HDAC Inhibitor Oxamflatin Induces Morphological Changes and has Strong Cytostatic Effects in Ovarian Cancer Cell Lines.

Ovarian epithelial carcinoma is the leading cause of deaths from gynecologic malignancy. New reagents with therapeutic potentials against ovarian cancer, especially the drug-resistant cases, are required for better treatment of ovarian cancer patients. Epigenetic events such as changes in DNA methylation and histone modification, through their effects on DNA-protein interaction, chromatin conformation, and gene expression, affect cell function, cancer behavior, clinical manifestations, and outcomes. Previous studies have shown that histone deacetylase (HDAC) inhibitors have strong cytostatic and apoptotic activities in hematologic and some solid cancer cells. Oxamflatin, a compound containing the aromatic sulfonamide and hydroxamic acid groups, is known to be a potent HDAC inhibitor capable of inhibiting the growth of mouse and human cancer cell lines. In this study we found that oxamflatin in the nM range induced morphological changes in OVCAR-5 and SKOV-3 ovarian cancer cell lines. Treatment with oxamflatin also led to decreased cell viability. Moreover, results of BrdU incorporation assay, cell counting, and Ki-67 immunostaining indicated that oxamflatin was able to significantly inhibit DNA synthesis and cell proliferation. Using real-time PCR and Western blot analyses we demonstrated that oxamflatin was capable of downregulating the expression of c-Myc, CDK4, E2F1, and the phosphorylation levels of Rb protein, but upregulating p21. These findings pave the way to examine if oxamflatin along with or in combination with other reagents could deliver anticancer effects against ovarian cancers in vivo.

Biochemical markers of brain tumours.

The paper presents the results of neurospecific proteins S-100 and glial fibrillary acidic protein (GFAP) determination in blood serum samples of 145 neuro-oncology patients and 69 healthy people. The significant elevation of S-100 and GFAP was revealed in glioblastoma (G IV) patients compare to the patients with anaplastic astrocytoma (G III), benign meningioma (GI), celebral metastasis and healthy controls. The concentration of S-100 in blood serum of patients with anaplastic astrocytoma, benign meningioma, and celebral metastasis did not significantly differ among themselves, and in relation to the control group there was a significantly increase only in patients with cerebral metastasis. GFAP was characterized by high frequency of its detection in patients with glioblastoma (83%) compare to other groups of patients and healthy donors, in which it was practically undetectable. These data suggest the possibility of using GFAP as a marker of glioblastoma and S-100- as an additional biochemical criteria of cerebral lesions in oncology patients.

Cardiac hypertrophy alters myocardial response to ischaemia and reperfusion in vivo.

The impact of cardiac hypertrophy on myocardial biochemical and physiological responses to ischaemia-reperfusion (I-R) was investigated in vivo. Hypertrophy was produced by aortic constriction (PH) or swimming training (TH). Open-chest rat hearts in PH, TH and a sedentary control group (SC) were subjected: (1) to ischaemia, by surgical occlusion of the main descending branch of the left coronary artery for 30 min; (2) to I-R, by releasing the occluded blood vessel for 15 min; or (3) to a sham operation. Ischaemia per se had little effect on heart oxidative and antioxidant status, or lipid peroxidation. However, I-R significantly decreased glutathione (GSH) content, increased glutathione disulfide (GSSG) content, and reduced GSH/GSSG ratio in the SC hearts. These alterations were associated with decreased activities of GSH peroxidase and GSSG reductase, and an increase in lipid peroxidation. Myocardial ATP, total adenine nucleotide content and energy charge in SC were significantly decreased after ischaemia, whereas levels of purine nucleotide derivatives, particularly adenosine, were elevated. No significant alteration of GSH status of adenine nucleotide metabolism occurred after ischaemia or I-R in hypertrophied hearts. In both PH and TH, glutathione content was significantly higher than in SC, whereas activities of GSH peroxidase and GSSG reductases were lower. TH rats maintained a higher heart rate (HR), peak systolic pressure, and energy charge during I-R. These data indicate that hypertrophied but well-functioned hearts may be more resistant to I-R induced disturbances of myocardial oxidative and antioxidant functions.

Myocardial response to regional ischemia and reperfusion in vivo in rat heart.

Ischemia-reperfusion-induced myocardial oxidative changes were investigated in open-chest hearts of anesthetized rats. Surgical occlusion of the left anterior descending coronary artery for 30 min followed by 15 min reperfusion resulted in a significant decrease of reduced glutathione, an increase in glutathione disulfide, and an enhanced lipid peroxidation in rapidly frozen left ventricular tissues. Direct electron paramagnetic resonance spectroscopy revealed an increase in free radical concentration in ischemic cardiac tissues reperfused for 45 s, but the increase diminished at 15 min. these alterations were associated with decreased activities of myocardial glutathione peroxidase, glutathione reductase, and catalase. Ischemia resulted in a significant reduction of high-energy phosphate compounds and an accumulation of nucleotide degradation products, particularly adenosine, in the myocardium. Deterioration of cardiovascular function in reperfused animals was also evident. It is concluded that regional ischemia followed by reperfusion in situ can produce biochemical and physiological alterations consistent with free radical injury in rat hearts, and that an increased purine nucleotide degradation and a decreased antioxidant defense may be responsible for the observed changes.