The various components of the endocannabinoid system (ECS), such as the cannabinoid receptors (CBRs), cannabinoid ligands, and the signalling network behind it, are implicated in several tumour-related states, both as favourable and unfavourable factors. This review analyses the ECS’s complex involvement in the susceptibility to cancer, prognosis, and response to treatment, focusing on its relationship with cancer biology in selected solid cancers (breast, gastrointestinal, gynaecological, prostate cancer, thoracic, thyroid, CNS tumours, and melanoma). Changes in the expression and activation of CBRs, as well as their ability to form distinct functional heteromers affect the cell’s tumourigenic potential and their signalling properties, leading to pharmacologically different outcomes. Thus, the same ECS component can exert both protective and pathogenic effects in different tumour subtypes, which are often pathologically driven by different biological factors. The use of endogenous and exogenous cannabinoids as anti-cancer agents, and the range of effects they might induce (cell death, regulation of angiogenesis, and invasion or anticancer immunity), depend in great deal on the tumour type and the specific ECS component that they target. Although an attractive target, the use of ECS components in anti-cancer treatment is still interlinked with many legal and ethical issues that need to be considered.

The synthesis and chemical characterization of the novel 2,6-diacetylpyridine-bis(selenosemicarbazone) metal complexes of Zn(II), Cd(II) and Ni(II) were published previously. Here we report first evidence on anti-proliferative activity of the complexes and molecular patterns that underlie it. The complexes and the corresponding ligand are shown to be cytotoxic on the panel of nine, malignant and non-malignant cell lines, with the exception of Ni(II) complex that did not achieve IC₅₀ value on any of the cell lines tested. Further experiments on the selected cell lines including A 549, MRC-5, EA.hy 926 and HeLa, have shown that the complexes posses unambiguous property of inducing necrosis in the cells treated for 6 hours, with the ligand and Zn(II) complex being the most active on all cell lines. On the contrary, only small portion of early apoptotic events was detected, under the same experimental condition. This was in complete concordance with the results obtained from Western blot analysis of the treated cells that showed no or slight increase of the protein amounts of two crucial apoptotic mediators: Cytochrome C and Caspase III. We propose the model, under which tested complexes induce necroptosis in treated cells, a recently described type of cell death with necrotic morphological features and acting via caspase independent pathway, and without elevated amounts of intracellular ROS. Endothelial EA.hy 926 cells have proven to be extremely sensitive on the necrosis-inducing effect of the complexes, which could indicate potential anti-angiogenic effect of the novel complexes that is to be investigated.

The aim of this study was to evaluate the prognostic potential of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) tumor tissue levels and examine the association between these biomarkers and classical prognostic factors in early node-negative luminal breast cancer patients. The clinical value of 4G/5G variants of PAI-1 gene was evaluated. This study involved 81 node-negative, estrogen receptor-positive and/or progesterone receptor-positive and human epidermal growth factor receptor 2-negative operable breast cancer patients who underwent radical surgical resection and received adjuvant endocrine therapy. Determination of uPA and PAI-1 concentrations in the breast cancer tissue extracts was performed using FEMTELLE® uPA/PAI-1 ELISA. An insertion (5G)/deletion (4G) polymorphism at position − 675 of the PAI-1 gene was detected by PCR-RFLP analysis. Our research showed that patients with uPA tumor tissue levels higher than 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) when compared to patients with uPA tumor tissue levels lower or equal to 3 ng/mg of protein. Patients with PAI-1 tumor tissue levels higher than 14 ng/mg of protein had significantly decreased OS in comparison with patients with PAI-1 tumor tissue levels lower or equal to 14 ng/mg of protein. ROC analysis confirmed the uPA and PAI-1 discriminative potential for the presence/absence of relevant events in these patients and resulted in higher cut-off values (5.65 ng/mg of protein for uPA and 27.10 ng/mg of protein for PAI-1) than standard reference cut-off values for both biomarkers. The prognostic importance of uPA and PAI-1 ROC cut-off values was confirmed by the impact of uPA higher than 5.65 ng/mg of protein and PAI-1 higher than 27.10 ng/mg of protein on poorer DFS, OS and event-free survival (EFS). We observed that patients with dominant allele in PAI-1 genotype (heterozygote and dominant homozygote, − 675 4G/5G and − 675 5G/5G) had significantly increased DFS, OS and EFS when compared with patients with recessive homozygote genotype (− 675 4G/4G). Our study indicates that uPA and PAI-1 tumor tissue levels and 4G/5G variants of PAI-1 gene might be of prognostic significance in early node-negative luminal HER2-negative breast cancer patients treated with adjuvant endocrine therapy.

Radiation therapy is an indispensable part of various treatment modalities for breast cancer. Specifically, for non-inflammatory locally advanced breast cancer (LABC) patients, preoperative radiotherapy (pRT) is currently indicated as a second line therapy in the event of lack of response to neoadjuvant chemotherapy. Still approximately one third of patients fails to respond favourably to pRT. The aim of this study was to explore molecular mechanisms underlying differential response to radiotherapy (RT) to identify predictive biomarkers and potential targets for increasing radiosensitivity. The study was based on a cohort of 134 LABC patients, treated at the Institute of Oncology and Radiology of Serbia (IORS) with pRT, without previous or concomitant systemic therapy. Baseline transcriptional profiles were established using Agilent 60 K microarray platform in a subset of 23 formalin-fixed paraffin-embedded (FFPE) LABC tumour samples of which 11 radiotherapy naïve and 3 post-radiotherapy samples passed quality control and were used for downstream analysis. Biological networks and signalling pathways underlying differential response to RT were identified using Ingenuity Pathways Analysis software. Predictive value of candidate genes in the preoperative setting was further validated by qRT-PCR in an independent subset of 60 LABC samples of which 42 had sufficient quality for data analysis, and in postoperative setting using microarray data from 344 node-negative breast cancer patients (Erasmus cohort, GSE2034 and GSE5327) treated either with surgery only (20%) or surgery with RT (80%). We identified 192 significantly differentially expressed genes (FDR < 0.10) between pRT-responsive and non-responsive tumours, related to regulation of cellular development, growth and proliferation, cell cycle control of chromosomal replication, glucose metabolism and NAD biosynthesis II route. APOA1, MAP3K4, and MMP14 genes were differentially expressed (FDR < 0.20) between pRT responders and non-responders in preoperative setting, while MAP3K4 was further validated as RT-specific predictive biomarker of distant metastasis free survival (HR = 2.54, [95%CI:1.42–4.55], p = 0.002) in the postoperative setting. This study pinpoints MAP3K4 as a putative biomarker of response to RT in both preoperative and postoperative settings and a potential target for radiosensitising combination therapy, warranting further pre-clinical studies and prospective clinical validation.

The synthesis and cytotoxic activities determination of new steroidal mono- and bis(thiazolidin-4-ones) 4a-f and 5a-f have been performed. Their anticancer action was also evaluated in comparison to previously synthesized and reported corresponding steroidal thiosemicarbazones. All compounds were obtained as stereoisomeric mixtures with different configuration (E or Z) in the hydrazone moiety at the C-3 position. After several consecutive crystallizations diastereomerically pure major (E)-isomers of mono-thiazolidin-4-ones were isolated. The structure and stereochemistry of 2,4-thiazolidinedione,2-[(17-oxoandrost-4-en-3-ylidene)hydrazone] were confirmed by X-ray analysis. A pathway for the formation of thiazolidin-4-one ring was proposed. The steroid thiazolidinone derivatives examined in this study exerted selective concentration-dependent cytotoxic activities on six tested malignant cell lines. Ten out of twelve examined compounds exhibited strong cytotoxic effects on K562 cells (IC50 values from 8.5μM to 14.9μM), eight on HeLa cells (IC50 values ranging from 8.9μM to 15.1μM) while against MDA-MB-361 cells six compouds exerted similar or even higher cytotoxic action (IC50 values from 12.7μM to 25.6μM) than cisplatin (21.5μM) which served as a positive control. Eight of these ten compounds showed high selectivity in the cytotoxic action against HeLa and K562 cancer cell lines when compared with normal human fibroblasts MRC-5 and normal human PBMC. The study of mechanisms of the anticancer activity of the two selected compounds, mono- and bis(thiazolidin-4-one) derivatives of 19-norandrost-4-ene-3,17-dione 4a and 5a, revealed that both of these compounds induced apoptosis in HeLa cells through extrinsic and intrinsic signalling pathways. Treatment of EA.hy926 cells with sub-toxic concentrations of these compounds led to the inhibition of cell connecting and sprouting, and tube formation. The synthesized compounds exhibited poor antioxidant activity.