Cerium oxide nanoparticles (CeO₂ NPs) are well known for their application in various fields of industry, as well as in biology and medicine. Knowledge of synthesis schemes, physicochemical and morphological features of nanoscale CeO₂ is important for assessing their antioxidant behavior and understanding the mechanism of oxidative stress and its consequences. The choice of the method of synthesis should be based on the possibility to choose the conditions and parameters for obtaining CeO₂ with controlled dimensions and a ratio of Се³⁺/Се⁴⁺ on their surface. In this study, CeO₂ NPs are synthesized by precipitation in mixed water-alcohol solutions at constant pH = 9. The properties of obtained NPs are studied using various methods of physical-chemical characterization such as X-ray diffraction, X-ray photoelectron spectroscopy, transmission electron microscopy, and dynamic light scattering. The size of CeO₂ NPs varied from 14 to 4.2 nm with increasing alcohol concentration, while the effect of constant pH during synthesis on the morphology of the particles was insignificant. The synthesized nanoparticles form highly stable aqueous suspensions since their zeta-potential is higher than + 40 mV. It is found that the ability of CeO₂ NPs to self-stabilize is associated with the presence of hydrated Ce⁴⁺ ions on their surface. In vitro biological studies have shown that, regardless of particle size, CeO₂ NPs have antioxidant potential, but smaller NPs with a higher percentage of Ce³⁺ on the surface had a more effective antioxidant effect. In addition, the size-depended activity of CeO₂ NPs to inhibit the amyloid formation of insulin is demonstrated.

Despite efforts in osteosarcoma (OS) research, the role of inductive moderate hyperthermia (IMH) in delivering and enhancing the antitumor effect of liposomal doxorubicin formulations (LDOX) remains unresolved. This study investigated the effect of a combination treatment with LDOX and IMH on Saos-2 human OS cells. We compared cell viability using a trypan blue assay, apoptosis and reactive oxygen species (ROS) measured by flow cytometry and pro-apoptotic Bax protein expression examined by immunocytochemistry in response to IMH (42 MHz frequency, 15 W power for 30 min), LDOX (0.4 μg/mL), and LDOX plus IMH. The lower IC₅₀ value of LDOX at 72 h indicated increased accumulation of the drug in the OS cells. LDOX plus IMH resulted in a 61% lower cell viability compared to no treatment. Moreover, IMH potentiated the LDOX action on the Saos-2 cells by promoting ROS production at temperatures of <42 °C. There was a 12% increase in cell populations undergoing early apoptosis with a less heterogeneous distribution of Bax after combination treatment compared to those treated with LDOX (p < 0.05). Therefore, we determined that IMH could enhance LDOX delivery and its antitumor effect via altered membrane permeabilization, ROS generation, and a lower level of visualized Bax heterogeneity in the Saos-2 cells, suggesting the potential translation of these findings into in vivo studies.

Lactate dehydrogenase (LDH) is a key glycolytic enzyme that catalyzes the interconversion of pyruvate and lactate, with LDHA gaining particular attention for its overexpression in various malignancies and pivotal role in the Warburg effect-driven metabolic reprogramming. Elevated LDHA activity supports rapid ATP production under hypoxic conditions, maintains NAD⁺ regeneration, and promotes lactate accumulation, creating an acidic tumor microenvironment (TME) that favors invasion and immune evasion. Accumulating evidence demonstrates that LDHA is essential for primary tumor growth and critically involved in circulating tumor cell (CTC) survival, anoikis resistance, and metastatic spread. These functions are mediated by its regulation of adhesion molecules, cytoskeletal remodeling, and energy adaptation that enable CTCs to withstand mechanical shear stress and immune surveillance in the bloodstream. Pharmacological inhibition of LDHA, particularly via sodium oxamate (oxamate), has shown substantial potential in reducing metastasis and enhancing chemotherapy sensitivity in preclinical models. Oxamate has emerged as a promising candidate for metabolic cancer therapy due to its unique double effects on tumor metabolism and anti-tumor immunity, which are an advantage rarely highlighted in broader LDHA-focused reviews. This review synthesizes the molecular mechanisms through which LDHA drives tumor progression, dissects its context-specific functions in CTC biology, and evaluates the translational potential of LDHA-targeted strategies, with a focused emphasis on oxamate, as a transformative anti-metastatic therapeutic paradigm. By filling a critical gap in synthesizing oxamate’s distinct metabolic–immune regulatory actions, this work addresses an unmet need in the management of advanced, treatment-refractory cancers.

Aerobic glycolysis that supports high proliferation rate and survival of tumor cells in unfavorable conditions is among fundamental features of tumor metabolism. The search for active modulators of energetic metabolism capable of suppressing tumor growth and metastasis could result in higher effectiveness of anticancer therapy. Aim: To study antitumor and antimetastatic activity of the modulators of energetic metabolism dichloroacetate (DCA) and 2-deoxy-D-glucose (2DG) used in combination treatment of Lewis lung carcinoma (LLC). Materials and Methods: As experimental tumor model, LLC/R9 variant was used. DCA and 2DG were administered per os to С57Bl/6 mice 5 times per week for 3 weeks at a total dose of 1.5 and 0.98 g/kg, respectively, as single agents or in combination starting from the following day after tumor cell transplantation. Growth of primary tumor and number and volume of lung metastases were registered. Lactate and pyruvate content was determined by enzymatic methods using lactate dehydrogenase. Electron paramagnetic resonance was used for analyzing the functional state of the components of mitochondrial respiratory chain. Engulfing activity and reactive oxygen species (ROS) production in tumor-associated CD14+ cells was analyzed by flow cytometer with the use of FITC-labeled staphylococcus, and by spectrofluorometry with the use of 2.7-dichlorofluorescein diacetate, respectively. Results: DCA administered as a single agent did not affect primary tumor growth but decreased the number and volume of lung metastases by 60% (p < 0.05) and 90% (p < 0.05), respectively. In mice treated with 2DG only, primary tumor volume as well as the number and volume of lung metastases were not affected. Combination treatment with DCA and 2DG resulted in the decrease of primary tumor volume, the number and volumes of lung metastases by 70; 46, and 90%, respectively (р < 0.05). High antitumor activity of DCA + 2DG was associated with 31% decrease (p < 0.05) of lactate content in tumor tissue and 120% increase (p < 0.01) of ROS production in СD14+ cells recruited to the region of tumor growth. Conclusion: 2DG that possesses neither antitumor nor antimetastatic activity against LLC/R9 significantly enhanced antitumor activity of DCA with accompanying inhibition of glycolysis and increase of cytotoxic activity of CD14+ cells infiltrating tumor tissue. Taking into account significant antimetastatic activity of DCA this substance could be considered as a promising antimetastatic agent.

Background: Anticancer action of sodium dichloroacetate (DCA) could be related to its ability to activate oxidative phosphorylation leading to enhanced generation of reactive oxygen species and induction of apoptosis. On the other hand, activation of oxidative phosphorylation could promote tumor cell survival, in particular, via increased ATP synthesis. Such ambiguous effects of DCA could influence its anticancer effectiveness, depending on biological properties of a tumor, schedule of DCA administration and its dosage. The aim of the study was to analyze anticancer effect of DCA against glioma С6 in rats under conditions of different schedules of its administration and various dosages. Materials and Methods: The study was carried out in Wistar rats with intracerebrally transplanted glioma С6 cells. Therapy with DCA was performed as follows: daily for 6 days starting from the second day after tumor cell transplantation (schedule І) or 7th day (schedule ІІ) at a dose of 1.0 g/kg, or daily for 13 days starting from the second day at doses of 1.0; 1.5 or 4.5 g/kg (schedule ІІІ). An influence of hypoxia on anticancer effect of DCA was studied using hypoxic chambers where oxygen content was maintained at a level of 12.5–13% for 3 h after DCA administration to glioma С6 bearing rats. The state of mitochondrial electron transport chain components in tumor cells was studied using electron paramagnetic resonance. Results: It has been shown that therapy with DCA using schedule I resulted in 15% decrease of animals life span (LS; р < 0.05), while the use of schedule II had no effect on this index. Prolonged administration of DCA (schedule ІІІ) resulted in significant antitumor effect and increased LS of rats by 25.5% (p < 0.05). Under hypoxic conditions, treatment with DCA resulted in a significant increase of animal LS by 15–22%. Dosage of DCA had a moderate effect of its anticancer action. Maximal effect, an increase of LS by 34.5% (p < 0.05) was detected at a dose of 1.5 g/kg. It has been shown that anticancer activity of DCA under all studied conditions is not related to its influence on a functional state of tumor cell mitochondria. Conclusion: Anticancer effect of DCA significantly depends on a schedule of its administration; being administered at equal total dose, but dependent on the schedule DCA could cause ambiguous effects varying from tumor growth stimulation to significant anticancer activity. Under hypoxic conditions, anticancer efficacy of DCA against glioma С6 is significantly enhanced.

Summary. It is known that the arsenal of chemotherapeutic agents for the treatment of malignant brain tumors is quite limited, which causes the high relevance of research aimed at finding new effective antitumor regimens, including the use of energy metabolism modifiers. Aim: To investigate the anti-glioma activity of sodium dichloroacetate (DCA) and metformin (MTF) used in combination in vitro and in vivo. Materials and Methods: Cell survival, cell cycle, apoptosis, mitochondrial membrane potential (Δψm), ATP level, the glucose consumption rate, and lactate production rate were determined in vitro in cultured glioma C6 cells. The antitumor action of agents in vivo was evaluated routinely by the prolongation of the life span of rats with transplanted intracerebral glioma C6 and was confirmed by histological examination of tumor tissue. Results: The half maximal inhibitory concentration (IC50) for DCA and MTF used separately was 79.2 ± 2.1 mM and 78.4 ± 4.0 mM, respectively, whereas IC50 for DCA used in combination with 7.8 mM MTF was 3.3 fold lower (24.0 ± 1.2 mM, p < 0.05). The 1-day incubation of cells with DCA at a concentration close to IC50 (25 mM), in combination with MTF at a concentration by order lower than IC50 (7.8 mM), in contrast to their separate use, resulted in a decrease in the number of viable cells by 40% (p < 0.05); redistribution of the cells by the cell cycle phases toward decreased proportion of cells in the S-phase by 46% (p < 0.05) and an increased percentage of cells in the G0/G1 phase by 24% (p < 0.05) compared to similar indices in the control. High proapoptotic activity of DCA in combination with MTF was supported by a significantly higher percentage of apoptotic cells in vitro than in the control (18.9 ± 4.4% vs 5.7 ± 1.3%, p < 0.05) and a high number of tumor cells with signs of apoptosis revealed during the histological examination of tumor pathomorphosis. The combined effect of DCA and MTF resulted in almost 4-fold decrease of the glucose consumption rate by glioma C6 cells (0.23 ± 0.05 μmol/106 cells/h vs 0.91 ± 0.12 μmol/106 cells/h, p < 0.05) compared to the corresponding parameters in the control, and 2-fold increased rate of lactate production (1.06 ± 0.03 μmol/106 cells/h vs 0.53 ± 0.03 μmol/106 cells/h, p < 0.05). At the same time, both Δψm and the level of intracellular ATP in the glioma C6 cells treated with DCA and MTF, both separately and in combination, did not differ significantly from those indices in the control. In in vivo studies, the average life span of rats with intracranial transplanted glioma C6, treated with DCA in combination with MTF in a total dose of 1.1 and 2.6 g/kg body weight, respectively, was 50% higher (p < 0.001) than in the control group. In contrast, in the case of single-use (at a dose of 2.6 g/kg), MTF increased the life span of tumor-bearing animals just by 19% (p < 0.01), whereas DCA alone (at a dose of 1.1 g/kg) did not significantly change the survival time of rats. Conclusions: The obtained data indicate synergism of anti-glioma action of DCA and MTF in a case of their combined use both in vitro and in vivo and may be considered a starting point for the development of effective treatment regimens for malignant brain tumors based on the combined use of DCA and MTF.