Search results for "Tos"
showing 10 items of 12217 documents
Targeting the chromosomal passenger complex subunit INCENP induces polyploidization, apoptosis and senescence in neuroblastoma
2019
Abstract Chromosomal passenger complex (CPC) has been demonstrated to be a potential target of cancer therapy by inhibiting Aurora B or survivin in different types of cancer including neuroblastoma. However, chemical inhibition of either Aurora B or survivin does not target CPC specifically due to off-target effects or CPC-independent activities of these two components. In a previous chromatin-focused siRNA screen, we found that neuroblastoma cells were particularly vulnerable to loss of INCENP, a gene encoding a key scaffolding component of the CPC. In this study, INCENP was highly expressed by neuroblastoma cells, and its expression decreased following retinoic acid–induced neuroblastoma …
9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma.
2018
Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen Synthase Kinase-3β (GSK-3β) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3β expression in 67% of human neuroblastomas (34 out of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD8 and 9-ING-41), suppressed the growth of neuroblastoma cells whereas 9-ING-41, a clinically relevant small molecule GSK-3β inhibitor with broad spectrum pre-clinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and…
Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody-"decoy" strategy
2018
MET, a master gene sustaining "invasive growth," is a relevant target for cancer precision therapy. In the vast majority of tumors, wild-type MET behaves as a "stress-response" gene and relies on the ligand (HGF) to sustain cell "scattering," invasive growth and apoptosis protection (oncogene "expedience"). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti-MET antibody (MvDN30) inducing "shedding" (i.e., removal of MET from the cell surface), with a "decoy" (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction-and …
Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of re…
2017
Hsp60 is a pro-carcinogenic chaperonin in certain tumor types by interfering with apoptosis and with tumor cell death. In these tumors, it is not known whether or not doxorubicin anti-tumor effects include a blockage of the pro-carcinogenic action of this protein. We used the human lung mucoepidermoid cell line NCI-H292 and different doses of doxorubicin to measure cell viability, cell cycle progression, cell senescence indicators, Hsp60 levels and its post-translational modifications as well as the release of the chaperonin into the extracellular environment. Cell viability was reduced in relation to doxorubicin dose and this was paralleled by the appearance of cell senescence markers. Con…
Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis
2017
Increased oxidative stress has been suggested to initiate and promote tumorigenesis by inducing DNA damage and to suppress tumor development by triggering apoptosis and senescence. The contribution of individual cell types in the tumor microenvironment to these contrasting effects remains poorly understood. We provide evidence that during intestinal tumorigenesis, myeloid cell-derived H2O2 triggers genome-wide DNA mutations in intestinal epithelial cells to stimulate invasive growth. Moreover, increased reactive oxygen species (ROS) production in myeloid cells initiates tumor growth in various organs also in the absence of a carcinogen challenge in a paracrine manner. Our data identify an i…
Transcriptional Profiles and Stromal Changes Reveal Bone Marrow Adaptation to Early Breast Cancer in Association with Deregulated Circulating microRN…
2020
Abstract The presence of a growing tumor establishes a chronic state of inflammation that acts locally and systemically. Bone marrow responds to stress signals by expanding myeloid cells endowed with immunosuppressive functions, further fostering tumor growth and dissemination. How early in transformation the cross-talk with the bone marrow begins and becomes detectable in blood is unknown. Here, gene expression profiling of the bone marrow along disease progression in a spontaneous model of mammary carcinogenesis demonstrates that transcriptional modifications in the hematopoietic compartment occurred as early as preinvasive disease stages. The transcriptional profile showed downregulation…
Nicotinamide Phosphoribosyltransferase Acts as a Metabolic Gate for Mobilization of Myeloid-Derived Suppressor Cells
2019
Abstract Cancer induces alteration of hematopoiesis to fuel disease progression. We report that in tumor-bearing mice the macrophage colony-stimulating factor elevates the myeloid cell levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, which acts as negative regulator of the CXCR4 retention axis of hematopoietic cells in the bone marrow. NAMPT inhibits CXCR4 through a NAD/Sirtuin 1–mediated inactivation of HIF1α-driven CXCR4 gene transcription, leading to mobilization of immature myeloid-derived suppressor cells (MDSC) and enhancing their production of suppressive nitric oxide. Pharmacologic inhibition or myeloid-specific ablation …
From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy.
2017
Artemisia annua L. is used throughout Asia and Africa as tea and press juice to treat malaria and related symptomes (fever, chills). Its active ingredient, artemisinin (ARS), has been developed as antimalarial drug and is used worldwide. Interestingly, the bioactivity is not restricted to malaria treatment. We and others found that ARS-type drugs also reveal anticancer in vitro and in vivo. In this review, we give a systematic overview of the literature published over the past two decades until the end of 2016. Like other natural products, ARS acts in a multi-specific manner against tumors. The cellular response of ARS and its derivatives (dihydroartemisinin, artesunate, artemether, arteeth…
LC3-Associated Phagocytosis (LAP): A Potentially Influential Mediator of Efferocytosis-Related Tumor Progression and Aggressiveness
2020
One aim of cancer therapies is to induce apoptosis of tumor cells. Efficient removal of the apoptotic cells requires coordinated efforts between the processes of efferocytosis and LC3-associated phagocytosis (LAP). However, this activity has also been shown to produce anti-inflammatory and immunosuppressive signals that can be utilized by live tumor cells to evade immune defense mechanisms, resulting in tumor progression and aggressiveness. In the absence of LAP, mice exhibit suppressed tumor growth during efferocytosis, while LAP-sufficient mice show enhanced tumor progression. Little is known about how LAP or its regulators directly affect efferocytosis, tumor growth and treatment respons…
The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma…
2015
Abstract Secreted protein acidic and rich in cysteine (SPARC) is a multi-functional protein which modulates cell-cell and cell-matrix interactions. In cancer cells, SPARC behaves as a tumor promoter in a number of tumors, but it can also act as a tumor suppressor factor. Our previous results showed that the synthetic cannabinoid WIN55,212-2 (WIN), a potent cannabinoid receptor agonist, is able to sensitize osteosarcoma MG63 cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis which is accompanied with endoplasmic reticulum (ER)-stress induction and the increase in autophagic markers. In the present investigation, we studied the role of SPARC in WIN/TRAIL-induced apoptosi…