Antitumour and Acute Toxicity Studies of 4-(pyridin-4-yl)-6-(thiophen-2-yl)pyrimidin-2(1H)-one Against Ehrlich Ascites Carcinoma and Sarcoma-180

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl)pyrimidin-2(1H)-one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC50 value of 1.95 μM and was found to instigate apoptosis. In the present study, the antitumour efficacy of SK-25 was investigated on Ehrlich ascites tumour (solid), Sarcoma 180 (solid) tumour and Ehrlich ascites carcinoma. The compound was found to inhibit tumour development by 94.71% in Ehrlich ascites carcinoma (EAC), 59.06% in Ehrlich tumour (ET, solid) and 45.68% in Sarcoma-180 (solid) at 30 mg/kg dose. Additionally, SK-25 was established to be non-toxic at a maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Computer-based predictions also show that the compounds could have an interesting DMPK profile. The current study provides insight for further investigation of the antitumour potential of the molecule.

Role of polyphenolic acetates and calreticulin induced hyperacetylation via epigenetic modulation on apoptosis in Ehrlich Ascites tumour mice model

Objective: Role of Polyphenolic acetates (PAs) was studied to explore their ability to impart acetylation of histone protein by the novel mechanism of acetylation in Ehrlich Ascites tumour (EAT) mice model. Effect of HDAC inhibitor Valproic acid (VA) alone and in combination with Polyphenolic acetates and also Polyphenolic acetates along with Calreticulin (CAL) induced hyperacetylation causing modulation of apoptosis was also investigated in view of possibility to develop target oriented combination therapy in cancer.Materials and Methods: EAT mice model was established. EAT mice were treated with different PAs, VA and purified, recombinant calreticulin and their combinations by Intra peritoneal route (I.P) which induced transacetylation of histones resulting in apoptosis. After 26 hrs of the above treatment, 2ml of peritoneal fluid was aspirated from mice of all the above groups. The peritoneal fluid was studied for the amount of acetylated histone proteins by Western blotting using commercially available specific Anti- Acetyl Histone (Ac-Lys) Antibodies and extent of apoptosis in peritoneal cells by Flow-Cytometry and fluorescence microscopy.Results: The number of apoptotic cells were represented by the Median (25th, 75th percentile) clearly illustrates significant increase in the no. of apoptotic cells in both PAs viz. 7,8-Diacetoxy-4-Methyl Coumarin (DAMC) and 6-Acetoxy Quinolone (6-AQ) and their combinations with CAL and VA as compared to DMSO control group and the maximum no. of apoptotic cells were observed in Group DAMC+CAL+VA. Increased extent of histone protein acetylation was observed by Western blotting using specific Anti- Acetyl Histone (Ac-Lys) Antibodies.Conclusion: PAs alone and also synergistically with CAL and VA are potential drug candidates for Cancer therapy.Asian Journal of Medical Sciences Vol.7(2) 2015 13-20

Antitumour and Anti-Inflammatory Effects of Palladium(II) Complexes on Ehrlich Tumour

Palladium(II) complexes are an important class of cyclopalladated compounds that play a pivotal role in various pharmaceutical applications. Here, we investigated the antitumour, anti-inflammatory, and mutagenic effects of two complexes: [Pd(dmba)(Cl)tu] (1) and [Pd(dmba)(N3)tu] (2) (dmba = N,N-dimethylbenzylamine and tu = thiourea), on Ehrlich ascites tumour (EAT) cells and peritoneal exudate cells (PECs) from mice bearing solid Ehrlich tumour. The cytotoxic effects of the complexes on EAT cells and PECs were assessed using the 3-(4,5-dimethylthiazol-3-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The effects of the complexes on the immune system were assessed based on the production of nitric oxide (NO) (Griess assay) and tumour necrosis factor-α (TNF-α), interleukin-12 (IL-12), and interleukin-10 (IL-10) (ELISA). Finally the mutagenic activity was assessed by the Ames test using the Salmonella typhimurium strain TA 98. Cisplatin was used as a standard. The IC50 ranges for the growth inhibition of EAT cells and PECs were found to be (72.8 ± 3.23) μM and (137.65 ± 0.22) μM for 1 and (39.7 ± 0.30) μM and (146.51 ± 2.67) μM for 2, respectively. The production of NO, IL-12, and TNF-α, but not IL-10, was induced by both complexes and cisplatin. The complexes showed no mutagenicity in vitro, unlike cisplatin, which was mutagenic in the strain. These results indicate that the complexes are not mutagenic and have potential immunological and antitumour activities. These properties make them promising alternatives to cisplatin

Antitumour and Antioxidant Activity of Some Red Sea Seaweeds in Ehrlich Ascites Carcinoma in vivo

1The antitumour activities of extracts from the Red Sea seaweeds Jania rubens, Sargassum subrepandum, and Ulva lactuca were investigated in an in vivo mice model based on intramuscular injection of Ehrlich ascites tumour cells. In parallel, antioxidant activities were measured. Tumour marker levels, liver biochemical parameters, and hepatic oxidant/antioxidant status were measured to prove the anticancer and antioxidant nature of the algal extracts. Significant decreases in carcinoembryonic antigen (CEA) and α-fetoprotein (AFP) levels, activities of liver enzymes, levels of nitric oxide (NO) and malondialdehyde (MDA), and an increase in total antioxidant capacity (TAC) were recorded in groups treated with the algal extracts. Jania rubens was selected for phytochemical screening of its phytoconstituents. In addition, carotenoids, halides, minerals, lipoidal matters, proteins, and carbohydrates were studied. Furthermore, 7-oxo-cholest-5(6)-en-3-ol () and cholesterol (2) were isolated from the dichloromethane fraction.