The in vitro anticancer activity of the dinuclear trithiolato-bridged arene ruthenium complex diruthenium-1 (DiRu-1) was evaluated against a panel of human cancer cell lines used as in vitro models for hepatocellular carcinoma (HepG2 cells), estrogen-responsive breast adenocarcinoma (MCF-7 cells), and triple-negative breast adenocarcinoma (MDA-MB-231 cells). DiRu-1 is highly cytotoxic to these cell lines, demonstrating half-maximal inhibitory concentrations (IC ) in the low-nanomolar range (77±1.4 to 268.2±4.4 nm). The main molecular mechanisms responsible for the high cytotoxicity of DiRu-1 against the most responsive MCF-7 cell line (IC =77±1.4 nm) were investigated on the basis of the capacity of DiRu-1 to induce oxidative stress, apoptosis, and DNA damage, and to inhibit the cell cycle and proliferation. The results show that DiRu-1 triggers caspase-dependent apoptosis in MCF-7 cells on both the intrinsic and extrinsic pathways. Moreover, the Ru complex also causes necrosis, mitotic catastrophe, and autophagy. DiRu-1 increases the intracellular levels of reactive oxygen species (ROS), which play a significant role in its cytotoxicity and pro-apoptotic activity. An important mechanism of the anticancer activity of DiRu-1 appears to be the induction of DNA lesions, mainly due to apoptotic DNA fragmentation and cell-cycle arrest at the G /M checkpoint. These changes are correlated with the concentration of DiRu-1, the duration of the cell treatment, and the post-treatment time.

Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called “autophagy paradox”, and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell’s energy needs, and that the over-programmed activity of this process can lead to cell death through apoptosis. The fight against cancer is a difficult process due to high levels of resistance to chemotherapy and radiotherapy. More and more research is indicating that autophagy may play a very important role in the development of resistance by protecting cancer cells, which is why autophagy in cancer therapy can act as a “double-edged sword”. This paper attempts to analyse the influence of autophagy and cancer stem cells on tumour development, and to compare new therapeutic strategies based on the modulation of these processes.

In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to the intense cell division in cancer. This is the main reason why the cancer cell does not “give up” on glycolysis despite the high demand for energy in the form of ATP. One of the evolving trends in the development of anti-cancer therapies is to exploit differences in the metabolism of normal cells and cancer cells. Currently constructed therapies, based on cell metabolism, focus on the attempt to reprogram the metabolic pathways of the cell in such a manner that it becomes possible to stop unrestrained proliferation.

With the aim of contributing to the knowledge about their potential therapeutic activity, we determined the biological activities of cyanidin and its selected O-glycosides in relation to erythrocytes (RBCs) and human dermal vascular endothelial cells (HMEC-1). Furthermore, on the basis of changes in the physical/functional properties of the cells, the structure–activity relationships of the compounds were determined. Concerning erythrocytes, we analyzed the antioxidant activity of the compounds and their impact on the RBCs’ shape and transmembrane potential. The compounds’ cytotoxic activity, ability to modulate apoptosis, cell cycle, and intracellular ROS generation, as well as inhibitory activity against AAPH-inducted oxidative stress, were determined in relation to HMEC-1 cells. We demonstrated that biological activity of cyanidin and its O-glycosides strongly depends on the number and type of sugar substituents, and varies depending on the extracellular environment and type of cells. The compounds are practically non-cytotoxic, and do not induce apoptosis or disturb the progression of the cell cycle. Additionally, the compounds alter the shape of RBCs, but they do not affect their transmembrane potential. They effectively protect erythrocytes against free radicals and affect intracellular reactive oxygen spices (ROS) generation under physiological and AAPH-induced oxidative stress conditions. Our results suggest a potential beneficial effect of cyanidin on the cardiovascular system.

Hexokinase 2 (HK2), an enzyme of the sugar kinase family, plays a dual role in glucose metabolism and mediating cancer cell apoptosis, making it an attractive target for cancer therapy. While positive HK2 expression usually promotes cancer cells survival, silencing or inhibiting this enzyme has been found to improve the effectiveness of anti-cancer drugs and even result in cancer cell death. Previously, benitrobenrazide (BNBZ) was characterized as a potent HK2 inhibitor with good anti-cancer activity in mice, but the effect of its trihydroxy moiety (pyrogallol-like) on inhibitory activity and some cellular functions has not been fully understood. Therefore, the main goal of this study was to obtain the parent BNBZ (2a) and its three dihydroxy derivatives 2b–2d and to conduct additional physicochemical and biological investigations. The research hypothesis assumed that the HK2 inhibitory activity of the tested compounds depends on the number and location of hydroxyl groups in their chemical structure. Among many studies, the binding affinity to HK2 was determined and two human liver cancer cell lines, HepG2 and HUH7, were used and exposed to chemicals at various times: 24 h, 48 h and 72 h. The study showed that the modifications to the structures of the new BNBZ derivatives led to significant changes in their activities. It was also found that these compounds tend to aggregate and exhibit toxic effects. They were found to contribute to: (a) DNA damage, (b) increased ROS production, and (c) disruption of cell cycle progression. It was observed that, HepG2, occurred much more sensitive to the tested chemicals than the HUH7 cells; However, regardless of the used cell line it seems that the increase in the expression of HK2 in cancer cells compared to normal cells which have HK2 at a very low level, is a serious obstacle in anti-cancer therapy and efforts to find the effective inhibitors of this enzyme should be intensified.