Synthesis, anticancer evaluation of novel hybrid pyrazole-based chalcones, molecular docking, DNA fragmentation, and gene expression: in vitro studies.

A unique series of pyrazolyl-chalcone derivatives was synthesized via the method of Claisen-Schmidt condensation. The desired chalcone derivatives 7a-d and 9a-f were obtained in good yields by reacting the 4-acetyl-5-thiophene-pyrazole with the appropriate heteroaryl aldehyde derivatives. The novel chalcones have undergone complete elemental analysis, 1H-NMR, 13C-NMR, mass spectrometry, and IR characterization. The three human cancer cell lines MCF7 (human Caucasian breast adenocarcinoma), PC3 (prostatic cancer) and PACA2 (pancreatic carcinoma) as well as the normal cell line BJ1 (normal skin fibroblasts) were tested in vitro for the anti-cancer properties of the newly synthesized chalcone derivatives. When compared to the reference medicine doxorubicin (IC50 = 52.1 µM), compound 9e showed the most promise derivative (IC50 = 27.6 µM) against PACA2 cells, while compound 7d demonstrated anticancer efficacy (IC50 = 42.6 µM against MCF7 cells compared to the reference drug doxorubicin (IC50 = 48 µM). Using breast and pancreatic cell lines, the gene expression, DNA damage, and DNA fragmentation percentages for compounds 7d and 9e were evaluated. Moreover, the molecular docking study of compounds 7d and 9e was assessed. The binding affinities of compound 9e toward P53 mutant Y220C was -22 kcal per mole, while those of compound 7d towards Bcl2 and CDK4 were -27.81 and -26.9 kcal per mole, respectively, compared to the standard values (-15.82, -33.96 and -29.9 kcal per mole).

Suppression of tumor growth and apoptosis induction by pomegranate seed nano-emulsion in mice bearing solid Ehrlich carcinoma cells.

Despite the high antioxidant and penetration ability of pomegranate seed oil (PSO), the in vivo antitumor activity of PSO nano-emulsion has not been well investigated. Therefore, this study was undertaken to estimate the antitumor activity and safety of PSO nano-emulsion in mice bearing Ehrlich solid carcinoma cells. For tumor inoculation, about 2 × 106 viable Ehrlich tumor cells (200 µl) were implanted intramuscularly in the left thigh of hind leg. Once a solid tumor appears on the 10th day of transplantation; the mice were randomly divided into five groups (5 animals/group). Characterization of the PSO nano-emulsion using a Zeta sizer Malvern instrument and transmission electron microscope (TEM) revealed that the PSO nano-droplets were well dispersed with an average particle size of 8.95 nm and a spherical shape. Treatment with PSO nano-emulsions caused a significant reduction in the tumor size and weight, in a dose dependent manner, compared to tumor control group. Marked dose dependent elevations in the DNA damage level together with significant increases in the tumor suppressor p53, Bax and Caspase genes and reductions in the anti-apoptotic Bcl2 gene were also observed in the tumor tissue of mice given PSO nano-emulsions. Histological examination also revealed apoptosis and necrosis of tumor cells and tumor infiltration with inflammatory cells after PSO nano-emulsion treatment. However, high DNA damage was noticed in the liver and kidney tissues of mice given the highest dose of PSO nano-emulsion (400 mg/kg). Therefore, we concluded that PSO nano-emulsion exhibited a potent antitumor activity through induction of DNA breaks that triggers apoptosis of tumor cells but the highest dose caused genotoxicity to liver and kidney tissues, thus it is recommended to use doses lower than 400 mg/kg of PSO nano-emulsion as an alternative drugs for chemotherapy.

Comparative analysis of Acomys cahirinus and Mus musculus responses to genotoxicity, oxidative stress, and inflammation.

The Egyptian spiny mouse, Acomys cahirinus, is a recently described model organism for regeneration studies. It has surprising powers of regeneration with relatively fast repairing mechanisms and reduced inflammation form compared to other mammals. Although several studies have documented the exceptional capabilities of Acomys to regenerate different tissues after injury, its response to different cellular and genetic stresses is not yet investigated. Therefore, the current study aimed to investigate Acomys abilities to resist genotoxicity, oxidative stress and inflammation induced by acute and subacute treatments with lead acetate. Responses of Acomys were compared with those of the lab mouse (Mus musculus), which displays signatures of the "typical" mammalian response to various stressors. Cellular and genetic stresses were induced by using acute and subacute doses of Lead acetate (400 mg/kg and 50 mg/kg for 5 days, respectively). The assessment of genotoxicity was carried out by using comet assay, while oxidative stress was evaluated by measuring the biomarkers; MDA, GSH and antioxidant enzymes CAT and SOD. Moreover, inflammation was assessed by analyzing the expression of some inflammatory-regeneration-related genes: CXCL1, IL1-ß, and Notch 2 and immunohistochemical staining of TNF-α protein in brain tissue, in addition to histopathological examination of brain, liver, and kidneys. The obtained results revealed a unique resistance potency of Acomys to genotoxicity, oxidative stress, and inflammation in certain tissues in comparison to Mus. Altogether, the results revealed an adaptive and protective response to cellular and genetic stresses in Acomys.

Apoptosis and oxidative stress as relevant mechanisms of antitumor activity and genotoxicity of ZnO-NPs alone and in combination with N-acetyl cysteine in tumor-bearing mice.

Background: Several in vitro studies have revealed that zinc oxide nanoparticles (ZnO-NPs) were able to target cancerous cells selectively with minimal damage to healthy cells. Purpose: In the current study, we aimed to evaluate the antitumor activity of ZnO-NPs in Ehrlich solid carcinoma (ESC) bearing mice by measuring their effect on the expression levels of P53, Bax and Bcl2 genes as indicators of apoptotic induction in tumor tissues. Also, we assessed the potential ameliorative or potentiation effect of 100 mg/kg N-acetyl cysteine (NAC) in combination with ZnO-NPs. Materials and methods: ESC bearing mice were gavaged with three different doses of ZnO-NPs (50, 300 and 500 mg/kg body weight) alone or in combination with NAC for seven consecutive days. In addition to measuring the tumor size, pathological changes, zinc content, oxidative stress biomarkers and DNA damage in ESC, normal muscle, liver and kidney tissues were assessed. Results: Data revealed a significant reduction in tumor size with a significant increase in p53 and Bax and decrease in Bcl2 expression levels in the tissues of ZnO-NPs treated ESC bearing mice. Moreover, a significant elevation of MDA accompanied with a significant reduction of CAT and GST. Also, a marked increase in all comet assay parameters was detected in ZnO-NPs treated groups. On the other hand, the combined treatment with ZnO-NPs and NAC significantly reduced reactive oxygen species production and DNA damage in liver and kidney tissues in all ZnO-NPs treated groups. Conclusion: ZnO-NPs exhibited a promising anticancer efficacy in ESC, this could serve as a foundation for developing new cancer therapeutics. Meanwhile, the combined treatment with ZnO-NPs and NAC could act as a protective method for the healthy normal tissue against ZnO-NPs toxicity, without affecting its antitumor activity.