scholarly journals Integration of Different “-omics” Technologies Identifies Inhibition of the IGF1R-Akt-mTOR Signaling Cascade Involved in the Cytotoxic Effect of Shikonin against Leukemia Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Benjamin Wiench ◽  
Yet-Ran Chen ◽  
Malte Paulsen ◽  
Rebecca Hamm ◽  
Sven Schröder ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Cellular Mechanism ◽  
Mtor Signaling ◽  
Leukemia Cells ◽  
Signaling Cascade ◽  
Chinese Medicinal Herb ◽  
Dimethyl Labeling ◽  
Wide Range ◽  
Direct Targeting ◽  
Therapy Success

Hematological malignancies frequently have a poor prognosis and often remain incurable. Drug resistance, severe side effects, and relapse are major problems of currently used drugs, and new candidate compounds are required for improvement of therapy success. The naphthoquinone shikonin derived from the Chinese medicinal herb,Lithospermum erythrorhizon, is a promising candidate for the next generation of chemotherapy. The basal cellular mechanism of shikonin is the direct targeting of mitochondria. Cytotoxicity screenings showed that the compound is particularly effective against leukemia cells suggesting an additional cellular mechanism. mRNA and miRNA microarrays were used to analyze changes in gene expression in leukemia cells after shikonin treatment and combined with stable-isotope dimethyl labeling for quantitative proteomics. The integration of bioinformatics and the three “-omics” assays showed that the PI3K-Akt-mTOR pathway was affected by shikonin. Deregulations of this pathway are frequently associated with cancerogenesis, especially in a wide range of hematological malignancies. The effect on the PI3K-Akt-mTOR axis was validated by demonstrating a decreased phosphorylation of Akt and a direct inhibition of the IGF1R kinase activity after shikonin treatment. Our results indicate that inhibiting the IGF1R-Akt-mTOR signaling cascade is a new cellular mechanism of shikonin strengthening its potential for the treatment of hematological malignancies.

Aldehyde biphenyl chalcones induce immunogenic apoptotic-like cell death and are promising new safe compounds against a wide range of hematologic cancers

2020 ◽  
Vol 12 (8) ◽  
pp. 673-688
Author(s):  
Mariana F Maioral ◽  
Natália M Stefanes ◽  
Patrícia D Neuenfeldt ◽  
Louise D Chiaradia-Delatorre ◽  
Ricardo J Nunes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Endoplasmic Reticulum Stress ◽  
Hematological Malignancies ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Promyelocytic Leukemia Protein ◽  
Wide Range ◽  
Antileukemic Effect

Aim: Investigate the apoptotic mechanisms of two new aldehyde biphenyl chalcones on leukemia cells. Materials & methods: From a series of 71 new chalcones, we selected the two most cytotoxic. Results: JA3 and JA7 were cytotoxic not only against hematological malignancies but also against solid tumor and cancer stem cells, yet with no toxicity to normal cells. Moreover, they induced immunogenic apoptotic-like cell death independently of promyelocytic leukemia protein, with extensive mitochondrial damages downstream of endoplasmic reticulum stress. Preventing endoplasmic reticulum stress and the upregulation of proapoptotic machinery inhibited JA3- and JA7-induced cell death. Likewise, blocking receptor Fas protected cells from killing. They increased the antileukemic effect of cytarabine and vincristine and killed leukemic cells collected from patients with different acute leukemia subtypes. Conclusion: JA3 and JA7 represent new promising prototypes for the development of new chemotherapeutics.

scholarly journals Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

2020 ◽  
Vol 13 (7) ◽  
pp. 140
Author(s):  
Sarah Baudet ◽  
Johann Bécret ◽  
Xavier Nicol
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Molecules ◽  
Therapeutic Strategies ◽  
Signaling Cascade ◽  
Molecular Tools ◽  
Pathological Conditions ◽  
Wide Range ◽  
Key Players ◽  
Direct Targeting ◽  
Stem Cell Niches

Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here.

scholarly journals Self-assembling ferritin-dendrimer nanoparticles for targeted delivery of nucleic acids to myeloid leukemia cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Federica Palombarini ◽  
Silvia Masciarelli ◽  
Alessio Incocciati ◽  
Francesca Liccardo ◽  
Elisa Di Fabio ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Targeted Delivery ◽  
Myeloid Leukemia ◽  
Electrostatic Interactions ◽  
Archaeoglobus Fulgidus ◽  
Leukemia Cells ◽  
Cellular Delivery ◽  
Self Assembling ◽  
Wide Range ◽  
Hybrid Nanoparticle

Abstract Background In recent years, the use of ferritins as nano-vehicles for drug delivery is taking center stage. Compared to other similar nanocarriers, Archaeoglobus fulgidus ferritin is particularly interesting due to its unique ability to assemble-disassemble under very mild conditions. Recently this ferritin was engineered to get a chimeric protein targeted to human CD71 receptor, typically overexpressed in cancer cells. Results Archaeoglobus fulgidus chimeric ferritin was used to generate a self-assembling hybrid nanoparticle hosting an aminic dendrimer together with a small nucleic acid. The positively charged dendrimer can indeed establish electrostatic interactions with the chimeric ferritin internal surface, allowing the formation of a protein-dendrimer binary system. The 4 large triangular openings on the ferritin shell represent a gate for negatively charged small RNAs, which access the internal cavity attracted by the dense positive charge of the dendrimer. This ternary protein-dendrimer-RNA system is efficiently uptaken by acute myeloid leukemia cells, typically difficult to transfect. As a proof of concept, we used a microRNA whose cellular delivery and induced phenotypic effects can be easily detected. In this article we have demonstrated that this hybrid nanoparticle successfully delivers a pre-miRNA to leukemia cells. Once delivered, the nucleic acid is released into the cytosol and processed to mature miRNA, thus eliciting phenotypic effects and morphological changes similar to the initial stages of granulocyte differentiation. Conclusion The results here presented pave the way for the design of a new family of protein-based transfecting agents that can specifically target a wide range of diseased cells. Graphic abstract

Cellular basis for genetically determined enhanced resistance of certain mouse strains to listeriosis

1980 ◽  
Vol 28 (2) ◽  
pp. 381-386
Author(s):  
C Sadarangani ◽  
E Skamene ◽  
P A Kongshavn
Keyword(s):  
Bacterial Growth ◽  
Resistant Strain ◽  
Early Phase ◽  
Dextran Sulfate ◽  
Cellular Mechanism ◽  
Mononuclear Phagocytes ◽  
Susceptible Strain ◽  
Mouse Strains ◽  
Wide Range ◽  
Genetically Determined

The characteristics of the mononuclear phagocytes mediating resistance to infection with Listeria during the early phase (0 to 48 h) of the response have been investigated in genetically determined susceptible (A/J) and resistant (C57BL/6, B10.A/SgSn) strains of mice. Irradiation immediately before infection profoundly enhanced the bacterial growth in the resistant strain, while having no effect in the susceptible strain, over a wide range (3 x 10(3) to 10(5)) of infective doses. This effect of irradiation is demonstrable at low-dose radiation (200 roentgens) and can be reversed by repopulation with 20 x 10(6) syngeneic nucleated bone marrow cells. Administration of dextran sulfate 500 24 h before infection profoundly enhanced the bacterial growth in the susceptible strain, while having much less effect in the resistant strain. Thus, the genetic advantage of the resistant mouse strains to listerial infection, at least during the early phase of the response, appears to be due to a cellular mechanism that is highly radiosensitive and relatively insensitive to dextran sulfate 500. In the susceptible strain, the early protective cellular mechanism is radioresistant and highly dextran sulfate 500 sensitive.

scholarly journals Insulin- and Leptin-Mediated Control of Aquaglyceroporins in Human Adipocytes and Hepatocytes Is Mediated via the PI3K/Akt/mTOR Signaling Cascade

2011 ◽  
Vol 25 (3) ◽  
pp. 546-547
Author(s):  
Amaia Rodríguez ◽  
Victoria Catalán ◽  
Javier Gómez-Ambrosi ◽  
Socorro García-Navarro ◽  
Fernando Rotellar ◽  
...  
Keyword(s):  
Mtor Signaling ◽  
Signaling Cascade ◽  
Human Adipocytes

The Akt/mTor signaling cascade is modified during placentation in the porcine uterine tissue

2013 ◽  
Vol 13 (3) ◽  
pp. 184-194 ◽  
Author(s):  
Karin Wollenhaupt ◽  
Klaus-Peter Brüssow ◽  
Dirk Albrecht ◽  
Wolfgang Tomek
Keyword(s):  
Mtor Signaling ◽  
Signaling Cascade ◽  
Uterine Tissue

scholarly journals mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

2020 ◽  
Vol 21 (8) ◽  
pp. 2718 ◽  
Author(s):  
Yasmine Lund-Ricard ◽  
Patrick Cormier ◽  
Julia Morales ◽  
Agnès Boutet
Keyword(s):  
Evolutionary Biology ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Human Diseases ◽  
Whole Body ◽  
Body Parts ◽  
Animal Kingdom ◽  
Structure Damage ◽  
Wide Range

A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.

scholarly journals mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells

2010 ◽  
Vol 9 (1) ◽  
pp. 292 ◽  
Author(s):  
Weina Chen ◽  
Elias Drakos ◽  
Ioannis Grammatikakis ◽  
Ellen J Schlette ◽  
Jiang Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mtor Signaling ◽  
Leukemia Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid
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