Recombinant human erythropoietin is widely used to treat anemia associated with cancer and with the myelosuppressive effects of chemotherapy, particularly platinumbased regimens. Erythropoietin is the principal regulator of erythroid cell proliferation, differentiation, and apoptosis. Recently, the antiapoptotic and proliferative effects of erythropoietin on nonhematopoietic cells were also established. We now show the effect of erythropoietin treatment on the response of A2780 and SKOV3 ovarian carcinoma cell lines to photodynamic therapy (PDT) using hypericin. SKOV3 exhibited an increased resistance to hypericin when cells were treated with erythropoietin. This resistance was reversed by treatment of SKOV3 cells with the specific Janus kinase 2 kinase inhibitor AG490 or the tyrosine kinase inhibitor genistein. These results support a role for the specific erythropoietin-induced Janus kinase 2/STAT signal transduction pathway in PDT resistance. Evidence of erythropoietin signaling was obtained by the demonstration of Akt phosphorylation in both A2780 and SKOV3 cells. Erythropoietin-treated SKOV3 cells exhibited decreased apoptosis induced by hypericin, an effect that was blocked by the phosphoinositide 3-kinase/Akt inhibitor wortmannin. These results may have important implications for ovarian cancer patients undergoing PDT and receiving erythropoietin.

SummaryBackgroundStudies of the biochemical properties of MAO-A (monoamine oxidase) are numerous, but the information about determination of MAO-A in human normal and tumour renal tissue is limited. Our objectives in the present study were to determine the localization of MAO-A in normal kidney and level of expression of this protein in tumour kidney.Material/MethodsEnzyme immunohistochemical method was chosen for detection of MAO-A in 63 clinical samples of all histopathological types of RCC (renal cell carcinoma). Our results were compared to basic clinical and histopathological parameters such as histopathological type and tumour grade. We also compared MAO-A expression between normal and tumour tissue samples.ResultsWe confirmed the elevated expression of MAO-A in high-grade tumours of renal cell carcinoma specimens. The percentage of MAO-positive samples progressively increased from 9% in grade 2 to 45% in grade 3. We also noted high levels of MAO-A immunoreactivity in epithelial cells of proximal tubules in normal renal tissue. MAO-A was absent or very low in epithelial cells of distal tubules and glomerular capsule, as well as in endothelial cells of renal vessels.ConclusionsTaken together, our results and findings of other studies show that MAO-A expression in high-grade tumours may have a direct role in maintaining a dedifferentiated phenotype and promoting aggressive behaviour. The ability of clorgyline (an MAO-A inhibitor) to counteract oncogenic pathways and promote differentiation suggests that MAO-A inhibitors, which have been used for many years in clinical practise for treating neurological disorders, could be therapeutic options for advanced stages of tumours.

SummaryBackgroundThis study aimed to examine the relationship between XRCC1, p53 and MDR1 protein, along with polymorphisms of their genes and their prognostic values in breast cancer. The following clinical and pathological parameters were evaluated: histopathological type of tumor, grade, stage, Her2/neu expression, ER, PR positivity and involvement of regional lymph nodes.Material/MethodsExpression of proteins was determined in 39 samples of breast cancer by immunohistochemistry. Nucleotide polymorphisms were analyzed by PCR-RFLP. For statistical analysis, chi-square test (Yates), Fisher’s exact test, and correlation test were used to analyze the data.ResultsThe highest protein expression was immunohistochemically found in MDR1 protein, with 54% of samples testing positive. In addition, the evaluation of MDR1 expression revealed higher positive immunoreactivity in lobular (LIC) and other types of tumor in comparison to ductal (DIC) type. The expression of p53 and XRCC1 protein was equal, but lower compared to MDR1, both testing positive in 36% of all tissue samples. Comparison of XRCC1 protein and histopathological type of tumor revealed that DIC and LIC types were mostly XRCC1-negative, while other types, papillary and mucinous were more likely to be XRCC1-positive. Interestingly, when evaluating LIC samples separately, a negative correlation between the Her2/neu and expression of XRCC1 was detected. Apparently, all Her2/neu-positive samples were XRCC1-negative (6/86%). The correlation test indicated a negative correlation between Her2/neu-positive samples and XRCC1-negative specimens (r=1, p<0.05). Statistical analysis did not reveal a correlation of p53 expression with clinical and pathological parameters. Similarly, no statistically significant difference was found between the tested polymorphisms and protein expression.ConclusionsWe did not find statistically significant correlation between tested polymorphisms and their protein expression.

We have evaluated the impact of chronic administration of clorgyline, a potent monoamine oxidase A inhibitor and a former antidepressant, on the preimplantation embryo development in Wistar rats. Females were injected intraperitoneally daily for 30 days with saline (control animals), or with a low-dose clorgyline (LDC, 0.1 mg/kg per d) or with a high-dose clorgyline (HDC, 1 mg/kg per d). Embryos were isolated on day 5 of pregnancy and urine was collected by puncture of the urinary bladder. The number of embryos per female did not differ between experimental groups and control, but we have recorded a decreased number of embryos in HDC group compared to LDC (P < .05). We have found that LDC significantly reduced the presence of healthy embryos and increased the presence of the degenerated embryos (P < .001). The administration of the LDC resulted in the lowest cell number in blastocysts. We have observed significantly increased serotonin levels in HDC group compared to both control (P < .05) and LDC animals (P < .01). Norepinephrine (NE) levels in both experimental groups were significantly elevated compared to controls. Dopamine levels did not differ between groups (P > .05). We speculate that lesser negative effect of HDC compared to LDC on the preimplantation embryo development could be the consequence of the lower NE levels and/or elevated serotonin levels. Potential mechanisms mediating clorgyline-induced impaired preimplantation embryo development are proposed.

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