New Target For Cancer Therapy Research Articles

The roles of mesenchymal stem cells in tumor inflammatory microenvironment

Tumor behavior is not entirely determined by tumor cells. Studies have demonstrated that a variety of non-tumor cells in the tumor microenvironment affect tumor behavior; thus, a new focus of cancer research has been the development of novel cancer treatment ideas and therapeutic targets based on the effects of these cells. Mesenchymal stem cells (MSCs) are an important component of the tumor microenvironment; however, previous studies have produced controversial results regarding whether MSCs promote or inhibit tumor growth and progression. In particular, Naïve MSCs and tumor-derived MSCs (T-MSCs) have different functions. Naïve MSCs could exert bidirectional effects on tumors because these cells can both promote and inhibit tumor progression while T-MSCs promote tumor progression due to influences from the tumor itself and from the inflammatory tumor microenvironment. As an unhealed wound, tumor produces a continuous source of inflammatory mediators and causes aggregation of numerous inflammatory cells, which constitute an inflammatory microenvironment. Inflammatory factors can induce homing of circulating MSCs and MSCs in adjacent tissues into tumors, which are then being “educated” by the tumor microenvironment to support tumor growth. T-MSCs could recruit more immune cells into the tumor microenvironment, increase the proportion of cancer stem cells and promote tumor angiogenesis, further supporting tumor progression. However, as plasticity is a fundamental feature of MSCs, MSCs can also inhibit tumors by activating various MSC-based signaling pathways. Studies of the mechanisms by which interactions among tumors, MSCs, and the inflammatory microenvironment occur and methods to disrupt these interactions will likely reveal new targets for cancer therapy.

Origin and pharmacological modulation of tumor‐associated regulatory dendritic cells

Protumorigenic activity of immune regulatory cells has been proven to play a major role in precluding immunosurveillance and limiting the efficacy of anticancer therapies. Although several approaches have been offered to deplete myeloid-derived suppressor cells (MDSC) and regulatory T cells, there are no data on how to control suppressive dendritic cell (DC) accumulation or function in the tumor environment. Although immunosuppressive function of DC in cancer was implicated to immature and plasmacytoid DC, details of how conventional DC (cDC) develop immunosuppressive properties remain less understood. Here, we show that the development of lung cancer in mice was associated with fast accumulation of regulatory DC (regDC) prior to the appearance of MDSC. Using the in vitro and in vivo approaches, we demonstrated that (i)both cDC and MDSC could be polarized into protumor regDC in the lung cancer environment; (ii) cDC → regDC polarization was mediated by the small Rho GTPase signaling, which could be controlled by noncytotoxic doses of paclitaxel; and (iii) prevention of regDC appearance increased the antitumor potential of DC vaccine in lung cancer. These findings not only bring new players to the family of myeloid regulatory cells and provide new targets for cancer therapy, but offer novel insights into the immunomodulatory capacity of chemotherapeutic agents used in low, noncytotoxic doses.

Photo-Reversible Inhibition of Mitotic Kinesin Eg5 by Photochromic STLC Analogues Composed of Azobenzene

The kinesin Eg5, is a microtubule plus-end directed homotetrameric molecular motor that is essential for the formation of a bipolar spindle during eukaryotic cell division. Eg5 exists only in proliferating cells, and is required for mitosis. Therefore, Eg5 is new target of cancer therapy. It is known that some small molecules specifically inhibit Eg5 activity. S-trityl-L-cysteine (STLC) is one of the potent Eg5 specific inhibitors. In this study, we tried to develop photochromic Eg5 inhibitors that control inhibitory activity of Eg5 by ultraviolet (UV) and visible (VIS) light irradiations reversibly. Azobenzene is one of the typical photochromic molecules, which shows cis, and trans isomerization by UV and VIS light irradiations respectively. In this study, we designed and synthesized photochromic inhibitors utilizing azobenzene. As the trityl group of STLC is a key moiety to exhibit inhibitory activity, we linked the trityl group to N-acetyl cysteine or maleic acid via azobenzene. The synthesized two photochromic inhibitors, TAB-MA and TAB-Ac-Cys inhibited the ATPase activity of Eg5 at the different inhibition constants between cis and trans isomers. Trans-isomers of the inhibitors showed more significant inhibition of ATPase activity than cis-isomers. Moreover, Eg5 driven microtubule gliding was photo controlled by TAB-Ac-Cys. Trans-TAB-Ac-Cys decreased the velocity of microtubule gliding more significantly than cis-TAB-Ac-Cys.

12. Prevention of cisplatin-induced nephrotoxicity by dichloroacetate

Background There is a continuing need to improve the efficacy of anticancer agents and to reduce the toxicity associated with them. Recently, reversal of the glycolytic phenotype of cancer cells with novel agents such as DCA (dichloroacetate) has been recognised as an important new target for cancer therapy. DCA is currently being assessed as a novel chemotherapeutic in clinical trials. It is anticipated that DCA will be used in combination with other well-established chemotherapeutic drugs. It is therefore critically important to determine the effects of DCA on therapeutic efficacy, and off-target effects of existing frontline anti-cancer drugs. We have recently discovered that DCA induces glutamate cysteine ligase, the rate-limiting step in glutathione (GSH) synthesis, a major cellular antioxidant. We hypothesised that the ability of DCA to stimulate GSH-synthesising capacity could reduce cisplatin-induced nephrotoxicity, which is thought to be mediated in part by oxidative stress. Aims To determine whether DCA can attenuate cisplatin-induced nephrotoxicity, and to determine if DCA influences the anti-cancer properties of cisplatin. Methods 120 Balb/c mice were injected subcutaneously with the syngeneic 4T1 breast cancer cell line and then co-treated with DCA and cisplatin weekly for 1 month. Controls included treatment with cisplatin alone, DCA alone, or normal saline injections. Serum blood urea nitrogen (BUN) and creatinine were measured and kidney damage was assessed histologically. Tumour size was monitored throughout. Results and conclusions DCA prevented increases in serum creatinine, BUN, and renal proximal tubule apoptosis evident in cisplatin-only treated mice. The tumour size in mice in the co-treated group decreased at the same rate as the cisplatin-only treated mice. We have thus concluded that DCA largely prevents the development of cisplatin-induced nephrotoxicity, and does not attenuate its anti-cancer properties.

Characterization of the effects of reverse transcriptase and protease inhibitors on ovarian cells

In Italy, every year new cases of ovarian cancer are approximately 5,000, 3,000 are the deaths; this means that 1 woman out of 70 is destined to fall ill and 1 out of 100 to die for this malignancy. Drugs of choice for the treatment of HIV, able to determine a decrease in viral load, have proven to be effective also against neoplasms (Kaposi sarcoma [1] and non-Hodgkin lymphomas [2]) frequent in subjects with acquired immunodeficiency syndrome (AIDS) that thanks to these drugs, are now in evident decline. Our research aims to highlight and characterize, therefore, the effects of anti-HIV drug therapy on Skov3 cells (ovarian adenocarcinoma), hoping for a possible role in the control of ovarian cancer, which is not among the cancers specific of HIV infection. Skov3 cells were cultured and then treated with the chosen drugs: abacavir, tenofovir, efavirenz, etravirine (reverse transcriptase inhibitors) and darunavir (protease inhibitor). At the cytofluorimetric analysis treated cells showed the following results: Abacavir (NRTIs) and Darunavir (PI) do not show any particular modulation of the cell cycle. Tenofovir (NtRTIs) showed an increase amount of cells in the G0/G1 phase of the cell cycle progression. Instead Efavirenz (NNRTIs) and Etravirine (NNRTIs) showed a block in the G0/G1 phase. Between the two drugs of the same class (NNRTIs) the block activity of Etravirine in G0/G1 of cell cycle is higher as compared to Efavirenz; at the same time, Etravirine determines the differentiation of Skov3. DAPI staining has allowed the identification of DNA damage in cells treated with efavirenz and an increased condensation of DNA in cells treated with etravirine. After treatment with tenofovir, efavirenz and etravirine, in Skov3 cells, we observed through immonoblotting: reduction of cyclin D1 concentration, hypophosphorylation of Rb and increase of p21 concentration. Only Skov3cells treated with etravirine showed high levels of E-cadherin expression. Reverse transcriptase, based on these data, can be considered an epigenetic regulator of cell proliferation and differentiation and may represent a new target in cancer therapy. Furthermore, we believe that the drugs used, modulating cell proliferation and differentiation, may represent a new frontier in the development of a therapeutic approach to ovarian cancer.

Role of Notch signalling pathway in cancer and its association with DNA methylation

The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organisms as diverse as humans and fruit flies. It plays a pivotal role in cell fate determination. Dysregulated Notch signalling is oncogenic, inhibits apoptosis and promotes cell survival. Abnormal Notch signalling is seen in many cancers like T-cell acute lymphoblastic leukaemia, acute myeloid leukaemia and cancers of the breast, cervix, colon, pancreas, skin and brain. Inhibition of Notch signalling leads to growth arrest and differentiation in those cells in which Notch pathway is activated and this represents a new target for cancer therapy. Cancer develops from genome defects, including both genetic and epigenetic alterations. Epigenetics deals with heritable changes in gene function that occur without a change in the DNA sequence. Among various epigenetic alterations such as acetylation, phosphorylation, ubiquitylation and sumoylation, promoter region methylation is considered as an important component in cancer development. Epigenetic alterations can be used as biomarkers in screening, detection, diagnosis, staging and risk stratification of various cancers. DNA methylation can be therapeutically reversed and demethylating drugs have proven to be promising in cancer treatment. This review focusses on the methylation status of genes in Notch signalling pathway from various cancers and how this epigenetic alteration can be used as a biomarker for cancer diagnosis and subsequent treatment.

RNAi screens in mice identify physiological regulators of oncogenic growth

SummaryTissue growth is the multifaceted outcome of a cell’s intrinsic capabilities and its interactions with the surrounding environment. Decoding these complexities is essential for understanding human development and tumorigenesis. Here, we tackle this problem by carrying out the first genome-wide RNAi-mediated screens in mice. Focusing on skin development and oncogenic (HrasG12V-induced) hyperplasia, our screens uncover novel as well as anticipated regulators of embryonic epidermal growth. Among top oncogenic screen hits are Mllt6 and the Wnt effector β-catenin; they maintain HrasG12V-dependent hyperproliferation. We also expose β-catenin as an unanticipated antagonist of normal epidermal growth, functioning through Wnt-independent intercellular adhesion. Finally, we document physiological relevance to mouse and human cancers, thereby establishing the feasibility of in vivo mammalian genome-wide investigations to dissect tissue development and tumorigenesis. By documenting some oncogenic growth regulators, we pave the way for future investigations of other hits and raise promise for unearthing new targets for cancer therapies.

ChemInform Abstract: New Drugs, Old Fashioned Ways: ER Stress Induced Cell Death

AbstractReview: 75 refs.

Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells.

The effects of diverse stresses on promoter selectivity and transcription regulation by the tumor suppressor p53 are poorly understood. We have taken a comprehensive approach to characterizing the human p53 network that includes p53 levels, binding, expression and chromatin changes under diverse stresses. Human osteosarcoma U2OS cells treated with anti-cancer drugs Doxorubicin (DXR) or Nutlin-3 (Nutlin) led to strikingly different p53 gene binding patterns based on chromatin immunoprecipitation with high-throughput sequencing experiments. Although two contiguous RRRCWWGYYY decamers is the consensus binding motif, p53 can bind a single decamer and function in vivo. Although the number of sites bound by p53 was six times greater for Nutlin than DXR, expression changes induced by Nutlin were much less dramatic compared with DXR. Unexpectedly, the solvent dimethylsulphoxide (DMSO) alone induced p53 binding to many sites common to DXR; however, this binding had no effect on target gene expression. Together, these data imply a two-stage mechanism for p53 transactivation where p53 binding only constitutes the first stage. Furthermore, both p53 binding and transactivation were associated with increased active histone modification histone H3 lysine 4 trimethylation. We discovered 149 putative new p53 target genes including several that are relevant to tumor suppression, revealing potential new targets for cancer therapy and expanding our understanding of the p53 regulatory network.

Development for Anticancer Therapy: Small-Molecule Inhibitors Targeting Protein Kinase B

Protein kinase B (PKB, also known as Akt) plays a critical role in the multiple cellular processes including glucose metabolism, cell growth, survival, apoptosis, transcription, and cell migration. Unregulated activation of protein kinase B is common in a significant fraction of human cancer, making enzyme an exciting new target for cancer therapy. A series of inhibitors with different mechanisms have been found, which is bound to be a positive impact on drug screening and cancer treatment. However, the development of inhibitors targeting PKB has been hampered by lacking of PKB-specific and isoform-specific inhibitors. This article describes the structure and functions of PKB as well as the recent advances in the development and biological evaluation of PKB's inhibitors. It was focused on the developments of selective small-molecule inhibitors with a well-defined, direct molecular interaction with protein kinase B, expecting to give information to design new inhibitors with high selectivity, bioavailability, and potency.

Histone Lysine-Specific Methyltransferases and Demethylases in Carcinogenesis: New Targets for Cancer Therapy and Prevention

Aberrant histone lysine methylation that is controlled by histone lysine methyltransferases (KMTs) and demethylases (KDMs) plays significant roles in carcinogenesis. Infections by tumor viruses or parasites and exposures to chemical carcinogens can modify the process of histone lysine methylation. Many KMTs and KDMs contribute to malignant transformation by regulating the expression of human telomerase reverse transcriptase (hTERT), forming a fused gene, interacting with proto-oncogenes or being up-regulated in cancer cells. In addition, histone lysine methylation participates in tumor suppressor gene inactivation during the early stages of carcinogenesis by regulating DNA methylation and/or by other DNA methylation independent mechanisms. Furthermore, recent genetic discoveries of many mutations in KMTs and KDMs in various types of cancers highlight their numerous roles in carcinogenesis and provide rare opportunities for selective and tumor-specific targeting of these enzymes. The study on global histone lysine methylation levels may also offer specific biomarkers for cancer detection, diagnosis and prognosis, as well as for genotoxic and non-genotoxic carcinogenic exposures and risk assessment. This review summarizes the role of histone lysine methylation in the process of cellular transformation and carcinogenesis, genetic alterations of KMTs and KDMs in different cancers and recent progress in discovery of small molecule inhibitors of these enzymes.

Abstract 852: Novel role and mechanism of the LDHA protein as a survival factor for cancer cells.

Abstract Rationale: Lactate dehydrogenase A (LDHA), which catalyzes the conversion of pyruvate to lactate, serves as a poor prognostic serum marker for many different types of human cancers; however, it is not known whether this is simply the result of LDHA being released from dying cancer cells in patients with high tumor burden or whether LDHA could also be a signaling molecule that portends poor clinical outcome. Based on the observation that extracellular LDHA was identified as the key survival factor for cardiomyocytes exposed to oxidative stress, we sought to determine whether extracellular LDHA can act as a cancer cell survival factor and hence contributes to poor clinical outcome. We reasoned that LDHA released from the damaged cells could activate intracellular signaling pathways in surrounding tumor cells by means of membrane receptors, ultimately protecting those surrounding tumor cells from oxidative stress-induced cell death. Methods: To investigate our hypothesis, recombinant LDHA and its isoform LDHB was produced by transforming E. coli strain BL21(DE3) with pET-SUMO expression vector (Clontech) containing full-length human LDHA or LDHB cDNA. The resulting recombinant proteins were purified using TALON Metal Affinity Resin and used for 16h pre-treatment of Ramos human Burkitt's lymphoma and A6L human pancreatic cancer cells cultured in full serum containing medium. The amount of recombinant proteins relative to serum albumin is estimated to be less 1% and hence any effects of LDHA could not be simply due to non-specific protein concentration effect. Following the pre-treatment procedure, these cancer cells were subjected to oxidative stress induced by hydrogen peroxide (H2O2) at 100 μM for 24h. Cells were then counted in a hemacytometer using trypan blue dye to exclude dead cells. Results: We observed that while LDHB had no effect on cell death induced by H2O2 as compared to the non-pretreatment group, LDHA can act as a protective factor against oxidative stress induced by H2O2, and ultimately cell death. We also investigated the mechanism involved in the protective role of LDHA by using recombinant LDHA as a molecular probe against membrane proteins that were extracted from cancer cells. Conclusion: Our study defines the novel role and mechanism of LDHA protein as a survival factor in cancer cells, in addition to its enzymatic activity, which may explain the prognostic significance of extracellular LDHA. Furthermore, this study can lead to the identification of new membrane receptor(s) for LDHA which may provide new targets for cancer therapy. Citation Format: Brad Poore, Joshua Kee Park, Iman Afif, Laura Shingleton, Chi Van Dang, Anne Le. Novel role and mechanism of the LDHA protein as a survival factor for cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 852. doi:10.1158/1538-7445.AM2013-852

Abstract 2146: Development of functional assays for p97/VCP inhibition.

Abstract p97 (also called VCP in metazoans and CDC48 in yeast) is a highly conserved, ubiquitously expressed, and essential AAA ATPase. p97 plays a key role in endoplasmic reticulum-associated degradation of misfolded secretory and membrane proteins as well as ubiquitin-dependent turnover of a subset of cytoplasmic substrates of the ubiquitin-proteasome system. p97 also plays a critical role in specific cellular processes including Golgi membrane reassembly, membrane fusion, autophagy and DNA repair mechanisms. p97 expression is elevated in a number of cancer types including prostate cancer, non-small-cell lung carcinoma and leukemia. Given its cellular functions in protein homeostasis and the successful clinical development of proteasome inhibitors, p97 has emerged as an exciting new target for cancer therapy. We used p97 siRNA and a recently identified small molecule p97 inhibitor, N2,N4-dibenzylquinazoline- 2,4-diamine (DBeQ) as tools to develop functional assays suitable for further evaluating the activity of potential p97 inhibitors. A panel of unfolded protein response marker genes that are consistently modulated by p97 siRNA or DBeQ treatment has been identified. In addition, methods to monitor autophagic activity have been developed, including high content analysis of LC3B-GFP puncta formation. Cell viability assays were used to determine the susceptibility of various cancer cell lines to p97 inhibition. These assays will be used to evaluate the effects of potential p97 inhibitors on p97-dependent pathways and anti-proliferative activity. Acknowledgement: Funded by NExT Chemical Biology Consortium, NCI Contract No. HHSN261200800001E. Citation Format: Yihui Shi, Xiaohe Liu, Joy Calaoagan, Steven Samuelsson, Tsui-Fen Chou, Raymond J. Deshaies, Lidia C. Sambucetti. Development of functional assays for p97/VCP inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2146. doi:10.1158/1538-7445.AM2013-2146

Abstract LB-346: The Oxysterol-CXCR2 axis plays a key role in the recruitment of tumor promoting neutrophils.

Abstract Tumor formation depends on molecular alterations responsible for neoplastic transformation of normal cells, as well as on the ability of tumor cells to co-opt inflammatory/immune cells to create a tumor growth-permissive microenvironment. Targeted therapies inhibiting molecular alterations in tumor cells have improved antitumor responses. However, overall survival has been enhanced only slightly. Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses. Among immune cells, neutrophils are recognized as playing an important pro-tumorigenic role, by favoring neoangiogenesis and/or by suppressing antitumor immune responses. We have recently shown that tumor-derived Liver X Receptor (LXR) ligands/oxysterols, known to be involved in cholesterol homeostasis and in modulating physiologic immune responses, favor tumor growth by inhibiting dendritic cell migration towards lymphoid organs. Here, we identify an unanticipated function of tumor-derived LXR ligands/oxysterols, which contribute to the recruitment of neutrophils within tumor microenvironment in an LXR-independent, CXCR2-dependent manner, ultimately favoring tumor growth. In particular, we show a continuous recruitment of neutrophils in oxysterol-releasing tumors, as evaluated by parabiosis experiments. We demonstrate by mass spectrometry and high-performance liquid chromatography analyses that the lymphoma RMA, the Lewis Lung Carcinoma (LLC) and the mesothelioma AB1 produce some oxysterols (22R-HC, 27-HC and 24S-HC), which are able to induce CD11b+Ly6G+ neutrophil migration in vitro and in vivo. Neutrophil migration is independent of LXR signaling both in vitro and in vivo, as demonstrated by using Lxrαβ-/- mice, while it depends on the oxysterol-CXCR2 interaction, as evaluated in vitro by migration experiments with Cxcr2-/- neutrophils, GTPγS binding assays, measurements of cAMP levels, and, in vivo by tumor challenge experiments in Cxcr2-/- bone marrow chimera mice. Tumor-recruited neutrophils are then able to favor tumor growth by promoting neoangiogenesis or immunosuppression of antitumor responses. Furthermore, we demonstrate that RMA, LLC and AB1 tumors engineered to express the oxysterol-inactivating enzyme sulfotransferase 2B1b (SULT2B1b), show a reduced number of tumor-infiltrating neutrophils as well as of CD31+CD45- endothelial cells, as compared to mock-expressing tumors. This reduction parallels tumor growth delay and prolonged survival of SULT2B1b-tumor-bearing mice. Antitumor responses are also obtained with genetic or pharmacologic inactivation of CXCR2, the latter mediated by the CXCR2 antagonist SB225002. These results, along with the observation that some human tumors release oxysterols, identify an unanticipated pro-tumor function of the oxysterol-CXCR2 axis and a possible new target for cancer therapy. Citation Format: Vincenzo Russo, Laura Raccosta, Raffaella Fontana, Daniela Maggioni, Claudia Lanterna, Aida Paniccia, Andrea Musumeci, Claudio Doglioni, Andrea Leiva, Eduardo J. Villablanca, Rodrigo Mora, Elena Chiricozzi, Maria Grazia Ciampa, Laura Mauri, Alessandro Prinetti, Sandro Sonino, Maria Letizia Trincavelli, Simona Daniele, Claudia Martini, Knut Steffensen, Jan-Ake Gustafsson, Safiyè Gozalvo Feo, Claudio Bordignon, Catia Traversari, Silvano Sozzani. The Oxysterol-CXCR2 axis plays a key role in the recruitment of tumor promoting neutrophils. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-346. doi:10.1158/1538-7445.AM2013-LB-346

Neuroglobin, a Novel Intracellular Hexa-Coordinated Globin, Functions as a Tumor Suppressor in Hepatocellular Carcinoma via Raf/MAPK/Erk

Hypoxia and oxidative stress are critical factors in carcinogenesis and exist throughout cancer development; however, the underlying mechanisms are far from clear. Here, for the first time to our knowledge, we reported that neuroglobin (Ngb), an intracellular hexa-coordinated globin serving as an oxygen/reactive oxygen species (ROS) sensor, functions as a tumor suppressor in hepatocelluar carcinoma (HCC). Ngb protein and mRNA expression were significantly down-regulated in tumor tissues, compared with its adjacent non-tumor tissues of human HCC samples and normal liver tissues. Knock-down of Ngb by RNA interference promoted human HCC cell line (HepG2) growth and proliferation, G0/G1-S transition in vitro, and tumor growth in vivo. On the contrary, overexpression of Ngb suppressed HepG2 cell growth and proliferation, G0/G1-S transition, colony formation in vitro, and tumorigenicity in vivo. These results established a tumor suppressor function of Ngb in HCC. The underlying mechanisms were further investigated. Overexpression of Ngb suppressed Raf/MEK/extracellular signal-regulated kinase (Erk), whereas knockdown of Ngb enhanced Raf/MEK/Erk activation in HepG2 cells in vitro and in vivo. Glutathione S-transferase pull-down showed that Ngb interacted with c-Raf-1 in HepG2 cells. Overexpression of Ngb suppressed serum- and H₂O₂-stimulated Erk activation in HepG2 cells. Pharmacological inhibition of Erk activation abolished the proliferative effect of Ngb knockdown in HepG2 cells. Mutation of Ngb at its oxygen-binding site (H64L) abolished the inhibitory effects of Ngb on Erk activation and HepG2 cell proliferation. Therefore, we propose that Ngb controls HCC development by linking oxygen/ROS signals to oncogenic Raf/mitogen-activated protein kinase (MAPK)/Erk signaling. Our data suggest that neuroglobin could be a new target for cancer therapy.

PRAME/EZH2-Mediated Regulation of TRAIL: A New Target for Cancer Therapy

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts a cancer cell-specific pro-apoptotic activity. This property made the TRAIL associated pathway one of the most promising strategies aimed at inducing tumor-selective death. In fact, several approaches have been considered to explore this pathway for cancer therapy, such as recombinant TRAIL, agonist antibodies for TRAIL receptors, and adenoviral TRAIL. However, all of these approaches have certain disadvantages that limit their clinical use. Our recent discovery that the complex PRAME/EZH2 is able to repress TRAIL expression, in a cancer-specific manner, suggests an alternative approach for combined cancer therapy. A genetic or pharmacological inhibition of TRAIL repressors in cancer cells could restore endogenous TRAIL expression, thereby overcoming some of the limitations of and/or cooperating with previous approaches.

Alkylsulfanyl-1,2,4-triazoles, a New Class of Allosteric Valosine Containing Protein Inhibitors. Synthesis and Structure–Activity Relationships

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.

Ovarian Cancer Stem Cells: A New Target for Cancer Therapy

Ovarian cancer is a highly lethal disease among all gynecologic malignancies and is the fifth leading cause of cancer-related death in women. Although the standard combination of surgery and chemotherapy was initially effective in patients with ovarian cancer, disease relapse commonly occurred due to the generation of chemoresistance. It has been reported that cancer stem cells (CSCs) are involved in drug resistance and cancer recurrence. Over the past decades, increasing studies have been done to identify CSCs from human ovarian cancer cells. The present paper will summarize different investigations on ovarian CSCs, including isolation, mechanisms of chemoresistance, and therapeutic approaches. Although there are still numerous challenges to translate basic research to clinical applications, understanding the molecular details of CSCs is essential for developing effective strategies to prevent ovarian cancer and its recurrence.

Survivin and Livin with Angiogenesis in Cancer

Survivin and Livin with Angiogenesis in Cancer Tumor promotion and progression depends on a complex interaction between cellular signaling pathways, apoptosis, angiogenesis and other mechanisms. Understanding these mechanisms and their interactions led to the development of targeted therapies such as antiangiogenic agents and mTOR inhibitors in cancer. In recent years, inhibitors of apoptosis proteins (IAP) like survivin and livin seem promising as new targets for cancer therapy. In this report, the role of survivin and livin with angiogenesis will be discussed.

Cohesin complexes with a potential to link mammalian meiosis to cancer.

Among multiple genes aberrantly activated in cancers, invariably, there is a group related to the capacity of cell to self-renewal. Some of these genes are related to the normal process of development, including the establishment of a germline. This group, a part of growing family of Cancer/Testis (CT) genes, now includes the meiosis specific subunits of cohesin complex. The first reports characterizing the SMC1 and RAD21 genes, encoding subunits of cohesin, were published 20 years ago; however the exact molecular mechanics of cohesin molecular machine in vivo remains rather obscure notwithstanding ample elegant experiments. The matters are complicated by the fact that the evolution of cohesin function, which is served by just two basic types of protein complexes in budding yeast, took an explosive turn in Metazoa. The recent characterization of a new set of genes encoding cohesin subunits specific for meiosis in vertebrates adds several levels of complexity to the task of structure-function analysis of specific cohesin pathways, even more so in relation to their aberrant functionality in cancers. These three proteins, SMC1β, RAD21L and STAG3 are likely involved in a specific function in the first meiotic prophase, genetic recombination, and segregation of homologues. However, at present, it is rather challenging to pinpoint the molecular role of these proteins, particularly in synaptonemal complex or centromere function, due to the multiplicity of different cohesins in meiosis. The roles of these proteins in cancer cell physiology, upon their aberrant activation in tumors, also remain to be elucidated. Nevertheless, as the existence of Cancer/Testis cohesin complexes in tumor cells appears to be all but certain, this brings a promise of a new target for cancer therapy and/or diagnostics.