Breaking the DNA Damage Response via Serine/Threonine Kinase Inhibitors to Improve Cancer Treatment.

Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/ threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death. Interestingly, key components of DDR signaling networks may constitute an attractive target for anti-cancer therapy through two distinct potential approaches: as chemoand radiosensitizers to enhance the effectiveness of currently used genotoxic treatment or as single agents to exploit defects in DDR in cancer cells via synthetic lethal approach. Moreover, the newest data reported that serine/threonine protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is also closely associated with cancer development and progression. Thereby, utilization of small-molecule, serine/threonine kinase inhibitors may provide a novel, groundbreaking, anti-cancer treatment strategy. Currently, a range of potent, highlyselective toward ATM, ATR and PERK inhibitors has been discovered, but after foregoing study, additional investigations are necessary for their future clinical use.

Antioxidative assessment of new trans-palladium (II) complexes in head and neck cancer.

BACKGROUND: Head and neck neoplasms stand for 6% of all malignant neoplasms worldwide. Chemotherapy has limited use due to the biological properties of the tumor (in the majority of cases moderately and poorly differentiated squamous cell carcinoma). The fundamental molecule used in treatment is cisplatin and its derivates, that can be associated with fluorouracil. The new chemotherapeutic agents are not in common use during the treatment of head and neck malignancies. However, the use of low molecular weight complexes Pd (II) carries the potential of being more effective in therapy. MATERIAL AND METHODS: Fifty-one patients, 30 men and 21 women (aged 52.9 ± 12.1 years) with head and neck cancer were included in the study. Fifty-one healthy subjects, 31 men and 20 women, (aged 54.1 ± 14.7 years) years formed the control group. Antioxidant enzymes, superoxide dismutase, and catalase activities in erythrocytes were examined. RESULTS: An increased level of antioxidant enzymes was seen in the blood samples from patients with head and neck cancer after incubation with Pd (II) complex. In the group we obtained a statistically significant result p = <0.001. DISCUSSION: That project may contribute to the development of new, more efficient head and neck cancer treatment strategies. In our opinion, the results can be used in the future to develop a valuable prognostic marker of the disease. This is important because the initial phase of cancer is asymptomatic. The search for factors involved in pathogenesis translates into economic benefits and makes therapy more effectiveness through the reduction of treatment expenses.

The relationship between HDAC6, CXCR3, and SIRT1 genes expression levels with progression of primary open-angle glaucoma.

BACKGROUND: Primary open-angle glaucoma (POAG) belongs to neurodegenerative diseases. Its etiology is not fully understood. However, a lot of reports have indicated that many biochemical molecules are involved in the retinal ganglion cell damage. Therefore, the purpose of this study was to evaluate a relationship between HDAC6, CXCR3, and SIRT1 genes expression levels with the occurrence risk of POAG and its progression. MATERIALS AND METHODS: The study included 34 glaucoma patients and 32 subjects without glaucoma symptoms. RNA was isolated from peripheral blood lymphocytes. Level of mRNA expression was determined by real-time PCR method. RESULTS: Our results have shown significant association of the HDAC6 and SIRT1 expression levels with progression of POAG according to rim area (RA) value, p = 0.041; p = 0.012. Moreover, the analysis of the CXCR3 expression level showed a correlation with progression of POAG based on RA and cup disc ratio (c/d) value, p = 0.006 and p = 0.012, respectively. CONCLUSIONS: The expression level of HDAC6, CXCR3, and SIRT1 genes may be involved in the progression of POAG.