Effect of Poly(methacrylic acid) on the Cytokine Level in an In Vivo Tumor Model.

Cancer is a leading cause of mortality globally. Despite remarkable improvements in cancer-treatment approaches, disease recurrence and progression remain major obstacles to therapy. While chemotherapy is still a first-line treatment for a variety of cancers, the focus has shifted to the development and application of new approaches to therapy. Nevertheless, the relationship between immune response, neoplastic diseases and treatment efficiency is not fully understood. Therefore, the aim of the study was to investigate the immunopharmacological effects of methacrylic acid homopolymer in an in vivo tumor model. MATERIALS AND METHODS: Monomeric methacrylic acid was used to synthesize polymers. Methacrylic acid was polymerized in dioxane in the presence of 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid. To study the molecular weight characteristics of PMAA by GPC, carboxyl groups were preliminarily methylated with diazomethane. An experimental cancer model was obtained by grafting RMK1 breast cancer cells. The serum levels of IL-6, IL-10, IL-17, transforming growth factor ß1 (TGF-ß1), and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: The effect of PMAA on the serum concentrations of several cytokines was studied upon its single administration to laboratory animals in early neoplastic process. The IL-6, IL-17 and TGF-ß1 concentrations were found to change significantly and reach the level observed in intact rats. The IL-10 concentration tended to normalize. CONCLUSION: The positive results obtained are the basis for further studies on the effect of methacrylic-acid polymers with different molecular-weight characteristics on the neoplastic process.

Insight into redox regulation of apoptosis in cancer cells with multiparametric live-cell microscopy.

Cellular redox status and the level of reactive oxygen species (ROS) are important regulators of apoptotic potential, playing a crucial role in the growth of cancer cell and their resistance to apoptosis. However, the relationships between the redox status and ROS production during apoptosis remain poorly explored. In this study, we present an investigation on the correlations between the production of ROS, the redox ratio FAD/NAD(P)H, the proportions of the reduced nicotinamide cofactors NADH and NADPH, and caspase-3 activity in cancer cells at the level of individual cells. Two-photon excitation fluorescence lifetime imaging microscopy (FLIM) was applied to monitor simultaneously apoptosis using the genetically encoded sensor of caspase-3, mKate2-DEVD-iRFP, and the autofluorescence of redox cofactors in colorectal cancer cells upon stimulation of apoptosis with staurosporine, cisplatin or hydrogen peroxide. We found that, irrespective of the apoptotic stimulus used, ROS accumulation correlated well with both the elevated pool of mitochondrial, enzyme-bound NADH and caspase-3 activation. Meanwhile, a shift in the contribution of bound NADH could develop independently of the apoptosis, and this was observed in the case of cisplatin. An increase in the proportion of bound NADPH was detected only in staurosporine-treated cells, this likely being associated with a high level of ROS production and their resulting detoxification. The results of the study favor the discovery of new therapeutic strategies based on manipulation of the cellular redox balance, which could help improve the anti-tumor activity of drugs and overcome apoptotic resistance.

Tumor-associated macrophages: Role in the pathological process of tumorigenesis and prospective therapeutic use (Review).

The aim of the present study was to evaluate the current body of knowledge regarding tumor-associated macrophages (TAMs) and their potential use in antitumor therapy, based on their role in the pathological process of tumorigenesis. For this purpose, a critical analysis of published data and summarization of the findings available from original studies, focusing on the role of TAMs in the pathological process, and their potential therapeutic application was performed. Promising key avenues of research were identified in this field. The following issues seem the most promising and thus worth further investigation: i) The process of M1/M2 macrophage polarization, macrophage characteristics at intermediate polarization steps and their role in the tumor process; ii) determining the conditions necessary for transitions between the M1 and M2 macrophage phenotypes and the role of signals from the microenvironment in this process; iii) cause-and-effect associations between the quantity and quality of macrophages, and the prognosis and outcome of the pathological process; iv) modulation of macrophages and stimulation of their phagocytic activity with drugs; v) targeted vector-based systems for drug delivery to macrophages; and vi) targeted drug delivery systems with macrophages as carriers, thus potentially combining chemotherapy and immunotherapy.