Purpose: Investigation of effects on DNA of γ-irradiated human cancer cells pretreated with free radical scavengers is aimed to create reference data which would enable assessment of the relative efficiency of high linear energy transfer (LET) radiations used in hadron therapy, i.e. protons and carbon ions. Materials and methods: MCF-7 breast and HTB177 lung cancer cells are irradiated with γ-rays. To minimize indirect effects of irradiation, dimethyl sulfoxide (DMSO) or glycerol are applied as free radical scavengers. Biological response to irradiation is evaluated through clonogenic cell survival, immunocytochemical and cell cycle analysis, as well as expression of proteins involved in DNA damage response. Results: Examined cell lines reveal similar level of radioresistance. Application of scavengers leads to the rise of cell survival and decreases the number of DNA double strand breaks in irradiated cells. Differences in cell cycle and protein expression between the two cell lines are probably caused by different DNA damage repair mechanisms that are activated. Conclusion: The obtained results show that DMSO and glycerol have good scavenging capacity, and may be used to minimize DNA damage induced by free radicals. Therefore, they will be used as the reference for comparison with high LET irradiations, as well as good experimental data suitable for validation of numerical simulations.

Adiponectin (ADIPOQ) as both a regulator of metabolic homeostasis and a protein involved in immune response might be of particular interest to contemporary laboratory medicine, especially in terms of minimally invasive diagnostics. The diverse roles of ADIPOQ with regard to the immune and metabolic aspects of colorectal carcinogenesis have been proposed. However, the expression of its receptors ADIPOR1 and ADIPOR2 is scarcely explored in peripheral blood mononuclear cells (PBMCs). Moreover, ADIPORs’ relationships with the immune response mediator TNF-α have not been previously investigated in the PBMCs of CRC patients. This study used both in silico and observational case–control analyses with the aim of exploring the association of ADIPOR gene expression and ADIPOQ single nucleotide polymorphisms (SNPs) with the inflammatory marker TNF-α and lipid status parameters in patients with CRC. Publicly available transcriptomic datasets (GSE47756, GSE44076) obtained from analyses of monocytes and CRC tissue samples were employed for the in silico evaluation of ADIPORs’ specific genetic traits. GSE47756 and GSE44076 datasets were processed with GSEA software to provide a genetic fingertip of different signaling pathways associated with ADIPORs’ mRNA levels. The case–control aspect of the study included the PBMC samples of 73 patients diagnosed with CRC and 80 healthy volunteers. The PCR method was carried out for the PBMC gene expression analysis (ADIPOR1, ADIPOR2, TNF-α mRNA levels) and for the subjects’ genotyping (ADIPOQ rs266729, ADIPOR1 rs7539542). GSEA showed significant associations of ADIPOR mRNA expression with gene sets related to metabolic and immune homeostasis in both datasets. The case–control study revealed the association of ADIPOR1 rs7539542 with reduced lipid status parameters in CRC. In addition, PBMC ADIPOR1 mRNA levels decreased in CRC (p < 0.001), whereas ADIPOR2 mRNA did not differ between the groups (p = 0.442). A reduction in PBMC TNF-α mRNA levels was noted in CRC (p < 0.05). Our results indicate that ADIPOR1 and ADIPOR2 play a significant role in the alteration of both metabolic and immune homeostasis during the progression of CRC. For the first time, ADIPOR1 is shown to be a specific receptor for mediating ADIPOQ’s effects in the PBMCs of CRC patients.

Due to the development of resistance to previously effective therapies, there is a constant need for novel treatment modalities for metastatic melanoma. Nischarin (NISCH) is a druggable scaffolding protein reported as a tumor suppressor and a positive prognostic marker in breast and ovarian cancers through regulation of cancer cell survival, motility and invasion. The aim of this study was to examine the expression and potential role of nischarin in melanoma. We found that nischarin expression was decreased in melanoma tissues compared to the uninvolved skin, and this was attributed to the presence of microdeletions and hyper-methylation of the NISCH promoter in the tumor tissue. In addition to the previously reported cytoplasmic and membranous localization, we observed nischarin in the nuclei in melanoma patients’ tissues. NISCH expression in primary melanoma had favorable prognostic value for female patients, but, unexpectedly, high NISCH expression predicted worse prognosis for males. Gene set enrichment analysis suggested significant sex-related disparities in predicted association of NISCH with several signaling pathways, as well as with different tumor immune infiltrate composition in male and female patients. Taken together, our results imply that nischarin may have a role in melanoma progression, but that fine-tuning of the pathways it regulates is sex-dependent.

Background: Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide. Current adjuvant chemotherapy regimens often lead to significant toxicities, so novel targets and targeted therapies are of great interest. Nischarin (NISCH, IR1, IRAS) is a non-adrenergic imidazoline-1 receptor protein that has been described as a tumor suppressor in breast and ovarian cancer. NISCH expression and its biological role in other types of cancer have not been investigated to date. Importantly, NISCH is a druggable target for which chemical agonists and antagonists have already been developed. The aim of this study was to examine the expression of nischarin in colon...

The antihypertensive drug rilmenidine has been investigated as a candidate for drug repurposing in oncology for its cytotoxic and antimetastatic properties through activation of the tumor suppressor nischarin. We recently observed that the presence of rilmenidine was associated with fluorescent dye accumulation in pancreatic ductal adenocarcinoma (PDAC) cell lines. This study was designed to examine whether rilmenidine has the potential to modulate the accumulation of dyes and chemotherapeutics known to be ABC transporter substrates. We screened a panel of PDAC cell lines for expression of MDR-related ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and selected PANC-1, MIA PaCa-2, and AsPC-1 cell lines as model systems. We found that rilmenidine treatment attenuated the efflux of calcein, Hoechst 33342, and doxorubicin, implying modulation of ABCB1, ABCC1, and ABCC2 pump activity in a manner comparable, but weaker than known inhibitors. In silico examination suggested that rilmenidine could bind to the ligand pockets of these pumps. Finally, rilmenidine potentiated the effects of 5-fluorouracil (5-FU) and paclitaxel in PDAC cells measured in vitro. These findings suggest that rilmenidine can modulate MDR-associated ABC transporter activity and should be considered when evaluating its potential for repurposing in cancer therapy.