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Many researchers are focusing on screening the biological activities of plants owing to their safety and possible pharmacological actions. Consequently, we aimed to explore the antiproliferative and cytotoxic properties of Cycas media methanolic extract on HepG2 cell lines. Moreover, we also explore the antitumor action against the experimentally induced solid Ehrlich carcinoma (SEC) model and investigate the possible involved molecular mechanisms. Also, the antibacterial action of the extract was elucidated. Different concentrations of the extract were incubated with HepG2 to determine cytotoxicity, followed by cell cycle analysis. The in vivo experiment was accomplished by grouping the animals into four different groups ( n = 10); normal control, SEC, C. media 100, and C. media 200. The extract was administered at 100 and 200 mg/kg. Tumor volume, tumor inhibition rate, toxicity profile, and antioxidant biomarkers were determined. Moreover, the PI3K/AKT/mTOR signaling pathway was investigated as a possible underlying antitumor mechanism. The tumor control group showed a remarkable upregulation for PI3K, p-AKT, and p-mTOR, along with downregulation for the antioxidant SOD and GPX4, as well as decreased levels of GSH and MDA. C. media extract reversed these parameters to a significant level and the higher dose showed a superior antitumor effect. C. media extract showed antiproliferative effects against HepG2 cells, along with a suppressive action on the PI3K/AKT/mTOR pathway and an antioxidant effect. Additionally, C. media had antibacterial consequences against S. aureus isolates with minimum inhibitory concentrations from 32 to 128 µg/mL. It also caused a noteworthy growth delay as well as a notable reduction in the membrane integrity of S. aureus isolates. These beneficial outcomes suggest C. media to have potential antitumor and antibacterial activities.

This study investigated the antitumoral, anti-inflammatory and oxidative effects of polysaccharides from tucum (Bactris setosa, TUC) using the Ehrlich carcinoma as a tumor model. Additionally, the glycogen content, cytochrome P levels, and gluconeogenesis from lactate were assessed in the liver of healthy animals. Tumor-bearing female mice were orally treated with 50 and 100 mg.kg -1 of TUC or vehicle, once a day, or with 1.5 mg.kg -1 methotrexate via i.p., every 3 days, along 21 days. Both doses of TUC reduced the tumor weight and volume. In the tumor tissue, it decreased GSH and IL-1β levels, and increased LPO, NAG, NO and TNF-α levels. The tumor histology showed necrosis and leukocytes infiltration. The metabolic effects of TUC were investigated by measurement of total cytochrome P (CYP) and glycogen in tumor-bearing mice, and by ex vivo liver perfusion on non-bearing tumor male mice, using lactate as gluconeogenic precursor. Metabolically, the hepatic glucose and pyruvate productions, oxygen uptake, and the total CYP concentration were not modified by TUC. Thus, tucum-do-cerrado polysaccharides have antitumor effects through the modulation of oxidative stress and inflammation, without impairing glucose production from lactate in the liver, the main organ responsible for the metabolism of organic and xenobiotic compounds., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexandra Acco, Lucimara Mach Cordeiro reports financial support was provided by National Council for Scientific and Technological Development. Kaue Marcel de Oliveira, Kahlile Youseff Abboud, Debora Rasec Radulski, Bruna Christ Faria, Claudia Martins Galindo, Gabriela Saidel Pereira, Maria Carolina Stipp reports financial support was provided by Coordination of Higher Education Personnel Improvement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aimed to screen the bioactive components in Streptococcus equinus WC 1 (SE-WC 1 ) and Limosilactobacillus reuteri GM 4 (LR-GM 4 ) and estimate the therapeutic role in Ehrlich solid tumors (EST) mice model. Forty-four male albino EST mice were assigned into 7 groups and treated daily for 2 weeks, including the EST group, the EST mice that received SE-WC 1 at a low or a high dose (0.5 ml *10 6 or 0.5 ml *10 8  cfu), the EST mice that received LR-GM 4 at the low or the high dose (0.5 ml *10 6 or 0.5 ml *10 8  cfu), and the EST mice that received SE-WC 1 plus LR-GM 4 at the low or the high dose. Tumors were harvested, weighed, examined, and used for the determination of apoptosis-related gene expression. Samples of the intestine, liver, and kidney were gathered for histological examination. The GC-MS identified 24 and 36 bioactive compounds in SE-WC 1 and LR-GM 4 , respectively. The main compound in SE-WC 1 was lupeol; however, the main compound in LR-GM 4 was retinaldehyde. EST mice showed disturbances in Bcl-2, Bax, and p53 mRNA expression along with histological changes in the intestine, liver, and kidney. Administration of both bacterial strains reduced the tumor weight, alleviated the disturbances in the gene expression, and improved the histological structure of the intestine, liver, and kidney in a dose-dependent. Moreover, LR-GM 4 was more effective than SE-WC 1 due to its higher content of bioactive compounds. It could be concluded that these strains of probiotics are promising for the treatment of solid tumors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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/EBPβ) induced by guanosine and 2'-deoxyguanosine. Furthermore, immunostaining revealed that C/EBPβ 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/EBPβ. Encouraged by these promising results, guanosine and 2'-deoxyguanosine show potential applications in cancer prevention., Competing Interests: A part of the research grant and DNA, hydrolyzed DNA and RNA materials were provided by Fordays Co., Ltd. We declare that these relationships do not affect the results and conclusions of this study. This does not alter on adherence to PLOS ONE politics on sharing data and materials., (Copyright: © 2024 Shiomi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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 (АСЕ) 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.

Magnetic Lipid-Based Hybrid Nanosystems (M-LC NPs ) 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-LC NPs 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-LC NPs 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 IC 50 values of M-LC NPs 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-LC NPs . Stimuli-responsive M-LCNPs exhibited no apparent systemic toxicity in addition to enhanced chemotherapeutic efficacy compared to nontargeted M-LC NPs 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-LC NPs presented a promising nanoplatform for breast cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Resistance to anti-tumor agents targeting the epidermal growth factor receptor (EGFR) reduces treatment response and requires the development of novel EGFR antagonists. Mutant epidermal growth factor (EGF) forms with reduced agonistic activity could be promising agents in cancer treatment., Methods: EGF D46G affinity to EGFR domain III was assessed with affinity chromatography. EGF D46G acute toxicity in Af albino mice at 320 and 3200 μg/kg subcutaneous doses was evaluated. EGF D46G activity in human epidermoid carcinoma cells at 10 ng/mL concentration in serum-free medium and in subcutaneous Ehrlich ascites carcinoma mice model at 320 μg/kg dose was studied., Results: The D46G substitution decreases the thermal stability of EGF complexes with EGFR domain III by decreasing the ability of the C-terminus to be released from the intermolecular β- sheet. However, with remaining binding sites for EGFR domain I, EGF D46G effectively competes with other EGF-like growth factors for binding to EGFR and does not demonstrate toxic effects in mice. EGF D46G inhibits the proliferation of human epidermoid carcinoma cells compared to native EGF. A single subcutaneous administration of EGF D46G along with Ehrlich carcinoma cells injection inhibits the proliferation of these cells and delays tumor formation for up to seven days., Conclusion: EGF D46G can be defined as a partial EGFR agonist as this mutant form demonstrates reduced agonistic activity compared to native EGF. The study emphasizes the role of the EGF C-terminus in establishing interactions with EGFR domain III, which are necessary for EGFR activation and subsequent proliferation of cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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 × 10 6 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.

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., (© 2023. Pleiades Publishing, Ltd.)

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.

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 13 C 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., (Copyright © 2021. Published by Elsevier Ltd.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2021 Wiley Periodicals LLC.)

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.

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-β, 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.

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., (Copyright © 2021. Published by Elsevier Inc.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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 2 nd 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.

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.

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., (© 2021 Wiley Periodicals LLC.)

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 (2.5x10 6 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.

Metastasis in breast cancer is a leading cause of mortality among women in many countries. This study investigated the anti-cancer role of benzoimidazoquinazoline and benzimidazotriazin; two novel compounds that were designed, synthesized, structurally elucidated, and biologically evaluated as potent anti-angiogenic agents that act through inhibition of vascular endothelial growth factor receptor-2 (VEGFR2). Breast cancer was induced by inoculation of Ehrlich Ascites Carcinoma (EAC) cells. Seventy swiss albino mice were randomly divided into 7 groups, 10 animals each: (1) normal, (2) control EAC group, (3) cisplatin treated group, (4&5) benzoimidazoquinazoline treated (5 mg/kg and 10 mg/kg), (6&7) benzimidazotriazin treated (5 mg/kg and 10 mg/kg). The expression of miR-122 was assessed in the tumor tissue by quantitative PCR, and the VEGF level was determined in serum by ELISA. VEGFR2 and cluster of differentiation (CD)34 were assessed by immunohistochemistry. Serum ALT, AST, creatinine, and urea were measured. Treatment with benzoimidazoquinazoline and benzimidazotriazin decreased tumor weight and serum levels of VEGF, and down-regulated expression of VEGFR2 and CD34 in the tumor tissue. miR-122 was upregulated, particularly in the benzimidazotriazin (10 mg/kg) group. Relative to cisplatin, the novel compounds were less toxic to kidneys. Benzoimidazoquinazoline and benzimidazotriazin are promising anti-cancer agents that act through inhibition of angiogenesis and thus provide a new strategy for advancement of chemotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study was carried out to investigate the potential effects of vitamin B12 and sitagliptin, and their possible synergistic effect with doxorubicin (DOX) on the Ehrlich solid tumor model. B12, sitagliptin, and their combination with DOX were administered to tumor-bearing mice for 21 days. Treatment with B12, sitagliptin, as well as their combinations with DOX caused a significant inhibition of tumor growth and increased the survival time. Malondialdehyde levels and the relative expression of tumor necrosis factor-α and nuclear factor kappa B were significantly decreased, whereas the total antioxidant capacity was significantly increased in all treated groups, except the DOX-treated one, when compared with the positive control group. Moreover, increased apoptosis was also observed by increased cleaved caspase-3 immunostaining and histopathological examination. In conclusion, the antitumor activity of B12 and sitagliptin could be attributed to their ability to induce apoptosis and suppress oxidative stress and inflammation., (© 2020 Wiley Periodicals LLC.)

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.

Recently, a high number of copper derivatives has been evaluated as DNA-targeting metallodrugs, due to the lower toxicity and its potential to cleave DNA. Several strategies have been testing to develop metal compounds effective against tumour cells. In this work, the ternary copper (doxycycline)-(1,10-phenanthroline) complex [Cu(dox)(phen)] 2+ was especially designed as an antitumoral drug, previously showing high cytotoxicity and DNA cleavage activity. We aimed to further investigate the in vitro cytotoxic activity in both tumoral and non-tumoral cells, in vitro genotoxic potential, and in vivo antitumor activity using BALB/C mouse injected with sarcoma S180 and Ehrlich cell lines. Our results indicated that this compound exhibits a moderate genotoxic potential, with selective growth inhibition of tumor cells, especially the murine melanoma B16F10. Its main mechanism of action seems to be through ROS generation. We have further shown a significant reduction of the implanted tumor size in the animal model, suggesting that this compound has great antitumoral potential against many tumor types. [Cu(dox)(phen)] 2+ is selectively cytotoxic for melanoma B16F10 and showed high chemotherapeutic potential in vivo against implanted sarcoma S180 and Ehrlich ascites tumours., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Recently, pyrrolizine derivatives have been reported to possess numerous anticancer activities. In a previous study, (EZ)-6-((4-chlorobenzylidene)-amino)-7-cyano-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine carboxamide (EZPCA) compound was synthesized and the cytotoxic activity of EZPCA toward COX-2 enzyme (overexpressed in cancer cells) was reported. In order to assess the suitability of this compound as a promising pilot structure for in vivo applications, EZPCA was radiolabeled with radioiodine-131 ( 131 I) and various factors affecting radiolabeling process were studied. Quality control studies of [ 131 I]iodo-EZPCA were performed using paper chromatography and HPLC was used as a co-chromatographic technique for confirming the radiochemical yield. Biodistribution studies of [ 131 I]iodo-EZPCA were undertaken in normal and tumor bearing mice. The radiochemical yield percentage of [ 131 I]iodo-EZPCA was 94.20 ± 0.12%. The biodistribution results showed evident tumor uptake of [ 131 I]iodo-EZPCA with promising target/non-target (T/NT) ratios. As a conclusion, these data suggest that [ 131 I]iodo-EZPCA had high binding efficiency, high tumor uptake and sufficient stability to be used be used in diagnostic studies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The importance of biogenic silver/silver chloride nanoparticles has become increasing day by day. In the present study, silver/silver chloride nanoparticles (Ag/AgCl-NPs) were synthesized from Kaempferia rotunda tuberous rhizome extract to evaluate the antiproliferative activity against human glioblastoma stem cells (GSCs) in vitro and Ehrlich ascites carcinoma (EAC) cells in vivo in mice. Synthesis of nanoparticles was confirmed by colour change and UV-visible spectrum and characterized by TEM, XRD, TGA, AFM and FTIR. K rotunda and recently synthesized Zizyphus mauritiana fruit extract-mediated Ag/AgCl-NPs inhibited 77.2% and 71% of GSCs growth at 32 µg/mL concentration with the IC 50 values of 6.8 and 10.4 µg/mL, respectively. Cell morphological studies and caspase-3 immunofluorescence assay revealed that both biogenic nanoparticles induced apoptosis in GSCs. Expression levels of several genes were checked by real-time PCR after treatment with K rotunda tuberous rhizome-mediated Ag/AgCl-NPs. PARP, EGFR, NOTCH2 and STAT3 gene expression were decreased with the increase of NFκB, TLR9, IL1, TNFα, IKK and p21 gene that would be the cause of induction of apoptosis in GSCs. The cell cycle arrest at G 2 /M phase was confirmed by flow cytometric assay. Both nanoparticles were injected intraperitoneally to rapidly growing EAC cells for 5 consecutive days. Approximately, 32.3% and 55% EAC cells growth were inhibited by K rotunda tuberous rhizome-mediated Ag/AgCl-NPs at 6 and 12 mg/kg/day doses, respectively while only 20% cell growth inhibition was monitored at 12 mg/kg/day dose of Z mauritiana-mediated Ag/AgCl-NPs. From the above results, it can be concluded that presently synthesized nanoparticles would be a potent anticancer agent., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: This study addresses the antitumoral properties of Penicillium purpurogenum isolated from a polluted lagoon in Northeastern Brazil., Methods: Ethyl Acetate Extracellular Extract (EAE) was used. The metabolites were studied using direct infusion mass spectrometry. The solid Ehrlich tumor model was used for antitumor activity. Female Swiss mice were divided into groups ( n = 10/group) as follows: The negative control (CTL-), treated with a phosphate buffered solution; the positive control (CTL+), treated with cyclophosphamide (25 mg/kg); extract treatments at doses of 4, 20, and 100 mg/kg; animals without tumors or treatments (Sham); and animals without tumors treated with an intermediate dose (EAE20). All treatments were performed intraperitoneally, daily, for 15 days. Subsequently, the animals were euthanized, and the tumor, lymphoid organs, and serum were used for immunological, histological, and biochemical parameter evaluations., Results: The extract was rich in meroterpenoids. All doses significantly reduced tumor size, and the 20 and 100 mg/kg doses reduced tumor-associated inflammation and tumor necrosis. The extract also reduced the cellular infiltration of lymphoid organs and circulating TNF-α levels. The extract did not induce weight loss or renal and hepatic toxic changes., Conclusions: These results indicate that P. purpurogenum exhibits immunomodulatory and antitumor properties in vivo. Thus, fungal fermentation is a valid biotechnological approach to the production of antitumor agents.

Breast cancer is not only one of the most prevalent types of cancer, but also it is a prime cause of death in women aged between 20 and 59. Although chemotherapy is the most common therapy approach, multiple side effects can result from lack of specificity and the use of overdose as safe doses may not completely cure cancer. Therefore, we aimed in this study is to combine the merits of NF-κB inhibiting potential of celastrol (CST) with glutathione inhibitory effect of sulfasalazine (SFZ) which prevents CST inactivation and thus enhances its anti-tumor activity. Inspired by the CD44-mediated tumor targeting effect of the hydrophilic polysaccharide chondroitin sulphate (ChS), we chemically synthesized amphiphilic zein-ChS micelles. While the water insoluble SFZ was chemically coupled to zein, CST was physically entrapped within the hydrophobic zein/SFZ micellar core. Moreover, physical encapsulation of oleic acid-capped SPIONs in the hydrophobic core of micelles enabled both magnetic tumor targeting as well as MRI theranostic capacity. Combining magnetic targeting to with the active targeting effect of ChS resulted in enhanced cellular internalization of the micelles in MCF-7 cancer cells and hence higher cytotoxic effect against MCF-7 and MDA-MB-231 breast cancer cells. In the in vivo experiments, magnetically-targeted micelles (154.4 nm) succeeded in achieving the lowest percentage increase in the tumor volume in tumor bearing mice, the highest percentage of tumor necrosis associated with significant reduction in the levels of TNF-α, Ki-67, NF-κB, VEGF, COX-2 markers compared to non-magnetically targeted micelles-, free drug-treated and positive control groups. Collectively, the developed magnetically targeted micelles pave the way for design of cancer nano-theranostic drug combinations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: 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., Aim: To study changes in polarization and functions of macrophages isolated from discrete anatomical niches in tumor-bearing mice at different stages of tumor growth., Materials and Methods: Ehrlich carcinoma was transplanted intramuscularly to Balb/c male mice. On days 7, 14, 21 and 28 after 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., Results: 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., Conclusion: Our findings demonstrated that growing tumor could be able to subvert functioning of macrophages at the systemic level.

An integrated microscopic study of the destruction of mouse Ehrlich ascites carcinoma (EAC) cells under starvation conditions has been carried out. It has been found that, in addition to apoptosis, necrosis, and apoptotic necrosis, already known for EAC, cell destruction can also occur through mitochondrial autolysis, which is proposed to be considered a new kind of mitoptosis. A mitoptosis in EAC is characterized by the appearance of many autolyzing mitochondria, the fusion of which leads to rupture of the cell membrane and the ejection of the nucleus from the cell. It is assumed that the polymorphism of EAC destruction patterns is explained by the different physiological state of the cells, which determines the "choice" of the cell death mechanism. This situation poses a challenge for researchers to develop complex inducers with the ability to stimulate all possible types of cancer cell death.

Cancer is one of the most urgent problems in medicine. In recent years, cancer is the second leading cause of death globally. In search for more effective and less toxic treatment against cancer, natural products are used as prototypes in the synthesis of new anticancer drugs. The aim of this study was to investigate the in vivo toxicity and the mechanism of antitumor action of 7-isopentenyloxycoumarin (UMB-07), a coumarin derivative with antitumor activity. The toxicity was evaluated in vitro (hemolysis assay), and in vivo (micronucleus and acute toxicity assays). Ehrlich ascites carcinoma model was used to evaluate in vivo antitumor activity of UMB-07 (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.), after 9 days of treatment, as well as toxicity. UMB-07 (2000 μg/mL) induced only 0.8% of hemolysis in peripheral blood erythrocytes of mice. On acute toxicity assay, LD 50 (50% lethal dose) was estimated at around 1000 mg/kg (i.p.), and no micronucleated erythrocytes were recorded after UMB-07 (300 mg/kg, i.p.) treatment. UMB-07 (25 and 50 mg/kg) reduced tumor volume and total viable cancer cells. In the mechanism action investigation, no changes were observed on the cell cycle analysis; however, UMB-07 reduced peritumoral microvessels density and CCL2 chemokine levels. In addition, UMB-07 showed weak toxicity on biochemical, hematological, and histological parameters after 9 days of antitumor treatment. The current findings suggest that UMB-07 has low toxicity and exerts antitumor effect by inhibit angiogenesis via CCL2 chemokine decrease.

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., .

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 6 mg/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 (50 Hz, 50 mT), 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.

Structural diversity characterizes natural products as prototypes for design of lead compounds. The aim of this study was to synthetize, and to evaluate the toxicity and antitumor action of a new piperine analogue, the butyl 4-(4-nitrobenzoate)-piperinoate (DE-07). Toxicity was evaluated against zebrafish, and in mice (acute and micronucleus assays). To evaluate the DE-07 antitumor activity Ehrlich ascites carcinoma model was used in mice. Angiogenesis, Reactive Oxygen Species (ROS) production and cytokines levels were investigated. Ninety-six hours exposure to DE-07 did not cause morphological or developmental changes in zebrafish embryos and larvae, with estimated LC 50 (lethal concentration 50%) higher than 100 μg/mL. On the acute toxicity assay in mice, LD 50 (lethal dose 50%) was estimated at around 1000 mg/kg, intraperitoneally (i.p.). DE-07 (300 mg/kg, i.p.) did not induce increase in the number of micronucleated erythrocytes in mice, suggesting no genotoxicity. On Ehrlich tumor model, DE-07 (12.5, 25 or 50 mg/kg, i.p.) induced a significant decrease on cell viability. In addition, there was an increase on ROS production and a decrease in peritumoral microvessels density. Moreover, DE-07 induced an increase of cytokines levels involved in oxidative stress and antiangiogenic effect (IL-1β, TNF-α and IL-4). No significant clinical toxicological effects were recorded in Ehrlich tumor transplanted animals. These data provide evidence that DE-07 presents low toxicity, and antitumor effect via oxidative and antiangiogenic actions by inducing modulation of inflammatory response in the tumor microenvironment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

There is a great demand to introduce new approaches into cancer treatment field due to incidence of increased breast cancer all over the world. The current study was designed to evaluate the role of imatinib mesylate (IM) and/or hesperidin (HES) nanoparticles alone or in combination in enhancing the anticancer activity and to investigate the ability of nanoencapsulation to reduce cardiotoxicity of IM in solid Ehrlich carcinoma (SEC)-bearing mice. IM and HES were loaded into PLGA (poly(lactic-co-glycolic acid) polymer. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n = 10). On day 28 from tumor inoculation, mice were sacrificed and blood samples were collected in heparinized tubes for hematological studies, biochemical determination of lactate dehydrogenase (LDH), and glutamic oxaloacetic transaminase (SGOT) levels. In addition, tumor and cardiac tissues were utilized for histopathological examination as well as determination of MDR-1 gene expression. Immunohistochemical staining of BAX and BCL-2 was done. Nano IM- and/or Nano HES-treated groups showed a significant reduction in tumor volume, weight, hematological, cardiac markers, and tumor MDR-1 gene downregulation compared to free conventional treated groups. In conclusion, the use of HES as an adjuvant therapy with IM could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, nanoencapsulation of IM and/or HES with PLGA polymer showed a remarkable anticancer activity., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

A new type of bioactive polypeptides of the neurosecretory hypothalamus called proline‑rich peptides (PRPs), which are isolated from bovine neurosecretory granules of the neurohypophysis, are synthesized in the form of a common precursor protein (neurophysin vasopressin‑associated glycoprotein). Proline‑rich polypetide 1 (PRP‑1; also known as galarmin) is comprised of 15 amino acids residues, and has been suggested to possess anti‑neurodegenerative, immunoregulatory, hematopoietic, antimicrobial and antitumor properties. The cytostatic, antiproliferative effect of PRP‑1 was demonstrated in the human chondrosarcoma JJ012 and triple negative breast carcinoma MDA MB 231 cell lines. PRP‑1 action is disease and tissue specific. To further explore the antitumorigenic and possible cytotoxic effects of PRP‑1, a morpho‑functional study on the effect of PRP‑1 on a mouse Ehrlich ascites carcinoma (EAC) model was conducted. The PRP‑1‑induced morphological features of EAC cells confirmed the apoptotic nature of PRP‑1, as manifested by cell shrinkage, membrane blebbing, chromosome condensation (pyknosis) and nuclear fragmentation (karyorrhexis). The effect of PRP‑1 on the number of tumor cells incubated for 24 h and their viability in trypan blue‑stained samples lead to a 44% reduction in the number of viable cells on day 11 post‑inoculation vs. 22% inhibition of viable cells after PRP‑1 treatment (0.1 µg/ml) on day 7 post‑inoculation. Apoptosis experiments using an Annexin V‑cyanine 3 apoptosis detection kit indicated that 24 h incubation with 0.1 µg/ml PRP‑1 caused a significant increase in the number of apoptotic cells, reaching 50.33%, compared to 8.33% in the sample control on day 7 post‑inoculation.

There is tremendous scope for identifying novel anti-cancer molecules from the unexplored reserves of plant kingdom. The application of dietary supplementation or medicine derived from such sources is a promising approach towards treatment of cancer. In the present study we have evaluated the antiproliferative potential of 4-hydroxyisophthalic acid (4-HIPA), which is a novel antioxidant compound isolated from the roots of the aqueous extract of Decalepis hamiltonii. 4-HIPA was screened in vitro against human breast cancer cell lines MCF-7, MDA-MB-468 and normal human breast epithelial cell MCF-10, and demonstrated that human breast cancer cell lines, in contrast to MCF-10, are sensitive to 4-HIPA .4-HIPA showed marked reduction in cell viability and short-term proliferation assays in these cells. Results of the long-term colony formation and scratch assay further reaffirmed that 4-HIPA inhibited the growth and proliferation in breast cancer cells. We further conducted in vivo studies using murine Ehrlich Ascites Tumor (EAT) cell model. Our in vivo results established that treatment with 4-HIPA reduced the tumorigenesis by promoting apoptosis in EAT-bearing mice. The results of our molecular docking predictions further warranted our claim. This study is valuable as 4-HIPA exhibits antiproliferative potential that can be exploited in the development of anticancer drugs.

Aims: Notch signaling is highly implicated in several cancers and chemoresistance. Therefore, Notch-targeted therapies might be beneficial in enhancing chemotherapeutic effect and cancer regression. This study aimed to investigate implication of Notch in development and progression of solid Ehrlich carcinoma (SEC) and enhancement of anticancer effect of cisplatin (CIS) by addition of thymoquinone (TQ) and pentoxifylline (PTX) through modulation of Notch., Main Methods: SEC was induced in mice as model for mammary carcinoma by s.c. injection of 1 × 10 6 Ehrlich cells into back of the mice. On 12 th day, solid tumor was developed and mice were divided into seven groups; tumor control, early CIS (ECIS), ECIS + ETQ, ECIS + ETQ + EPTX, late CIS (LCIS), LCIS + LTQ, and LCIS + LTQ + LPTX. Early treatment was started on 12 th day, whereas late treatment was begun on 19 th day from tumor inoculation. At the endpoint, samples were collected for detection of Notch1, Hes1, Jagged1, β-catenin, TNF-α, IL-6, IFN-γ, IL-2, VEGF, apoptosis, CD4, and CD8., Key Findings: Adding PTX and TQ to CIS significantly reduced Notch1, Hes1, Jagged1, β-catenin, TNF-α, IL-6, IFN-γ, and VEGF with increment in IL-2, CD4, CD8, and apoptotic cells. Moreover, early treated groups showed remarkable attenuation in tumor growth and the relevant parameters compared to their counterpart later groups., Significance: Addition of PTX with TQ to CIS showed a synergistic chemotherapeutic action and induced better oncostatic effect mainly through Notch suppression. Consequently, shutting Notch could be of great interest in promoting chemosensetivity and cancer control., Competing Interests: Declaration of competing interest The authors have no conflicts of interests related to this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Blockade of α6, α3β2, α9α10, and α7 subtypes of nicotinic acetylcholine receptors slows tumor growth in vivo, increases cytotoxic activity of splenocytes from tumor-bearing mice, and, to some extent, reduces the viability of Ehrlich carcinoma cells in vitro. These data indicate that nicotinic acetylcholine receptors are involved in oncogenesis, affecting the survival of tumor cells, inter alia, via modulation of the antitumor immunity.

Breast cancer is the most common cancer in females, and the leading cause of cancer-related mortality in the world. Among the available treatment options for cancer, chemotherapy is the therapy for treating a variety of cancer patients. However, the therapeutic efficacy of current agents is minimal and these drugs do not retard the progression of disease pathology. Lack of appropriate therapy may increase the prevalence of disease in world. Hence, more effective strategies and novel therapies must be pursued for altering the progression of the disease acting through different mechanisms. There is a continuing need for new and improved therapy. Hence, Vitamin B17 is suggested a therapeutic potential for treating breast cancer. This study is to evaluate the potential therapy of vitamin B17 (Vit B17, amygdalin) against Ehrlish solid tumors, bearing mice (EST) induced DNA damage, NF-Kb, TNFα and apoptosis. Sixty female mice were randomly divided into four groups: (I, control group; II, VitB17 group; III, EST group; IV, EST+VitB17 group). EST induced group had elevated in the levels of serum ALT, AST, ALP, creatinine, urea, potassium ions, cholesterol, triglycerides, cytokine IFNγ, NF-kb, DNA damage, tumor TNF-α, VEGF expressions and had an associated reduction in serum albumin, total proteins, sodium ions, tumor NF-kb, Bcl2 and survivin expressions. Treatment of EST with vitamin B17 (EST+VitB17) modulates the changes in liver and kidney functions, electrolytes, cytokines, NF-kb and apoptosis in mice bearing EST. Hence, these findings suggest that vitamin B17 can be a reliable and novel therapy for breast cancer, further validate the neoplastic activity of Vitamin B17 as a potential therapy for other types of cancer is needed.

Aims: In the present study, the flavonoid fraction of Tabernaemontana divaricata flavonoid fraction(TdFf) leaves was investigated for its in vitro and in vivo antioxidative and antitumor activity., Subjects and Methods: The flavonoid fraction of ethyl acetate extract was assessed for their in vitro antioxidant activity by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), superoxide radicals, ferric reducing antioxidant power (FRAP), hydrogen peroxide, hydroxyl radicals and nitric oxide and in vivo antioxidative activity by enzymic and nonenzymic antioxidants in the liver of intraperitoneally implanted Ehrlich's lymphoma (EAC) and Dalton's lymphoma ascites (DLAs) model. The in vitro cytotoxicity was assessed using trypan blue exclusion assay and in vivo antitumor activity was assessed by screening the ILS, serum liver marker enzymes and histopathology of the liver., Statistical Analysis Used: The data were expressed as the mean ± standard deviation of the means, and statistical analysis was carried out employing one-way and two-way analysis of variance using Web Agri Stat Package 2.0., Results: The dose-dependent percentage scavenging of ABTS, DPPH, FRAP, OH, superoxide radical, and nonradical NO and H 2 O 2 by TdFf indicated their antioxidative potential. Incubation of EAC/DLA tumor cells with TdFf showed a concentration-dependent cytotoxic effect, and the extract killed 50% of EAC/DLA tumor cells at a concentration of 80 μg of TdFf. Coadministration of TdFf with EAC/DLA-induced mice showed a significant increase in the liver enzymic and nonenzymic antioxidants and significant decrease in the serum liver marker enzymes to prove the in vivo antioxidative and antitumor activity of TdFf. It was also confirmed by the histopathology of the liver., Conclusions: It may be concluded that the flavonoid fractions of Td possess considerable antioxidative and antitumorigenic activity against the tested DLA/EAC in both in vitro and in vivo system., Competing Interests: None

The antitumor effects of thiophene and acridine compounds have been described; however, the clinical usefulness of these compounds is limited due to the risk of high toxicity and drug resistance. The strategy of molecular hybridization presents the opportunity to develop new drugs which may display better target affinity and less serious side effects. Herein, 2-((6-Chloro-2-methoxy-acridin-9-yl)amino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophene-3-carbonitrile (ACS03), a hybrid thiophene-acridine compound with antileishmanial activity, was tested for toxicity and antitumor activity. The toxicity was evaluated in vitro (on HaCat and peripheral blood mononuclear cells) and in vivo (zebrafish embryos and acute toxicity in mice). Antitumor activity was also assessed in vitro in HCT-116 (human colon carcinoma cell line), K562 (chronic myeloid leukemic cell line), HL-60 (human promyelocytic leukemia cell line), HeLa (human cervical cancer cell line), and MCF-7 (breast cancer cell line) and in vivo (Ehrlich ascites carcinoma model). ACS03 exhibited selectivity toward HCT-116 cells (Half maximal inhibitory concentration, IC50 = 23.11 ± 1.03 µM). In zebrafish embryos, ACS03 induced an increase in lactate dehydrogenase, glutathione S-transferase, and acetylcholinesterase activities. The LD50 (lethal dose 50%) value in mice was estimated to be higher than 5000 mg/kg (intraperitoneally). In vivo, ACS03 (12.5 mg/kg) induced a significant reduction in tumor volume and cell viability. In vivo antitumor activity was associated with the nitric oxide cytotoxic effect. In conclusion, significant antitumor activity and weak toxicity were recorded for this hybrid compound, characterizing it as a potential anticancer compound.

In this investigation, we examined the effect of anthracycline antibiotics on oxygen radical metabolism in Ehrlich tumor cells. In tumor microsomes and nuclei, doxorubicin increased superoxide anion production in a dose-dependent fashion that appeared to follow saturation kinetics; the apparent K m and V max for superoxide formation by these organelles was 124.9  μ M and 22.6 nmol/min/mg, and 103.4  μ M and 4.8 nmol/min/mg, respectively. In both tumor microsomes and nuclei, superoxide formation required NADPH as a cofactor, was accompanied by the formation of hydrogen peroxide, and resulted from the transfer of electrons from NADPH to the doxorubicin quinone by NADPH:cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4). Anthracycline antibiotics also significantly enhanced superoxide anion production by tumor mitochondria with an apparent K m and V max for doxorubicin of 123.2  μ M and 14.7 nmol/min/mg. However, drug-stimulated superoxide production by mitochondria required NADH and was increased by rotenone, suggesting that the proximal portion of the electron transport chain in tumor cells was responsible for reduction of the doxorubicin quinone at this site. The net rate of drug-related oxygen radical production was also determined for intact Ehrlich tumor cells; in this system, treatment with doxorubicin produced a dose-related increase in cyanide-resistant respiration that was enhanced by changes in intracellular reducing equivalents. Finally, we found that in the presence of iron, treatment with doxorubicin significantly increased the production of formaldehyde from dimethyl sulfoxide, an indication that the hydroxyl radical could be produced by intact tumor cells following anthracycline exposure. These experiments suggest that the anthracycline antibiotics are capable of significantly enhancing oxygen radical metabolism in Ehrlich tumor cells at multiple intracellular sites by reactions that could contribute to the cytotoxicity of this class of drugs., Competing Interests: There are no conflicts of interest associated with this paper., (Copyright © 2019 James H. Doroshow.)

Breast cancer is the current leading cause of cancer death in females worldwide. Although current chemotherapeutic drugs effectively reduce the progression of breast cancer, most of these drugs have many unwanted side effects. Salvianolic acid B (Sal-B) is a bioactive compound isolated from the root of Danshen Radix with potent antioxidant and anti-inflammatory properties. Since free radicals play a key role in the initiation and progression of tumor cells growth and enhance their metastatic potential, the current study was designed to investigate the antitumor activity of Sal-B and compare it with the antitumor activity of the traditional anticancer drug, cisplatin. In vitro, Sal-B decreased the human breast cancer adenocarcinoma (MCF-7) cells proliferation in a concentration and time dependent manner. In vivo and similar to cisplatin treatment, Sal-B significantly reduced tumor volume and increased the median survival when compared to tumor positive control mice group injected with Ehrlich solid carcinoma cell line (ESC). Sal-B decreased plasma level of malondialdehyde as a marker of oxidative stress and increased plasma level of reduced glutathione (GSH) as a marker of antioxidant defense when compared to control ESC injected mice. Either Sal-B or cisplatin treatment decreased tumor tissue levels of tumor necrosis factor (TNF-α), matrix metalloproteinase-8 (MMP-8), and Cyclin D1 in ESC treated mice. Contrary to cisplatin treatment, Sal-B did not decrease tumor tissue Ki-67 protein in ESC injected mice. Immunohistochemical analysis revealed that Sal-B or cisplatin treatment increased the expression of the apoptotic markers caspase-3 and P53. Although Sal-B or cisplatin significantly reduced the expression of the angiogenic factor vascular endothelial growth factor (VEGF) in ESC injected mice, only Sal-B reduced expression level of COX-2 in ESC injected mice. Our data suggest that Sal-B exhibits antitumor features against breast cancer cells possibly via enhancing apoptosis and reducing oxidative stress, inflammation, and angiogenesis.

Background: Cyclophosphamide (CP) causes premature ovarian failure (POF) due to ovarian toxicity. The toxicity mechanism is attributed to oxidative stress, inflammation, and apoptosis. We assessed whether quercetin and rosuvastatin could promote ovarian protection against CP ovotoxicity., Methods: A total of 80 female BALB/c mice were randomly assigned; 10 mice into each of eight groups. Group 1 (control), group 2 (EH), group 3 (CP), group 4 (QH), group 5 (QL), group 6 (RH), group 7 (RL), and group 8 (COM)., Results: Quercetin and rosuvastatin groups (4:8) showed signs of restored ovarian function in the form of a significant, dose-dependent increase in primordial follicles number, serum anti-Mullerian hormone level, and ovarian tissue glutathione level ( p < 0.05) versus group 3, and a significant, dose-dependent decrease in atretic follicles number and ovarian tissue level of malondialdehyde ( p < 0.05) versus group 3. Immunohistochemistry analysis demonstrated a lower expression of caspase and nuclear factor-kappa B of groups (4:8) versus group 3, although quercetin and rosuvastatin showed a nonsignificant reduction in tumor volume., Conclusions: We demonstrated the protective effect of quercetin and rosuvastatin against ovarian toxicity and POF induced by CP without compromising its antitumor effect.

Many cancer therapies indirectly activate apoptosis by chemical or physical damage of DNA. This study was performed to evaluate protective potential of vitamin B17 (VitB17) against Ehrlich solid tumor (EST) induced changes in the oxidative stress, DNA damage, apoptosis and proliferation in mice. In the experiment, 60 female CD1 mice were randomly and allocated to the following four equal-sized groups [G1, negative control; G2, positive control (VitB17); G3, untreated EST; G4, EST treated with VitB17 (EST+VitB17)]. The untreated EST group displayed major increases in tumor volume, significant increase in the levels of MDA, H 2 O 2 , NO, PCNA, TNF-α, AFP and dsDNA and notable reductions in the catalase, GSH, P53 and SOD activities. By contrast, reduced levels of TNF-α, AFP, MDA, H 2 O 2 , NO, PCNA and dsDNA, along with enhanced levels of P53 and the antioxidant indicators catalase, GSH and SOD were observed in the EST+VitB17 group. These results indicate the antineoplastic and antioxidant properties of vitamin B17 with the potential to decrease the oxidative stress associated with ESTs by augmenting the antioxidant defence system.