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Myeloid-derived suppressor cells are heterogenic immature myeloid cells, which possess suppressor activity and play an important role in both, tumor progression and metastasis. The accumulation of MDSCs is induced primarily by factors that are secreted by the tumor microenvironment, which disturb myelopoiesis that occurs in the bone marrow and enables the migration of immature myeloid cells into the tumor. MDSCs promote tumor growth by inhibiting the activity of immunocompetent cells, as well as by activating non-immunological processes, such as tumor angiogenesis, the degradation of extracellular matrix and the formation of premetastatic niche. Due to their significant impact on the development of cancer, MDSCs became clinically relevant in tumor diagnostics. In recent years, various therapeutic strategies were developed in order to inhibit the proliferation, accumulation or suppressor activity of MDSCs, as well as to render the differentiation or total depletion of these cells. The proposed therapies often combine factors that reduce MDSCs suppression with conventional chemotherapy or with immune checkpoints inhibitors.///In this review, we describe the current state of knowledge about factors that enable the accumulation of MDSCs, methods of phenotypic identification of these cells, as well as the mechanisms of suppression used by them. Moreover, we provide insight into the therapeutic approaches, which aim to restore the reactivity of the immune system by reducing the suppressor effects of MDSCs. [ABSTRACT FROM AUTHOR]

Inhibitors of histone deacetylases (HDIs), by affecting the process of histone acetylation, lead to changes in chromatin condensation, and in consequence, to changes in the expression of numerous genes responsible for the cell cycle and differentiation. Therefore, they can be effective in the treatment of cancer. The antitumor activity for over 15 HDIs has been confirmed so far, and some of them have been approved in the USA and Europe, mainly in combination with cytostatics or radiotherapy. For several HDIs, large clinical trials are being carried out to estimate their effectiveness, in monotherapy and new combinations. Other synthetic and natural compounds with HDI activity are tested in preclinical studies.///HDIs differ in terms of chemical structure, biological activity and specificity in relation to individual HDACs. The compounds active against classic HDACs (Zn2+-dependent metalloproteins) are usually characterized by the presence the Zn2+ binding group, the linker part and the capping group. Taking into account the type of Zn2+ binding group, classic HDIs are classified as short-chain fatty acids, hydroxamic acids, cyclic peptides and benzamides. In turn, the nicotinamide adenine dinucleotide- -dependent SIRTs inhibitors are small molecules, mostly nicotinamide and β-naphthol derivatives.///The presented paper summarizes the most important information regarding the use of HDIs as anticancer drugs, regarding their diversified chemical structure, activity against HDACs, additional therapeutic properties and side effects. The review was made taking into account the literature from the last five years (2013-2017). [ABSTRACT FROM AUTHOR]

Nowadays, cancer and anticancer therapy are increasingly mentioned topics. Groups of researchers keep looking for a tool that will specifically and efficiently eliminate abnormal cells without any harm for the normal ones. Such method entails the reduction of therapy's side effects, thus also improving patient's recovery. Discovery of synthetic lethality has become a new hope to create effective, personalized therapy of cancer. Researchers noted that pairs of simultaneously mutated genes can lead to cell death, whereas each gene from that pair mutated individually does not result in cell lethality. Cancer cells accumulate numerous changes in their genetic material. By defining the pairs of genes interacting in cell pathways we are able to identify a potential anticancer therapy. It is believed that such a process has evolved to create cell resistance for a single gene mutation. Proper functioning of a pathway is not dependent on a single gene. Such a solution, however, also led to the evolution of multifactorial diseases such as cancer. Research techniques using iRNA, shRNA or small molecule libraries allow us to find genes that are connected in synthetic lethality interactions. Synthetic lethality may be applied not only as an anticancer therapy but also as a tool for identifying the functions of recently recognized genes. In addition, studying synthetic lethality broadens our understanding of the molecular mechanisms governing cancer cells, which should be helpful in designing highly effective personalized cancer therapies. [ABSTRACT FROM AUTHOR]

The term triple-negative breast cancer (TNBC) defines breast tumors that do not express estrogen receptors, progesterone receptor or epidermal growth factor receptor HER2 on immunohistochemical analysis. TNBC accounts for 12-17% of all types of breast cancer. Molecular profiling indicated that triple-negative breast cancer represents a heterogeneous subgroup of breast cancer. Triple-negative breast cancer shares histological and genetic abnormalities with basal-like subtype of breast cancer; however, this overlap is incomplete. Breast cancer found in BRCA1 mutation carriers is also frequently TNBC. Triple-negative breast cancer does not benefit from hormonal therapies or treatments targeted against HER2. The results of ongoing studies as well as the results of clinical trials suggest that poly(ADP-ribose) polymerase inhibitors, EGFR, Hedgehog, Notch, Wnt/β-catenin, VEGF signaling inhibitors, and mTOR, Src, and Bcr/Abl kinase inhibitors used alone or in combination with other anticancer drugs might be effective in triple-negative breast cancer treatment. In this review, current knowledge on molecular characteristics of triple-negative breast cancer and its subtypes’ treatment options is presented. [ABSTRACT FROM AUTHOR]

Dogs have accompanied humankind for thousands of years. They share the same environment, and thus are exposed to the same environmental factors such as air pollution, tobacco smoke, and various chemicals. Recent development of veterinary care has led to a significant extension of dogs' lifespan and allowed the diagnosis and treatment of a growing number of different diseases in this species. Among all diseases in dogs, cancer is considered the main cause of mortality, with lymphoproliferative disorders accounting for up to 30% of all canine cancers. Some of them, such as non-Hodgkin lymphoma (NHL) and lymphocytic leukemia, are very similar in the etiology, pathogenesis and response to treatment to the diseases occurring in humans. Due to anatomical and physiological similarities to humans, the dog is a useful model for the study of new therapeutic strategies for humans. Studies on the canine neoplasia are currently limited by the lack of well-characterized and widely available cell lines; thus, recently obtained canine NHL cell lines may become a valuable model for such studies. Investigation of their sensitivity to the antiproliferative effects of different factors should allow the creation of a database similar to the existing classification of human leukemias and lymphomas. This should enable quick and accurate diagnosis and selection of appropriate treatment based on phenotypic analysis and histopathological examination of clinical samples. The cooperation between human and veterinary oncologists gives the opportunity to use the dog as a model for the study of certain types of cancers presenting a challenge for modern medicine [ABSTRACT FROM AUTHOR]

HMGB1 is an evolutionarily conserved protein with a wide spectrum of action. Its main receptors are RAGE and TLR found on the surface of immune system cells as well as endothelial cells. Although signaling pathways for both receptor groups are different, ultimately they both activate NFκB transcription factor which, in turn, activates genes encoding adhesion proteins, proinflammatory cytokines and proangiogenic factors. Inside cells, HMGB1 is found mainly in the cell nucleus, where it participates in replication, recombination, transcription and DNA repair processes. Following release into the extracellular space, HMGB1 becomes a proinflammatory cytokine which stimulates formation of new blood microvessels, enhances cell migration, activates the inflammatory condition and affects cell proliferation. HMGB1 protein also takes part in regeneration of damaged tissues and stimulates autophagy. HMGB1 plays a potential role in anticancer therapy. Increased amounts of HMGB1 in cancer cells and elevated levels in the bloodstream are noted among patients afflicted with various cancers. HMGB1 protects cells from apoptosis, as it affects telomere stability. HMGB1 also stimulates a number of proteins involved in proliferation of cancer cells and inhibits signals that control cell growth. Ability to arrest HMGB1 release from cells or to inhibit its activity appears to be a promising therapeutic approach. At present, several inhibitors of HMGB1 are known and can be used in anticancer therapy. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme is the most common and a particularly aggressive form of glial primary brain tumors. This malignancy accounts for ca. 70% of all diagnosed cases. Unfortunately, average survival of glioma patients does not exceed one year from diagnosis. Specific vascularization pattern (presence of numerous microvessels and glomerular vessels) and exceptional invasiveness are characteristic features of glioblastoma tumors. Both of these features reflect complex underlying processes forming two vicious circles. Common to both of these circles is the state of tumor underoxygenation. Hypoxia that occurs in the vicinity of abnormal tumor blood vessels stimulates formation of novel microvessels and invasiveness of tumor cells. In their essence, both of the vicious circles are processes allowing tumor cells to adapt to an underoxygenated tumor milieu. These processes play an important role in tumor progression, which reflects a specific type of evolution of cancer cells. Late effects of this evolution include appearance of highly aggressive, chemo- and radiotherapy resistant neoplastic cells. Increased adaptation capabilities of such cancer cells have a negative influence on the therapeutic process. Effective therapeutic strategies should not be directed against single cancer cell markers; instead, they should be targeted so as to break both vicious cycles. Herein we discuss several such strategies. In our opinion, effective therapeutic approaches must include a combination of several agents that recognize and simultaneously break both vicious cycles, i.e. vascularization and invasiveness. Also, agents that decrease hypoxia in cancer cells, for example drugs inhibiting activity of HIF-1α, might also prove therapeutically effective in such approaches. [ABSTRACT FROM AUTHOR]

A majority of currently used anticancer drugs belong to a group of chemical agents that damage DNA. The efficiency of the treatment is limited by effective DNA repair systems functioning in cancer cells. Many chemotherapeutic compounds cause strong systemic toxicity. Therefore, there is still a need for new anticancer agents which are less toxic for nontransformed cells and selectively kill cancer cells. One of the most promising molecular targets in cancer therapy is poly(ADP-ribose) polymerases (PARP). PARP play an essential role in repairing DNA strand breaks. Small molecule inhibitors of these enzymes have been developed and have proved to be extremely toxic for cancer cells that lack the functional BRCA1 and BRCA2 proteins that are involved in homologous recombination, a complex repair mechanism of DNA double strand breaks. Mutations in BRCA1/2 genes are associated with genetically inherited breast and ovarian cancers. Therefore PARP inhibitors may prove to be very effective and selective in the treatment of these cancer types. This review is focused on the function of BRCA1/2 proteins and poly(ADP- -ribose) polymerases in DNA repair systems, especially in the homologous recombination process. A short history of the studies that led to synthesis of high specificity small molecule PARP inhibitors is also presented, as well as the results of clinical trials concerning the most effective PARP inhibitors in view of their potential application in oncological treatment, particularly breast cancers. [ABSTRACT FROM AUTHOR]

The basis for targeting specific components of the apoptotic machinery for anticancer therapy is the detailed knowledge on molecular mechanisms that regulate this complex cell death pathway. As the mitochondrial pathway of apoptosis is the major route to respond to stress stimuli including anticancer drugs, and that pathway is largely impaired in cancer cells, leading to tumor formation and treatment resistance, a variety of approaches have been developed to restore the function of the mitochondrial pathway in cancer cells. BH3-only proteins, being important inducers of the mitochondrial pathway, either directly stimulate proapoptotic Bax-like proteins or interfere with antiapoptotic Bcl-2 proteins. Therefore, the development of molecules able to mimic the function of BH3-only proteins is considered a promising strategy to improve cancer cell response to treatment. Several BH3 mimetics have been designed and studied in various tumors, in both in vitro and in vivo settings. Some of them are currently being evaluated in clinical trials either alone or in combination with conventional anticancer drugs. BH3 profiling of cancer cells was introduced to better predict the responsiveness of tumor cells to BH3 mimetics combined with conventional therapies. In this review, we summarize the current knowledge on BH3-only proteins and describe the spectrum of strategies employing BH3 mimetics in preclinical and clinical studies that aim at tumor targeting. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that belong to the hormone nuclear receptor superfamily. Their main role is control of fatty acid metabolism and to maintain glucose homeostasis. Isotype g of PPAR can also be implicated in proliferation and cellular differentiation of both normal and cancer cells. Compounds that are PPARg ligands have a negative influence on cancer cells and can induce apoptosis, inhibit proliferation or induce cellular differentiation of these cells. This review summarizes general information about PPAR and focuses on anticancer activities of PPARg ligands and their use in combined therapy. Combination treatment using PPARg ligands and other agents, especially retinoids and specific kinase inhibitors, may be an effective strategy for chemoprevention and treatment of some cancers. [ABSTRACT FROM AUTHOR]