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Copyright of Advancements of Microbiology is the property of Sciendo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Endometrial cancer is one of the most common malignancies in women in Western Europe. Its incidence is constantly increasing. The prognosis is poor, especially in the case of recurrent and advanced stages of the disease. Therefore, new therapeutic options are constantly sought to improve the prognosis for women with this type of cancer. One of the targets of modern diagnostic and therapeutic methods for endometrial cancer may be cancer stem cells. These are cells with the properties of a bone marrow stem cell that has acquired an oncogenic mutation, gained the ability to self-renew, differentiate and generate the entire cancer cell population. Many studies are focused on searching for a marker (or markers) of cancer stem cells that would allow their precise identification and development of individualized targeted therapy. The CD133 glycoprotein, also known as prominin-1, appears to be a promising surface marker for identifying cancer stem cells, including endometrial cancer. The aim of the paper is to present studies on the concept of cancer stem cells in endometrial cancer, especially those related to CD133 cells, which display stem-like properties. [ABSTRACT FROM AUTHOR]

Because of increased incidence of cancer and the development of resistance after treatment with typical drugs, new insights into the mechanisms of action of individual compounds are extremely valuable. In this article, we focus on taxanes, drugs belonging to the group of microtubule stabilizers, and their new generation - epothilones. Facing the fact that the molecular target for these compounds are microtubules, our attention was focused primarily on the role of overexpression of one of tubulin isotypes in response of tumor cells, particularly ovarian cancer to treatment with these compounds. On the basis of the literature data it can be concluded that one reason for the ineffectiveness of taxane is the resistance growing in the case of overexpression of β-tubulin class III- (TUBB3). Epothilones, however, due to their ability to bind equally to β-tubulin class I and III are effective in these cells, giving them an advantage over taxanes. It is necessary to emphasize the role of mikroRNA, transcription factors and other proteins associated with the activation of microtubules in development of resistance to taxanes and overcoming the resistance of the epothilones. Particularly interesting tubuseems to be the link between expression of TUBB3 and Glis proteins, which are end-effectors of Hedgehog pathway. Thanks to the confirmation that Gli1 overexpression is associated with decreased response to chemotherapy, it was possible to sensitize cells to epothilones after addition a suitable inhibitor. [ABSTRACT FROM AUTHOR]

Multidrug resistance of cancer cells is one of the most serious barriers to success in cancer disease therapy. Multidrug resistance, i.e. the principal mechanism via which many cancers develop resistance to chemotherapy drugs, is a major factor in the failure of many forms of chemotherapy. The best known mechanism is often attributed to the function of drug transporter proteins in the plasma membrane, which actively remove drugs from neoplastic cells. Abnormal overexpression of these proteins is the most frequently described factor connected with resistance to cytostatics. Among cellular transporter proteins, glycoprotein P (P-gp) plays the most important role. An increased level of this protein is considered a poor prognostic factor in many tumors. Clinical significance of other multidrug resistance proteins remains the subject of intensive studies. Another mechanism to protect the refractory cancer cell against an increasing concentration of cytostatic agents inside the cell is the increased ability to convert the drug into a non-toxic form. An increased activity of detoxifying enzymes such as glutathione transferase, glutathione peroxidase and superoxide dismutase leads to neutralization of the products formed by metabolism of drugs. Recent results of research on ovarian cancer have shown that the factor increasing the risk of this cancer is the presence and expression of the human gene polymorphisms of glutathione S-transferase. High concentrations of glutathione S-transferase is a poor prognostic factor in ovarian cancer and other cancers such as colorectal cancer, lung cancer, stomach cancer, chronic lymphocytic leukemia and gliomas. [ABSTRACT FROM AUTHOR]

Each year about 11,000 new breast cancer cases are recognized and almost half of these people die. Such great mortality may result from too late diagnosis, lack of specific and efficient drugs and multidrug resistance (MDR) observed in cancer cells. The basic mechanism triggering multidrug resistance is an increased expression and activity of membrane transporters that mostly belong to the ABC superfamily (ATP binding cassette). Among those proteins, glycoprotein P (ABCB1 gene expression product) is the best known one. The substrate spectrum of glycoprotein P is very broad and contains xenobiotics and cytotoxic drugs, protein inhibitors, immunosuppressive agents, steroids, statins, calcium channel blockers, beta-blockers, antihistamine drugs, antidepressants and antiemetic drugs. In these gene sequences, numerous polymorphisms were described and especially three of them reveal great clinical significance: cytosine into thymine transition in 1236 position of exon 12 - (C1236T, rs1128503), substitution in exon 21 - G2677A/T (rs2032582) and in exon 26 - C3435T (rs1045642). Those polymorphisms may affect ABCB1 expression (C3435T), glycoprotein P structure (G2677T/A) or protein capability to bind substrates (C1236T). It is suggested that consequently these polymorphisms may modify the chemotherapy response in cancer cells. In this review we describe the modulating effect of ABCB1 gene polymorphisms in breast cancer chemotherapy. [ABSTRACT FROM AUTHOR]

In view of the increasing number of breast cancer cases, it is important to develop methods of prevention of formation of this type of cancer as well as inhibition of its growth. Numerous scientific researches show decreased levels of carotenoids in the blood serum of women suffering from breast cancer. Therefore, the aim of this study was to review the available literature on varied properties of lycopene and possibilities of its application as adjuvants in the anticancer therapy. Lycopene is a natural, red dye carotenoid, mostly occurring in tomatoes. It is a relatively heat-stable substance, which subjected to thermal processes such as heating, stewing, roasting or frying, increases its bioavailability/bioassimilability in the body. Lycopene has a multi-anticancer activity which is associated with antioxidant, anti-inflammatory and immunomodulatory properties and it affects gene expression of ARE (Antioxidant Response Element). Lycopene inhibits proliferation of cancer cells, induces their apoptosis and prevents formation of blood vessels. In addition, lycopene competes with estrogen for active sites of estrogen receptors, thus decreasing the expression of ERE (Estrogen Response Element). A critical review of available literature suggests that dietary lycopene, due to its multi-chemopreventive activity, can be used in the prevention of breast cancer. Studies on the possible use of lycopene in the treatment of cancer are still ongoing. There are positive promises from cell culture studies, however further efforts to evaluate the effect of lycopene in women diagnosed with breast cancer are needed. [ABSTRACT FROM AUTHOR]

Fullerenols, the water-soluble derivatives of fullerenes, are currently being recently intensively studied in the context of the possibility of their application in the biomedicine. Due to their hydrophilic properties and the ability to eliminate free radicals, fullerenols may in the future provide a solid alternative to currently used pharmacological methods in chemotherapy, treatment of neurodegenerative diseases and radiobiology. Depending on the research protocol applied, fullerenols may also act as pro oxidants. The dualistic nature of fullerenols may contribute to finding new biomedical applications of these agents in the future, by exerting a cytotoxic or protective effect respectively against cancer cells or healthy cells. Because of the encapsulated structure of fullerenols, there exists the possibility of their application in medical diagnostics in the transfer of contrast agents or in the drug transport. During the planning of an experiment designed to investigate the effects of radiation in combination with derivatives of water-soluble fullerenes, the possibility of appearance of the "dose-response effect" should be taken into consideration since it significantly contributes to one of the two possible effects: protection or sensitization. The same applies to the possibility of using these compounds as potential neuroprotectors. Fullerenol may protect neurons in the particular areas of the brain but in the definedcertain doses it may also induce cell death. A giant leap in the field of nanotechnology not only leads scientists to search for new applications of nanomaterials such as fullerenols, but also raises the question about their harmful effect on the environment. High utilization of hardly biodegradable fullerenols increases the likelihood of their accidental release into natural systems and their bioaccumulation. Despite convincing evidences about the potential applications of fullerenols in biomedicine, we still have insufficient knowledge about the mechanism of action of these molecules and their possible side effects. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (As2O3) has recently been identified as an effective drug in different types of cancer therapy. It is a useful pharmacological agent in acute promyelocytic leukemia (APL) treatment, especially the form that is resistant to conventional chemotherapy with all-trans retinoic acid (ATRA). What is more, laboratory data suggest that As2O3 is also active when it comes to several solid tumor cell lines. However, the mechanism of action is not fully understood. As2O3 in high doses triggers apoptosis, while in lower concentrations it induces partial differentiation. The As2O3 mechanism of action involves effects on mitochondrial transmembrane potential which lead to apoptosis. It also acts on the activity of JNK kinase, glutathione, caspases, NF-κB nuclear factor or pro- and antiapoptotic proteins. This publication presents the current knowledge about the influence of arsenic trioxide in cancer cells [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is one of the major energy sensor at both: cellular and whole body level. It exists as heterotrimer containing three subunits: the catalytic α subunit, βand regulatory γ. AMPK is localized both in the cytoplasm and in the nucleus. It is activated by increasing concentrations of AMP during the energy shortage, causing activation of catabolic pathways and inhibition of energy consuming processes. AMPK activity can be regulated allosterically: by binding AMP to a regulatory γ subunit, as well as by phosphorylation on Thr172 of the catalytic α subunit by other kinases. Activated AMPK can effectively inhibit the mTOR pathway which is hyperactive in many types of cancer. On the other hand AMPK inactivation associates with the type II diabetes, diet-induced obesity, insulin resistance and the development of other metabolic disorders. The AMPK dysfunction is also observed in inflammation. It was discovered during last years that abnormalities in the AMPK function can induce the metabolic reprogramming in cancer cells known as the Warburg effect. Additionally, AMPK is activated during irradiation. Its activation leads to inhibition of growth. On the other hand, active AMPK enables cells to survive in difficult conditions such as hypoxia, or glucose deprivation. Because of its crucial role in maintaining of the energy homeostasis AMPK is an excellent therapeutic target. However, it still remains unknown what is better: to activate or inhibit the AMPK function [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression implicated in cancer pathogenesis. Inhibitors of HDACs (HDI) are under investigation as novel anti-cancer drugs, which induce histone hyperacetylation. These agents modulate chromatin structure leading to transcriptional changes of a very large number of genes, which affect signaling pathways, inhibit cell cycle progression and angiogenesis, and induce apoptosis in cancer cells. Currently, several HDI are in clinical trials used in monotherapy or in combination with other cytostatics, showing promising anticancer effects. To date, more than 15 HDIs have been found as potential drugs. This paper reviews the molecular mechanisms of HDI action on cancer cells and summarizes clinical trials of the most promising HDIs in the treatment of patients with hematologic malignancies and solid tumors [ABSTRACT FROM AUTHOR]

Autophagy is a process necessary for maintaining cell homeostasis in physiological conditions, as well as during certain stresses like nutrients or oxygen deprivation. Autophagy also plays an essential role in tumorigenesis. It prevents cell transformation, but on the other hand, autophagy enables existing cancer cells to adapt to harmful conditions and increased glucose demand, supports maintaining of cellular metabolism and accelerates tumor growth. Among others, it refers to Ras-transformed cells. Recent research unveiled BNIP3 protein as one of the key players involved in autophagy. Although BNIP3 is classified as proapoptotic member of BH3-only subfamily, its proapoptotic activity is questionable. However, BNIP3 demonstrates ability to induce or stimulate autophagy and its specific variant -- mitophagy. This paper aims to summarize the existing body of knowledge related to the role of BNIP3 in autophagy, as well as the importance of this process in tumorigenesis. In particular, we emphasize the relation between autophagy and BNIP3 expression induced by Ras oncogene [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a group of small molecules, about twenty nucleotides in length. They are involved in the regulation of gene expression mainly at a posttranscriptional level. This function depends on their complementarity to the 3'UTR regions of mRNAs. MicroRNAs are essential for proper development and functioning of the organism. They are so important because of their participation in such processes as angiogenesis, apoptosis, cell cycle control and oncogenesis. Over thirty percent of human genes are controlled by miRNAs. This indicates the great importance of these molecules. Alterations of numerous cellular processes can be caused by the dysregulation of miRNA expression. Such disturbances are observed in cancer cells, and signatures of microRNA expression are specific to particular types of cancer. It is suggested that miRNAs may serve as diagnostic and prognostic factors in oncologic and hematooncologic disorders. The expression of specific miRNAs can indicate benign or aggressive course of disease. The overall survival or time to treatment are also possible to estimate based on the microRNA expression profile. Knowledge about changes in miRNA expression observed in leukemia patients may enable the selection of appropriate individual therapy. Recent reports indicate that various hematooncologic disorders may be well characterized by microRNAs circulating in plasma or serum. It is of great potential importance, considering the availability of material for analysis, simplicity of diagnostic procedures and shortening of time required to conduct them [ABSTRACT FROM AUTHOR]

Vitamin D is a potent cellular antiproliferative and prodifferentiation agent. Nearly 90% of all vitamin D in the human body has to be formed in the skin through the action of UV-radiation. It has been demonstrated in laboratory and epidemiological research that vitamin D may have direct effect on cancer cells and influence the growth and outcome of internal malignancies, e.g.: breast, colon, prostate and ovarian cancer. There is accumulating evidence that vitamin D may also be important in melanoma development and progression. In this cancer the relationship between solar irradiation and the disease is more complex. There is no doubt that solar radiation is mutagenic and there is evidence of an association between melanoma and sun exposure. On the other hand, there is a line of studies supporting the protective role of vitamin D in melanoma. This problem is controversial, especially according to health campaigns promoting strict sun protection procedures to prevent skin cancer. In this article, the authors present the results of both laboratory and epidemiological studies concerning vitamin D and melanoma. [ABSTRACT FROM AUTHOR]

Autophagy is a catabolic process involving the degradation of long-lived proteins and organelles through the lysosomal machinery. In eukaryotic cells, among the three types of autophagy the most extensively studied is macroautophagy. Macroautophagy (hereafter referred to as autophagy) is characterized by sequestration of bulk cytoplasm in double-membrane vesicles, called autophagosomes, which ultimately fuse with lysosomes, resulting in degradation of their contents. Autophagy is responsible for the maintenance of intracellular homeostasis and enables cell survival under stress conditions. However, this process is also involved in the pathogenesis of diverse diseases, including cancers. In the cancer cell, autophagy plays a dual role, as a mechanism responsible for protecting or killing the cell. In most cases chemotherapy-induced autophagy in tumor cells is a prosurvival response which potentially leads to development of drug resistance. However, autophagy can also lead to cell death, thus enhancing treatment efficacy. It is important for the anticancer therapy to find the type of cancer cells which are susceptible to autophagy and to determine whether the autophagy induced by the applied therapy leads to cells' death or their survival and subsequently to therapy resistance. In this review, the molecular mechanism of macroautophagy and the most important signaling transduction pathways involved in regulation of this process in cancer cells are presented. The dual function of autophagy in tumorigenesis and the implications of autophagy modulation for cancer therapy are also discussed. [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]

Resistance to cytotoxic drugs is a significant problem of systemic treatment of cancers. Apart from drug inactivation, changes in target enzymes and proteins, increased DNA repair and suppression of apoptosis, an important mechanism of resistance is an active drug efflux from cancer cells. Drug efflux across the cell membrane is caused by transport proteins such as ABC proteins (ATP-binding cassette). This review focuses on the ABCC protein subfamily, whose members are responsible for multidrug cross-resistance of cancer cells to cytotoxic agents. The authors discuss the structure of ABCC proteins, their physiological function and diseases provoked by mutations of respective genes, their expression in many different malignancies and its connection with resistance to anticancer drugs, as well as methods of reversion of such resistance. [ABSTRACT FROM AUTHOR]

Introduction: MIP-1-α, a cytokine encoded by CCL3 gene, is described as potentially involved in pathogenesis and clinical outcome of some lymphoproliferative disorders. The aim of the study was in vitro verification of a hypothesis of CCL3 expression involvement in pathogenesis and clinical outcome of acute lymphoblastic leukemia (ALL) in children. Establishment of the possible predictive value of CCL3 expression for prognosis in ALL. Material and methods: In a group of 28 children (19 boys, 9 girls) with ALL, with the median value of the age at onset 63 and half months, the molecular analysis was performed on neoplasmatic cells collected at the day of diagnosis. To evaluate the increase of product of amplification in real-time the RT-PCR technique has been used. The clinical analysis was related to gender, response to glucocorticosteroid therapy (according to ALLIC BFM 2002), relapse and death of the patient. Results: The mean value of CCL3 expression given as Δ was 5.55 with SD±3.7. We established a strong association between CCL3 expression level and gender. The median value of CCL3 expression in boys (Δ=5,57 with qs=0.15-5.92) was lower than in girls group (Δ=7.33; qs=4.07-8.79). The p value for this correlation was equal 0,03. The statistic analysis of the correlation of CCL3 expression and probability of relapse was not performed due to low level of cases. There were no data suggesting the influence of CCL3 expression on other aspects of clinical analysis. Conclusions: The expression of MIP-1-α gene in ALL cells seems not to be related with clinical outcome and prognosis in pediatric group. Our results requires further research in a bigger group of patients. [ABSTRACT FROM AUTHOR]

Pancreatic carcinoma is a commonly diagnosed neoplasia, presenting with an extremely poor prognosis. Presently used therapies give dissapointing results. New treatment strategies concern blocking of epidermal growth factor receptor (EGFR). Its function in promoting development of many types of cancer cells is very well documented. Novel drugs are already used in the treatment of breast, colon, head and neck cancers. The two groups of them (monoclonal antibodies anti-EGFR and tyrosine kinase inhibitors) are currently tested in patients with pancreatic carcinoma. Preclinical data showed very encouraging results. Initial results from clinical studies were also positive and additionaly proved low toxicity of those drugs. Erlotinib - a tyrosine kinase inhibitor is the first substance approved by Food and Drug Administration (FDA) for the combination therapy with gemcitabine of pancreatic cancer with metastases. Phase III clinical studies showed it to be the only therapy which increases the survival of those patients. There are also many preclinical studies which focus on different mechanisms of EGFR blockage. Their initial results are encouraging. [ABSTRACT FROM AUTHOR]