Summary. Quinazolines are among the most useful heterocyclic compounds due to their diverse chemical reactivity and a wide range of biological activity. Despite a large number of publications devoted to quinazolines and their derivatives, information is presented predominantly regarding the features of the synthesis of these compounds and their structure. The studies of specific pharmacological activity and antitumor activity of these compounds are mainly limited to primary screening using enzyme systems and cell lines. In this mini review information concerning the potential targets for antitumor action of quinazoline compounds is summarized and discussed.

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.

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.

It is well-known that the survival of metastatic cells during their dissemination plays an important role in metastasis. However, does this mean that the final result of the metastatic cascade (the volume of metastatic damage to distant organs and tissues) depends on, or at least correlates with, the degree of resistance to anoikis (distinctive hallmarks of metastatic cells)? This question remains open.The aim of the work was to study in vitro the changes in the survival rates, proliferative activity, oxidative stress, and glycolysis intensity during three days of anchorage-dependent and anchorage-independent growth of two Lewis lung carcinoma cell lines (LLC and LLC/R9) and compare these changes with the status of mitochondria and metastatic potential of the cells in vivo. The number and volume of lung metastases were estimated for each cell line after intramuscular inoculation of the cells in C57Bl/6 mice. For the in vitro study, the cells were seeded on Petri dishes pretreated with poly-HEMA or untreated dishes and then allowed to grow for 3 days. Cell viability, cell cycle progression, the level of reactive oxygen species (ROS), glucose consumption and lactate production rates were investigated daily in both growth conditions. An electron microscopy study of intracellular structures was carried out. The study showed (as far as we know for the first time) a correlation between the metastatic potential of cells (determined in vivo) and their sensitivity to anoikis (assessed in vitro). The transition of LLC/R9 cells with an inherently defective mitochondrial system to the conditions of anchorage-independent growth was characterized by a decrease in survival, a slowdown in growth rates, an increase in both glucose consumption rate and intracellular ROS levels and manyfold lower metastatic potential, compared to highly metastatic LLC cells with the normal mitochondrial system.

Significant variability of anticancer efficacy of dichloroacetate (DCA) stimulated an active search for the agents capable to enhance it antitumor action.

It is known that metformin is a hypoglycemic drug used to treat type II diabetes mellitus. Recently active studies of its antitumor activity in relation to different types of malignant cells are conducted. Aim: To determine the relationship between cytotoxic activity of metformin in vitro and its antitumor activity in vivo. Materials and Methods: The rat C6 glioma cell line and mouse Lewis lung carcinoma cells (LLC) were used in this work. The number of living cells in the cytotoxic test was evaluated using sulforhodamine B. Parameters of tumor cell susceptibility to metformin activity in vitro were calculated using nonlinear and linear regression of experimental data. The antitumor action of metformin in vivo was evaluated routinely by the extension of survival time (ST) (in rats with intracerebral C6 glioma) and its effect on the volume of the primary tumor, the number and volume of metastases (in mice with LLC). Results: In cultured LLC cells in vitro, the proportions of metformin-resistant (A1, %) and metformin-sensitive (A2, %) subpopulations were 10.0 ± 2.2% and 92.0 ± 3.5%, respectively, in terms of the total number of living cells. Parameter t, which characterizes the sensitivity of cancer cells to metformin action (the lower is the value of this parameter the higher is sensitivity of cells to metformin cytotoxicity), for metformin-resistant and metformin-sensitive subpopulations was: t1(mM) = ∞ and t2(mM) = 2.9 ± 0.3, correspondingly. For metformin-sensitive subpopulation of LLC cells IC50 (mM) = 2.42 ± 0.34. The volume of the primary tumor, the amount and volume of metastases in mice receiving metformin at a dose of Dmin (0.15 g/kg) and Dmax (0.3 g/kg) values did not significantly differ from those in the control. However, in the case of Dmin, there was a tendency to increased volume of the primary tumor, in the case of Dmax, there was a tendency to increased volume of metastases. The analogical parameters (A1, A2, b1, b2, IC50 (1), IC50 (2)) characterizing cell sensitivity to the action of metformin in vitro were obtained in relation to C6 glioma cells. In metformin-resistant subpopulation, these parameters were: A1 (%) = 72.3 ± 1.4; b1 (%/mM) = 0.43 ± 0.005; IC50 (1) (mM) = 84.1 ± 2.4. For metformin-sensitive subpopulation, these parameters were: A2 (%) = 30.8 ± 2.3; b2 (%/mM) = 2.87 ± 0.4; IC50 (2) (mM) = 5.37 ± 0.45. In vivo, a statistically significant anti-glioma effect of metformin was observed: at a dose of Dmax (5.2 g/kg) administration of this preparation resulted in a prolongation of the mean ST of tumor-bearing rats by 23% (p < 0.05) compared with that in the control. Conclusions: We found no correlation between the cytotoxic/cytostatic action of metformin in vitro and its antitumor activity in vivo on the two types of tumor cells; these results indicate a significant contribution of the tumor microenvironment to the implementation of the antitumor activity of the drug.