The effect of silencing the Tip60 gene on the response to radiotherapy in breast cancer cells.

Since patients with triple-negative breast cancer do not respond to hormone therapy, the main treatment method is the combination of chemotherapy and radiotherapy. Because the DNA of the tumor cell is the target in both some chemotherapeutics and radiotherapy, problems may occur in individuals with a high DNA repair pathway. It is suggested that high expression of the Tip60 gene, which has an important role in repairing DNA damage, will increase the repair of DNA double-strand breaks in tumor cells, especially during radiotherapy treatment, thus reducing the response to treatment and adversely affecting treatment. In this study, for the first time, the role of the silenced and active Tip60 gene in response to radiotherapy in MDA-MB-231 and MCF-7 cells was investigated. For this purpose, the Tip60 gene was silenced by applying siRNA to the cell lines and UV was applied. In the study, cytotoxicity and DNA breaks were measured by MTT and COMET methods, and mRNA and protein expression values were measured by PCR and Raman spectrophotometer in silenced, unsilenced, UV-treated, and non-UV-treated cell lines. According to the results of the study, increased DNA damage was observed in MCF-7 cell lines in which the Tip60 gene was silenced, and radiotherapy was applied, compared to the cell lines with the Tip60 gene active. It was observed that DNA damage in MDA-MB-231 cell lines was less than in cell lines with the active Tip60 gene.

Investigation of mRNA Expression Levels of Tip60 and Related DNA Repair Genes in Molecular Subtypes of Breast Cancer.

INTRODUCTION: Studies in breast cancer (BC) have been shown that many tumor cells carry mutations that disrupt the DNA damage response mechanism. In eukaryotic cells, the overexpression or deprivation of DSBs repair genes is linked closely to a higher risk of cancer. PATIENTS AND METHODS: In this study, mRNA expression levels of some genes, such as Tip60, ATM, p53, CHK2, BRCA1, H2AX, which are associated with DNA damage repair, were measured using RT-PCR method in tumor and matched-normal tissues of 58 patients with BC. RESULTS: According to the study results, 55% in Tip60, 59% in ATM, 57% in BRCA1, 48% in H2AX, 66% in CHK2, and 43% in p53 decreased in tumor tissue of patients compared to the matched normal tissue. When evaluated according to molecular subtypes, expression of all genes in the pathway was found significantly higher in normal tissues than in tumor tissues especially in Luminal B and Luminal B+HER2 groups. One of the most important results of the study is that CHK2 mRNA expressions in normal tissues were higher than tumor tissue in 90% of patients in Luminal B and Luminal B-HER2 + groups. This is the first study showing DNA repair genes' expressions in molecular subtypes of breast cancer. In general, the decrease in the expression of DNA damage repair genes in tumor tissue indicates that these genes may have a role in the development of BC. Our study results also suggest that CHK2 may be a candidate marker in the molecular classification of breast cancer.

New therapy strategies in the management of breast cancer.

Breast cancer (BC), the second leading cause of cancer-related deaths after lung cancer, is the most common cancer type among women worldwide. BC comprises multiple subtypes based on molecular properties. Depending on the type of BC, hormone therapy, targeted therapy, and immunotherapy are the current systemic treatment options along with conventional chemotherapy. Several new molecular targets, miRNAs, and long non-coding RNAs (lncRNAs), have been discovered over the past few decades and are powerful potential therapeutic targets. Here, we review advanced therapeutics as new players in BC management.

An overview of microtubule targeting agents for cancer therapy.

The entire world is looking for effective cancer therapies whose benefits would outweigh their toxicity. One way to reduce resistance to chemotherapy and its adverse effects is the so called targeted therapy, which targets specific molecules ("molecular targets") that play a critical role in cancer growth, progression, and metastasis. One such specific target are microtubules. In this review we address the current knowledge about microtubule-targeting agents or drugs (MTAs/MTDs) used in cancer therapy from their synthesis to toxicities. Synthetic and natural MTAs exhibit antitumor activity, and preclinical and clinical studies have shown that their anticancer effectiveness is higher than that of traditional drug therapies. Furthermore, MTAs involve a lower risk of adverse effects such as neurotoxicity and haemotoxicity. Several new generation MTAs are currently being evaluated for clinical use. This review brings updated information on the benefits of MTAs, therapeutic approaches, advantages, and challenges in their research.

Normal and Tumour Tissue mRNA Expressions of Telomerase Complex Genes in Several Types of Cancer.

AIMS: To investigate the changes in mRNA expression levels of telomerase-related significant proteins in several types of cancer. METHODS: Human telomerase reverse transcriptase, pontin, reptin and dyskerin expressions were measured in normal and tumour tissues obtained from 26 patients with colorectal, breast and gastric cancers, using the real-time reverse transcriptase-polymerase chain reaction method. RESULTS: For all patients, no significant difference was found in mRNA expressions of human telomerase reverse transcriptase and dyskerin (p>0.05), although their levels in tumour tissues were found to be higher than in normal tissues. However, pontin and reptin mRNA expressions were significantly higher in tumour tissues than in normal tissues (p<0.01). While human telomerase reverse transcriptase showed a high correlation with only pontin (p<0.001) in normal tissues, high positive correlations were observed between human telomerase reverse transcriptase with pontin (p<0.005), reptin (p<0.01) and dyskerin (p<0.01) in tumour tissues. CONCLUSION: The increased mRNA expressions of all four genes in tumour tissues may suggest a role in cancer development. Correlations of pontin, reptin and dyskerin with human telomerase reverse transcriptase support the hypotheses describing their roles in telomerase complexes.

Variability of total thiol compounds, oxidative and nitrosative stress in uncomplicated pregnant women and nonpregnant women.

PURPOSE: The objective of this study was to determine the changes in total plasma thiols (homocysteine, cysteine and cysteinylglycine), lipid peroxidation and nitric oxide concentrations during normal pregnancy. METHODS: These variables were measured in 28 uncomplicated pregnant women at first, second and third trimesters and in 19 nonpregnant women. RESULTS: The mean concentrations of homocysteine, cysteine and cysteinylglycine were significantly lower in all trimesters of pregnancy compared with nonpregnant controls. There was significant elevation in serum lipid peroxidation levels of pregnant women within first and third trimesters compared with nonpregnant women. In spite of increase in mean nitric oxide levels in pregnant women, this increase did not reach statistically significant levels. CONCLUSION: This study provides information about the changes in plasma levels of many variables having important role in pregnancy complication during all trimesters in uncomplicated pregnancy compared with nonpregnant women.

Increased levels of 8-hydroxydeoxyguanosine and its relationship with lipid peroxidation and antioxidant vitamins in lung cancer.

BACKGROUND: Reactive oxygen species produced either endogenously or exogenously can attack lipids, proteins and DNA in human cells and cause potentially deleterious consequences. In recent years, their role in the pathogenesis of lung cancer and the preventive effect of antioxidants have been studied extensively. In this study, our aim was to investigate the levels of 8-hydroxy-2'-deoxyguanosine (8OHdG) and malondialdehyde as a marker for the effects of reactive oxygen species on DNA and lipids, the levels of antioxidant vitamins and the correlations between these oxidative stress markers and antioxidants in lung cancer. METHODS: Serum malondialdehyde, beta-carotene, retinol, and vitamins C and E were measured by high-performance liquid chromatography methods in fasting blood samples and 8OHdG was measured by gas chromatography-mass spectrometry in 24-h urine samples of patients with lung cancer (n=39) and healthy controls (n=31). RESULTS: The levels of 8OHdG and malondialdehyde were significantly higher (p<0.05 and p<0.005, respectively) and beta-carotene, retinol, and vitamins C and E (p<0.0001, p<0.0001, p<0.0001, and p<0.05, respectively) were significantly lower in patients than in controls. There was a significantly positive correlation between 8OHdG and malondialdehyde (r=0.463, p=0.01) and a negative correlation between the levels of 8OHdG and retinol (r=-0.419, p=0.021) in the patient group. CONCLUSIONS: Our results demonstrate that the oxidant/antioxidant balance was spoiled in favor of lipid peroxidation and DNA damage in lung cancer patients. Significant increases in the levels of malondialdehyde and 8OHdG and decreases in the levels of antioxidants suggest the possible involvement of oxidative stress in lung cancer.

Usefulness of homocysteine as a cancer marker: total thiol compounds and folate levels in untreated lung cancer patients.

BACKGROUND: Apart from being a risk factor for atherosclerotic cardiovascular diseases, the latest research suggests homocysteine as a marker for cancer. We aimed to explore the clinical utility of plasma homocysteine levels as a marker in lung cancer. PATIENTS AND METHODS: Changes in serum total thiols and folate levels were investigated in newly diagnosed untreated lung cancer patients (n = 37) and compared with healthy controls (n = 26). Fluorometric HPLC methods were used for the determination of thiols. Other parameters were determined with commercial diagnostic kits. RESULTS: Increased total homocysteine (t-Hcy), decreased total glutathione (t-GSH) and folate levels were observed in lung cancer patients compared with healthy controls. Total levels of thiols and folate did not show any significant difference between SCLC and NSCLC patients. However, there were significantly higher t-Hcy, lower t-GSH and folate levels in the advanced-stage group compared with controls. Prevalence of hyperhomocysteinemia was 65% in lung cancer patients when 12 micromol/l were taken as a cut-off value for t-Hcy levels. CONCLUSION: Homocysteine is suggested as a marker for several types of cancer, but our result did not support this hypothesis for lung cancer. Although higher homocysteine levels were observed in the present study, further investigation in the larger cancer population would clarify the importance of homocysteine as a cancer marker.

Oxidation of uric acid in rheumatoid arthritis: is allantoin a marker of oxidative stress?

Free radicals are implicated in many diseases including atherosclerosis, cancer and also in rheumatoid arthritis. Reaction of uric acid with free radicals, such as hydroxyl radical and hypochlorous acid (HOCl) results in allantoin production. In this study, we measured the serum allantoin levels, oxidation products of uric acid, as a marker of free radical generation in rheumatoid arthritis. Fasting blood samples were obtained from 21 rheumatoid patients and 15 healthy controls. In this study, the serum allantoin and uric acid levels were measured by a gas chromatography-mass spectrometry method and the ratios were calculated. The mean allantoin and uric acid levels and ratios in the patient group were 22.1 +/- 11.3, 280.5 +/- 65.0 and 8.0 +/- 3.7 microM, while in the control group they were 13.6 +/- 6.3, 278.3 +/- 53.6 and 4.9 +/- 2.1 microM, respectively. The effects of gender, age, menopausal status, duration of disease and medications on serum allantoin and uric acid levels of the patient and control groups were studied. Our results suggest that uric acid acts as a free radical scavenger and thus is converted to allantoin. Increased allantoin levels suggest the possible involvement of free radicals in rheumatoid arthritis.

The role of plasma thiol compounds and antioxidant vitamins in patients with cardiovascular diseases.

BACKGROUND: Increased levels of homocysteine (Hcy) and cysteine (Cys) are associated with risk of cardiovascular diseases (CVD). These thiol compounds can generate various free radicals and so cause endothelial dysfunction. Antioxidant vitamins are effective scavengers of reactive oxygen species (ROS) and prevent endothelial dysfunction. In this study, we investigated the plasma homocysteine, cysteine, vitamins E, C and A, and beta-carotene (BC) levels in cardiovascular patients to compare with controls. We also investigated whether there is a correlation between the plasma thiol compounds and antioxidant vitamins. METHODS: Blood samples were collected from 47 patients with cardiovascular disease (16 women and 31 men) and 21 healthy subjects (8 women and 13 men) in the overnight fasting state. Serum thiol compound and antioxidant vitamin levels were measured by high-pressure liquid chromatography (HPLC) methods. RESULTS: The plasma homocysteine and cysteine levels were significantly higher in patients than those of controls. While vitamin C (VC), vitamin A (VA) and beta-carotene levels were significantly lower in patients than in controls, vitamin E (VE) levels did not change in both groups. There is a positive correlation between homocysteine and cysteine levels (r=0.622, p=0.000) in all study population. We found that the plasma level of homocysteine was significantly correlated in negative manner with vitamins E and A levels (r=-0.260, p=0.033 and r=-0.255, p=0.036, respectively) of all study population. Plasma cysteine levels were negatively correlated with only vitamin C levels (r=-0.320, p=0.008) in all study populations. CONCLUSIONS: Our data suggest that Hcy and Cys are associated with cardiovascular disease and there is negative but weak correlation's between thiol compounds and antioxidant vitamins.