by regulation of the PTEN/Akt/mTOR signaling pathway.
Subject(s)
Antineoplastic Agents , Carcinoma, Ehrlich Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Oxidative Stress , PTEN Phosphohydrolase , Proto-Oncogene Proteins c-akt , Quinolines , Signal Transduction , TOR Serine-Threonine Kinases , Animals , PTEN Phosphohydrolase/metabolism , TOR Serine-Threonine Kinases/metabolism , Mice , Oxidative Stress/drug effects , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/pathology , Carcinoma, Ehrlich Tumor/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Cell Proliferation/drug effects , Quinolines/pharmacology , Quinolines/chemistry , Quinolines/chemical synthesis , Structure-Activity Relationship , Dose-Response Relationship, Drug , Molecular Structure , Cell Survival/drug effects , Apoptosis/drug effects , Indole AlkaloidsABSTRACT
Novel and effective treatments are urgently needed for cancer, which is still the leading cause of death in the world. Biological characteristics linked to thiazole derivatives span a wide range. Thiazole derivatives are used in the creation of medications for therapy as well. The aim of current study is to evaluate the anticancer and antioxidant properties of the newly synthesized thiazole derivatives, compounds 1 and 2, on Ehrlich ascites carcinoma (EAC) cells in female mice. Our findings indicated that thiazole derivatives, compounds 1 and 2 have anticancer activity by elevating the p53 expression and cytochrome c levels in groups treated with compounds 1 and 2 compared to the positive control group. Furthermore, thiazole derivatives compounds 1 and 2 showed a potent antioxidant effect by increasing enzymatic antioxidants, catalase (CAT) activity, and non-enzymatic antioxidants, GSH, and lowering Malondialdehyde (MDA) in hepatic and renal tissues of treated groups. Additionally, the target compounds were capable of providing corrective effects against EAC-induced biochemical and histopathological changes without harmful side effects. CONCLUSION: The target studied thiazol derivatives compounds were capable of providing corrective effects against EAC-induced without harmful side effects.
Subject(s)
Carcinoma, Ehrlich Tumor , Neoplasms , Female , Animals , Mice , Antioxidants/pharmacology , Antioxidants/therapeutic use , Ascites/drug therapy , Ascites/pathology , Carcinoma, Ehrlich Tumor/metabolism , Neoplasms/pathology , Liver/metabolismABSTRACT
The aim of this study was to investigate the therapeutic potential of resveratrol in combination with cisplatin on the inhibition of tumour angiogenesis, growth, and macrophage polarization in mice bearing the solid form of an Ehrlich ascites tumour (EAT) that were exposed to whole-body hyperthermia treatment. In addition, we investigated whether a multimodal approach with hyperthermia and resveratrol could abolish cisplatin resistance in tumour cells through the modulation of histone deacetylase (HDAC) activity and levels of heat shock proteins (HSP70/HSP90) and contribute to the direct toxicity of cisplatin on tumour cells. The tumour was induced by injecting 1 × 106 EAT cells subcutaneously (sc) into the thighs of Balb/c mice. The mice were treated with resveratrol per os for five consecutive days beginning on day 2 after tumour injection and/or by injecting cisplatin intraperitoneally (ip) at a dose of 2.5 mg/kg on days 10 and 12 and at a dose of 5 mg/kg on day 15. Immediately thereafter, the mice were exposed to systemic hyperthermia for 15 min at a temperature of 41 °C. The obtained results showed that the administration of resveratrol did not significantly contribute to the antitumour effect of cisplatin and hyperthermia, but it partially contributed to the immunomodulatory effect and to the reduction of cisplatin toxicity and to a slight increase in animal survival. This treatment schedule did not affect microvessel density, but it inhibited tumour growth and modulated macrophage polarization to the M1 phenotype. Furthermore, it abolished the resistance of tumour cells to cisplatin by modulating HDAC activity and the concentration of HSP70 and HSP90 chaperones, contributing to the increased lifespan of mice. However, the precise mechanism of the interaction between resveratrol, cisplatin, and hyperthermia needs to be investigated further.
Subject(s)
Carcinoma, Ehrlich Tumor , Hyperthermia, Induced , Animals , Mice , Cisplatin/pharmacology , Cisplatin/therapeutic use , Resveratrol/pharmacology , Resveratrol/therapeutic use , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/metabolism , Angiogenesis Inhibitors/therapeutic useABSTRACT
The study evaluated the antitumor efficacy of APAN, "synthesized indoloquinoline analog derived from the parent neocryptolepine isolated from the roots of Cryptolepis sanguinolenta", versus the chemotherapeutic drug etoposide (ETO) in Ehrlich solid tumor (EST)-bearing female mice as well as its protective effect against etoposide-triggered hepatic disorders. APAN showed an ameliorative activity against Ehrlich solid tumor and hepatic toxicity, and the greatest improvement was found in the combined treatment of APAN with ETO. The results indicated that EST altered the levels of tumor markers (AFP, CEA, and anti-dsDNA) and liver biomarker function (ALT, AST, ALP, ALB, and T. protein). Furthermore, EST elevated CD68 and anti-survivin proteins immuno-expressions in the solid tumor and liver tissue. Molecular docking studies were demonstrated to investigate their affinity for both TNF-α and topoisomerase II as target proteins, as etoposide is based on the inhibition of topoisomerase II, and TNF-α is quite highly expressed in the solid tumor and liver tissues of EST-bearing animals, which prompted the authors' interest to explore APAN affinity to its binding site. Treatment of mice bearing EST with APAN and ETO nearly regularized serum levels of the altered parameters and ameliorated the impact of EST on the tissue structure of the liver better than that by treatment with each of them separately.
Subject(s)
Carcinoma, Ehrlich Tumor , Chemical and Drug Induced Liver Injury , Neoplasms , Mice , Female , Animals , Etoposide/pharmacology , Etoposide/therapeutic use , Cryptolepis , Tumor Necrosis Factor-alpha , Molecular Docking Simulation , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , DNA Topoisomerases, Type II/therapeutic useABSTRACT
Self-assembled microparticles from chitosan (SAMC) was prepared by depolymerization induced by potassium persulfate. Particle size distribution data showed averaged around 5 µm size and SEM indicated the sequential formation of "RBC" shaped particles. Soluble SAMC consists of 'deacetylated' residues as revealed by 13C NMR. SAMC showed antitumor efficacy in human breast cancer cell lines through mitigation in cell proliferation, colony formation and cell migration. Anti-tumor and anti-angiogenic properties of SAMC was found in vivo Ehrlich ascites tumor (EAT) bearing mice model resulting in tumor growth inhibition (EAT control, 17.4 ml; SAMC treated, 6.8 ml) and improved survival potency (15 days). Moreover, the decrease in ascites VEGF secretion (EAT control, 1354 ng; SAMC treated, 351 ng) accompanied with reduction in neovessel formation. Apoptosis induction by SAMC was confirmed by DNA fragmentation, caspase activities and fluorescence staining methods respectively. SAMC may be a safe candidate for anti-tumor dietary supplement production in food industry.
Subject(s)
Apoptosis/drug effects , Carcinoma, Ehrlich Tumor/drug therapy , Chitosan/pharmacology , Neovascularization, Pathologic/drug therapy , Animals , Carbohydrate Conformation , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Chitosan/chemical synthesis , Chitosan/chemistry , Drug Screening Assays, Antitumor , Female , Humans , Mice , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Neovascularization, Pathologic/pathologyABSTRACT
Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich's mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich's solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-ß, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Ehrlich Tumor/drug therapy , Hydroxybenzoates/therapeutic use , Neovascularization, Pathologic/drug therapy , Nitrofurans/therapeutic use , Signal Transduction/drug effects , Animals , Carcinoma, Ehrlich Tumor/metabolism , Female , Interleukin-6/metabolism , Janus Kinase 2/metabolism , Mice , Molecular Docking Simulation , Neovascularization, Pathologic/metabolism , STAT3 Transcription Factor/metabolismABSTRACT
Queen bee acid or 10-hydroxy-2-decenoic acid (10-HDA) is one of the main and unique lipid components (fatty acids) in royal jelly. Previous studies have demonstrated that 10-HDA has various pharmacological and biological activities. The present study aims to evaluate the anti-tumor effects of 10-HDA alone and combined with cyclophosphamide (CP), as an alkylating agent which widely used for the treatment of neoplastic cancers, against the Ehrlich solid tumors (EST) in mice. Methods: A total of 72 female Swiss albino mice were divided into eight groups. EST mice were treated with 10-HDA (2.5 and 5 mg/kg) alone and combined with CP (25 mg/kg) orally once a day for 2 weeks. Tumor growth inhibition, body weight, the serum level of alpha-fetoprotein (AFP) and carcinoembryonic antigen tumor (CAE), liver and kidney enzymes, tumor lipid peroxidation (LPO) and nitric oxide (NO), antioxidant enzymes (e.g. glutathione reductase (GR), glutathione peroxidase (GPx), catalase enzyme (CAT)), tumor necrosis factor alpha level (TNF-α), and the apoptosis-regulatory genes expression were assessed in tested mice. Results: the findings exhibited that treatment of EST-suffering mice with 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP significantly (p < 0.001) decreased the tumor volume and inhibition rate, tumor markers (AFP and CEA), serum level of liver and kidney, LPO and NO, TNF-α level, as well as the expression level of Bcl-2 in comparison with the mice in the C2 group; while 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP significantly (p < 0.001) improved the level of antioxidant enzymes of GPx, CAT, and SOD and the expression level of caspase-3 and Bax genes. Conclusions: According to the results of the present investigations, 10-HDA at the doses of 2.5 and 5 mg/kg especially in combination with CP showed promising antitumor effects against EST in mice and can be recommended as a new or alternative anticancer agent against tumor; nevertheless, further investigations, particularly in clinical setting, are required to confirm these results.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Ehrlich Tumor , Fatty Acids, Monounsaturated/pharmacology , Neoplasm Proteins/metabolism , Animals , Antineoplastic Combined Chemotherapy Protocols/chemistry , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Cyclophosphamide/chemistry , Cyclophosphamide/pharmacology , Dose-Response Relationship, Drug , Fatty Acids/chemistry , Fatty Acids, Monounsaturated/chemistry , Female , MiceABSTRACT
A fundamental goal in molecular oncology is to unravel the underlying mechanisms which cause the cell transformation. In line with this approach, genome-wide functional screening approaches have revealed exciting insights into heterogeneous nature of cancer. Rapidly expanding horizons of research have unraveled myriad of pathways which play instrumental role in carcinogenesis and metastasis. Oxidative stress has also been reported to be significantly involved in cancer onset and progression. In line with this approach, oxidative stress modulating chemicals have always been sharply divided into antioxidants and oxidative stress-inducing agents. Conceptual and experimental advancements have enabled us to critically analyze full potential of these two different groups of chemicals in cancer chemoprevention. Different antioxidants are currently being analyzed in different phases of clinical trials. Although it has been reported in the literature that antioxidant supplements reduce tumor cells in some tumors or cause volume reduction in solid tumor sizes, there is no definite consensus. Therefore, an antioxidant supplement guideline based on more detailed clinical research and as a result of these is needed to achieve the best care for cancer patients and to avoid risky treatments for cancer patients.
Subject(s)
Antioxidants/therapeutic use , Apoptosis/drug effects , Carcinoma, Ehrlich Tumor/prevention & control , Dietary Supplements , Gene Expression Regulation, Neoplastic/drug effects , Oxidative Stress/drug effects , Animals , Antioxidants/administration & dosage , Apoptosis/genetics , Carcinoma, Ehrlich Tumor/genetics , Carcinoma, Ehrlich Tumor/metabolism , Flavonoids/therapeutic use , Humans , Inflammation/metabolism , Inflammation/pathology , Inflammation/prevention & control , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/prevention & control , Phytotherapy/methods , Plant Extracts/therapeutic use , Plants, Medicinal/chemistryABSTRACT
In breast cancer, there has been evidence of atypical activation of signal transduction and activators of transcription 3 (STAT3). Thymoquinone (TQ) exerts its anti-neoplastic effect through diverse mechanisms, including STAT3 inhibition. The tumor suppressor, microRNA-125a-5p was reported to be downregulated in various breast cancer cells. Therefore, we investigated the influence of TQ and/or doxorubicin on microRNA-125a-5p and its correlation with STAT3 activation as well as tumor growth in mice bearing solid Ehrlich tumors. We found that TQ markedly suppressed inducible and constitutive phosphorylation of STAT3 in tumor tissue without affecting STAT5. Moreover, it attenuated tumor growth, downregulated STAT3 downstream target proteins, and increased the apoptotic activities of caspase-3 and -9. Interestingly, TQ-elicited synergism of doxorubicin anti-neoplastic activity was coupled with upregulation of tumoral microRNA-125a-5p. Taken together, the current findings raise the potential of TQ as a promising chemomodulatory adjuvant to augment mammary carcinoma sensitivity to doxorubicin.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Benzoquinones/pharmacology , Carcinoma, Ehrlich Tumor/drug therapy , Doxorubicin/therapeutic use , MicroRNAs/metabolism , STAT3 Transcription Factor/metabolism , Up-Regulation/drug effects , Animals , Biomarkers, Tumor/metabolism , Carcinoembryonic Antigen/metabolism , Carcinoma, Ehrlich Tumor/genetics , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Cell Line, Tumor , MiceABSTRACT
The search for new antitumor agents or combinations that are more effective and, hopefully, provide fewer health hazards is ongoing. Therefore, this study investigated the efficacy of a novel combination of ponatinib, a multi-targeted tyrosine kinase inhibitor, and the natural phytochemical gossypol against murine solid Ehrlich carcinoma. Six groups of ten mice each received vehicle (I), ponatinib in doses of 10 and 15 mg/kg (II, III) respectively, gossypol in a dose of 4 mg/kg (IV), and ponatinib (10 or 15 mg/kg) in combination with gossypol (4 mg/kg; V, VI). All treatments started on the 12th post-Ehrlich ascites carcinoma (EAC) implantation day and were administered intraperitoneally in daily doses for 3 weeks. Treatment of EAC-bearing mice with ponatinib/gossypol combination improved anticancer efficacy over either drug alone, as demonstrated by greater decreases in tumor weight and volume, and ponatinib (10 mg/kg)/gossypol combination was more efficient than ponatinib (15 mg/kg). Mechanistically, the ponatinib/gossypol combination significantly increased apoptotic markers p53, Bax, and caspase-9 while decreasing anti-apoptotic marker Bcl-2. Furthermore, it greatly decreased proliferative and angiogenic markers, FGFR4 and VEGF, respectively. Histopathology revealed a significant decline in neoplastic cells, the majority of which have necrotic changes and numerous apoptotic bodies, as well as a decrease in mitotic figures and tumor giant cells, indicating the capacity to suppress cancer proliferation/persistence. Overall, gossypol could be used as an adjuvant medication for ponatinib in cancer treatment, possibly leading to successful dose reductions and fewer side effects; however, further research is needed before a clinical application could be feasible.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Carcinoma, Ehrlich Tumor/drug therapy , Cell Proliferation/drug effects , Gossypol/pharmacology , Imidazoles/pharmacology , Neovascularization, Pathologic , Pyridazines/pharmacology , Animals , Apoptosis Regulatory Proteins/metabolism , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Cell Line, Tumor , Female , Mice , Oxidative Stress/drug effects , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Signal Transduction , Tumor Burden/drug effects , Vascular Endothelial Growth Factor A/metabolismABSTRACT
BACKGROUND: Recent studies have shown the potential of using different approaches for immunotherapy in cancer treatment. Macrophages (Mph) are one of the promising targets for immunotherapy. AIM: To investigate changes in the functional activity of Mph in mice with Ehrlich carcinoma by nitric oxide (NO)/arginase (Arg), IRF4/IRF5 and STAT1/STAT6 ratios caused by administration of lectin from B. subtilis IMV-7724. MATERIALS AND METHODS: From the 2nd day after Ehrlich carcinoma inoculation into female Balb/c mice, lectin from B. subtilis IMV B-7724 (0.02 mg/mouse) was administered for 10 days. The peritoneal Mph were isolated on days 14, 21, and 28 after tumor transplantation and their functional state (NO production, Arg activity and cytotoxic activity) was examined. The levels of mRNA expression of transcription factors STAT-1, STAT-6, IRF5, IRF4 were evaluated. RESULTS: In lectin-treated animals with Ehrlich carcinoma, the functional state of Mph (NO/Arg ratio, index of cytotoxic activity) was maintained at the level of intact mice exceeding the values in untreated animals with Ehrlich carcinoma at late terms of tumor growth (21, 28 days). Analysis of mRNA expression levels of transcription factors in these animals showed a significant increase (p < 0.05) in the ratio of STAT1/STAT6 on the day 21 and IRF5/IRF4 on day 28 of tumor growth compared to that in untreated mice. CONCLUSIONS: Administration of lectin from B. subtilis IMV B-7724 to mice with Ehrlich carcinoma led to the prevalence of Mph exhibiting the functional properties of M1 type at late-term tumor growth. The transcription factors of the STAT and IRF signaling pathways are involved in the process of Mph polarization induced by lectin from B. subtilis IMV B-7724.
Subject(s)
Arginase/metabolism , Bacillus subtilis/metabolism , Carcinoma, Ehrlich Tumor/drug therapy , Gene Expression Regulation/drug effects , Lectins/pharmacology , Macrophage Activation/immunology , Nitric Oxide/metabolism , Animals , Carcinoma, Ehrlich Tumor/immunology , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Male , Mice , Mice, Inbred BALB C , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , STAT6 Transcription Factor/genetics , STAT6 Transcription Factor/metabolismABSTRACT
Cisplatin is an approved cancer therapeutic drug used to treat many solid tumors but its accumulation in the kidney, which causes nephrotoxicity, limits its clinical use. Therefore, investigators seek new alternatives to cisplatin that may be more effective and/or safer. Thiosemicarbazides are of great significance due to their expected biological activity including anticancer activities. The aim of this work is the study of the antitumor effect of Schiff base 4-ethyl-1-(pyridin-2-yl) thiosemicarbazide (HEPTS) on Ehrlich solid tumor-bearing mice in comparison to cancer therapeutic drug cisplatin. The experiment was run using sixty adult female Swiss albino mice. Mice were allocated into six groups (n = 10 mice). Healthy control, EAC control (untreated tumor), EAC + cisplatin, EAC + HEPTS, Healthy + HEPTS, and Healthy + solvent. After scarification, blood samples, liver organs, and solid tumors were collected. Tumor weights and volumes were registered. The concentrations of malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase (CAT), total antioxidant capacity (TAC), nitric oxide (NO), uric acid, creatinine, and urea were assessed. Median survival time (MST) and the percentage increase in lifespan (%ILS) were also calculated. Treatment of tumorized mice with HEPTS significantly reduced both tumor volume and weight while it significantly increased the MST, antioxidant marks and prolonged the %ILS. It also, significantly reduced MAD, creatinine, urea, uric acid, and NO levels. Compared to cisplatin, HEPTS effects were better. Our results recommend HEPTS as one of the probable cisplatin-alternatives for tumor treatment after more validation.
Subject(s)
Antineoplastic Agents/pharmacology , Antioxidants/metabolism , Carcinoma, Ehrlich Tumor/drug therapy , Semicarbazides/pharmacology , Up-Regulation/drug effects , Animals , Antineoplastic Agents/chemistry , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Female , Mice , Molecular Structure , Schiff Bases/chemistry , Schiff Bases/pharmacology , Semicarbazides/chemistryABSTRACT
Annonacea species have been reported to possess antitumor properties. However, the in vitro and in vivo antitumor activities of Xylopia aromatica (Annonacea) have not yet been elucidated. This study aimed to investigate the effects of Xylopia aromatica leaves hexane fraction (XaHF) on Ehrlich ascites carcinoma cells lines (EAC), both in vitro and in vivo. In vitro assays revealed a significant cytotoxic effect with the two lower XaHF concentrations (62.5 and 32.3mg/mL). EAC (2.5x106 cells) were inoculated in the right flank of Swiss mice, and the animals were treated intraperitoneally with 32.3mg kg-1 of XaHF daily, for 20 days. Our findings indicate that XaHF suppressed the growth of EAC in vivo, with a significant decrease (46%) in tumor volume. There was also a decrease in the necrosis area (71%), inflammatory infiltrate, and MMP-2 expression. High-Performance Liquid Chromatography with Diode Array Detector (HPLC-DAD) identified secondary metabolites possibly related to phenolic acids, flavonoids, and alkaloids. Thus, the results confirmed the antitumoral activity that may be related to the presence of the identified metabolites in XaHF extract.
Subject(s)
Carcinoma, Ehrlich Tumor/metabolism , Cell Proliferation/drug effects , Matrix Metalloproteinase 2/drug effects , Plant Extracts/pharmacology , Plant Leaves , Xylopia , Alkaloids/chemistry , Animals , Aporphines/chemistry , Carcinoma, Ehrlich Tumor/pathology , Catechin/chemistry , Cell Line, Tumor , Chlorogenic Acid/chemistry , Chromatography, High Pressure Liquid , Down-Regulation , Flavonoids/chemistry , Gallic Acid/chemistry , Lymphocytes, Tumor-Infiltrating/drug effects , Matrix Metalloproteinase 2/metabolism , Mice , Necrosis , Phenols/chemistry , Plant Extracts/chemistry , Quercetin/chemistry , Rutin/chemistry , Tumor Burden/drug effectsABSTRACT
It has been widely reported that cancer, along with its treatment regimens, cause severe toxicity in the host. A suitable agent having chemopreventive properties as well as capabilities of ameliorating tumor- and drug-induced toxicities is of imminent need. Pomegranate has been projected as an excellent anti-tumor, anti-inflammatory and anti-oxidant agent. In this study, for the first time, we delineated the exact signaling cascade by which dietary supplementation of pomegranate fruit extract (PFE) protects tumor-bearing mice from tumor-induced hepatotoxicity. Increased activities of serum Alanine transaminase, Aspartate transaminase, Lactate dehydrogenase and Alkaline phosphatase, as well as histological studies confirmed the establishment of a state of hepatic dysfunction in tumor-bearers. Further investigations revealed that increased hepatic reactive oxygen species content and glutathione depletion-initiated apoptosis in these hepatocytes as we observed an alteration in the apoptotic proteins. PFE supplementation in tumor-bearing mice, on the other hand, differentially modulated redox-sensitive transcription factors Nrf2 and NF-κB, ultimately decreasing tumor-induced hepatic oxidative damage and cell death. siRNA-mediated inhibition of Nrf2 and NF-κB completely abolished the hepato-protective activities of PFE while pre-treatment of tumor-conditioned hepatocytes with N-acetyl cysteine augmented the cyto-protective properties of PFE. The present study clearly identified Nrf2/NF-κB/glutathione axis as the key factor behind the hepatoprotective potential of PFE. These findings would add to the existing knowledge about cancer chemoprevention by dietary polyphenols and might lead to the application of pomegranate polyphenols as supplement to escalate the effectiveness of cancer therapy by protecting normal cells from cancer related toxicities.
Subject(s)
Carcinoma, Ehrlich Tumor/complications , Glutathione/metabolism , Liver Diseases/prevention & control , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Polyphenols/administration & dosage , Pomegranate , Animals , Antioxidants/metabolism , Carcinoma, Ehrlich Tumor/metabolism , Cytokines/metabolism , Dietary Supplements , Female , Hepatocytes/physiology , Inflammation , Liver/metabolism , Liver Diseases/etiology , Liver Diseases/metabolism , Liver Diseases/pathology , Mice , Oxidative Stress , Plant Extracts/administration & dosageABSTRACT
The combined effect of the irradiation with a proton pencil scanning beam (PBS) at a total dose of 80 Gy and neutron radiation at a dose of 5 Gy on the growth of solid Ehrlich ascites carcinoma (EAC) and the remote effects in tumor-bearing mice was studied. Combined irradiation of mice with neutrons before and after irradiation with PBS, as well as irradiation only with PBS, effectively suppressed the growth of solid EAC within 1 month. In terms of the frequency and severity of radiation-induced skin reactions of mice observed 15-40 days after therapy, neutron irradiation after the irradiation with PBS showed better values of these parameters as compared to only PBS; however, exposure to neutrons before PBS was more damaging as compared to the other two options. It was also shown that the tumor relapse rate in the groups of animals with combined irradiation was higher, and the total lifespan was lower than the group of mice irradiated with PBS alone.
Subject(s)
Carcinoma, Ehrlich Tumor/radiotherapy , Mammary Neoplasms, Experimental/radiotherapy , Neutrons/therapeutic use , Proton Therapy , Animals , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Female , Male , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: The field of nanotechnology offers great opportunities for cancer therapy. OBJECTIVE: This study aimed to compare the therapeutic impact of Zn oxide nanoparticles (ZnO NPs) and thymoquinone (TQ) alone or as cotherapy in Ehrlich ascites carcinoma (EAC) induced in mice. MATERIALS AND METHODS: This study was performed on 75 female albino mice divided into Group I: EAC-bearing control group, Group II: EAC treated with TQ, Group III: EAC treated with low-dose ZnO NPs, Group IV: EAC treated with high-dose ZnO NPs, Group V: EAC treated with TQ and low-dose ZnO NPs. All groups were subjected to measurement of cell viability, ascites fluid volume, Bcl2 protein expression by Western blot analysis, cyclooxygenase 2 (COX2) gene expression by a real-time polymerase chain reaction, enzyme-linked immunosorbent assay levels of Beclin 1, interferon γ (INFγ), interleukin 13 (IL-13), and estimation of Zn concentrations in EAC cells and liver homogenate to evaluate its toxicity. RESULTS: Cotherapy has an efficient anticancer effect by enhancing apoptosis and autophagy, resulting in reducing tumor cell viability and ascites fluid volume together with downregulation of Bcl2 protein expression. This cotherapy increases Beclin 1 and INFγ and decreases IL-13. ZnO NPs upregulate COX2 expression, whereas TQ downregulates its expression. High-dose ZnO NPs have more toxic effects on liver enzymes. Using TQ together with ZnO NPs can eliminate ZnO NPs liver toxicity. CONCLUSION: The cotherapy has an efficient anticancer effect by enhancing apoptosis and autophagy. High-dose ZnO NPs have more toxic effects on liver enzymes. Using TQ together with ZnO NPs can eliminate ZnO NP liver toxicity.
Subject(s)
Benzoquinones , Carcinoma, Ehrlich Tumor , Gene Expression Regulation, Neoplastic/drug effects , Nanoparticles , Neoplasm Proteins/biosynthesis , Zinc Oxide , Animals , Benzoquinones/chemistry , Benzoquinones/pharmacology , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Female , Mice , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Zinc Oxide/chemistry , Zinc Oxide/pharmacologyABSTRACT
Soybean (Glycine max L.) is one of the most important and widely consumed food plants worldwide. The objective of this study was to investigate the metabolite profiling of three Egyptian soybean cultivars (Giza 22, Giza 35 and Giza 111) and their in vivo antitumor effect. Random amplified polymorphic DNA (RAPD) analysis developed polymorphism level of 75% in 72 distinct markers. Applying LC-ESI-MS analysis, twenty-nine metabolites were recognized from the 80% methanol extract of all cultivars. In vivo antitumor activity of the 80% methanolic extract against solid Ehrlich ascites carcinoma (EAC) inoculated in mice model, showed a significant diminishing in tumor volume and reduced Glutathione (rGSH) and a significant increase in malondialdehyde (MDA) which was supported by histopathological examination. Among the studied cultivars, Giza 22 cultivar contained the highest total phenolic content (TPC) that may contribute to its impressive antioxidant capacity and antitumor activity.