Anticancer activity of osmium(VI) nitrido complexes in patient-derived glioblastoma initiating cells and in vivo mouse models

The role of vitamin D is implicated in carcinogenesis through numerous biological processes like induction of apoptosis, modulation of immune system inhibition of inflammation and cell proliferation and promotion of cell differentiation. Its use as additional adjuvant drug with cancer treatment may be novel combination for improved outcome of different cancers. Numerous preclinical, epidemiological and clinical studies support the role of vitamin D as an anticancer agent. Anticancer properties of vitamin D have been studied widely (both in vivo and in vitro) among various cancers and found to have promising results. There are considerable data that indicate synergistic potential of calcitriol and antitumor agents. Possible mechanisms for modulatory anticancer activity of vitamin D include its antiproliferative, prodifferentiating, and anti-angiogenic and apoptic properties. Calcitriol reduces invasiveness and metastatic potential of many cancer cells by inhibiting angiogenesis and regulating expression of the key molecules involved in invasion and metastasis. Anticancer activity of vitamin D is synergistic or additive with the antineoplastic actions of several drugs including cytotoxic chemotherapy agents like paclitaxel, docetaxel, platinum base compounds and mitoxantrone. Benefits of addition of vitamin D should be weighed against the risk of its toxicity.

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Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892815666200131120618 ◽

2020 ◽

Vol 15 (1) ◽

pp. 2-13 ◽

Cited By ~ 3

Author(s):

Hongyu Tao ◽

Ling Zuo ◽

Huanli Xu ◽

Cong Li ◽

Gan Qiao ◽

...

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

Cdk Inhibitors ◽

Comprehensive Overview ◽

P53 Expression ◽

Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

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627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0627 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A663-A663

Author(s):

Keegan Cooke ◽

Juan Estrada ◽

Jinghui Zhan ◽

Jonathan Werner ◽

Fei Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Growth ◽

Mouse Models ◽

T Cell Activation ◽

Phase 1 ◽

Phase 1 Study ◽

Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

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Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation

Pharmaceutics ◽

10.3390/pharmaceutics13040493 ◽

2021 ◽

Vol 13 (4) ◽

pp. 493

Author(s):

Dimitrios T. Trafalis ◽

Sofia Sagredou ◽

Panayiotis Dalezis ◽

Maria Voura ◽

Stella Fountoulaki ◽

...

Keyword(s):

Anticancer Activity ◽

Human Colon ◽

Tumor Xenograft ◽

Atp Binding Site ◽

Anticancer Properties ◽

Extensive Range ◽

Dependent Inhibition ◽

Ht 29

The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time- and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents.

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The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models

Scientific Reports ◽

10.1038/s41598-021-84571-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rayko Evstatiev ◽

Adam Cervenka ◽

Tina Austerlitz ◽

Gunther Deim ◽

Maximilian Baumgartner ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Models ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Food Additives ◽

Colorectal Carcinogenesis ◽

Testing Procedures ◽

Inflammatory Models ◽

Inflammatory Bowel

AbstractInflammatory bowel disease is a group of conditions with rising incidence caused by genetic and environmental factors including diet. The chelator ethylenediaminetetraacetate (EDTA) is widely used by the food and pharmaceutical industry among numerous other applications, leading to a considerable environmental exposure. Numerous safety studies in healthy animals have revealed no relevant toxicity by EDTA. Here we show that, in the presence of intestinal inflammation, EDTA is surprisingly capable of massively exacerbating inflammation and even inducing colorectal carcinogenesis at doses that are presumed to be safe. This toxicity is evident in two biologically different mouse models of inflammatory bowel disease, the AOM/DSS and the IL10−/− model. The mechanism of this effect may be attributed to disruption of intercellular contacts as demonstrated by in vivo confocal endomicroscopy, electron microscopy and cell culture studies. Our findings add EDTA to the list of food additives that might be detrimental in the presence of intestinal inflammation, but the toxicity of which may have been missed by regulatory safety testing procedures that utilize only healthy models. We conclude that the current use of EDTA especially in food and pharmaceuticals should be reconsidered. Moreover, we suggest that intestinal inflammatory models should be implemented in the testing of food additives to account for the exposure of this primary organ to environmental and dietary stress.

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1,25(OH) 2 D 3 attenuates sleep disturbance in mouse models of Lewis lung cancer, in silico and in vivo

Journal of Cellular Physiology ◽

10.1002/jcp.30458 ◽

2021 ◽

Author(s):

Min Ai ◽

Shuang‐shuang Li ◽

Hong Chen ◽

Xi‐ting Wang ◽

Jiang‐nan Sun ◽

...

Keyword(s):

Lung Cancer ◽

Sleep Disturbance ◽

Mouse Models ◽

In Silico ◽

Lewis Lung ◽

Lewis Lung Cancer

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Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

Viruses ◽

10.3390/v13050776 ◽

2021 ◽

Vol 13 (5) ◽

pp. 776

Author(s):

Kazutaka Terahara ◽

Ryutaro Iwabuchi ◽

Yasuko Tsunetsugu-Yokota

Keyword(s):

Mouse Models ◽

Humanized Mice ◽

Lymphoid Tissues ◽

Humanized Mouse ◽

Hiv Pathogenesis ◽

Hematopoietic Stem ◽

Critical Issues ◽

In Vivo Animal Models ◽

Humanized Mouse Models

A variety of humanized mice, which are reconstituted only with human hematopoietic stem cells (HSC) or with fetal thymus and HSCs, have been developed and widely utilized as in vivo animal models of HIV-1 infection. The models represent some aspects of HIV-mediated pathogenesis in humans and are useful for the evaluation of therapeutic regimens. However, there are several limitations in these models, including their incomplete immune responses and poor distribution of human cells to the secondary lymphoid tissues. These limitations are common in many humanized mouse models and are critical issues that need to be addressed. As distinct defects exist in each model, we need to be cautious about the experimental design and interpretation of the outcomes obtained using humanized mice. Considering this point, we mainly characterize the current conventional humanized mouse reconstituted only with HSCs and describe past achievements in this area, as well as the potential contributions of the humanized mouse models for the study of HIV pathogenesis and therapy. We also discuss the use of various technologies to solve the current problems. Humanized mice will contribute not only to the pre-clinical evaluation of anti-HIV regimens, but also to a deeper understanding of basic aspects of HIV biology.

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Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains

Science Advances ◽

10.1126/sciadv.aau8857 ◽

2019 ◽

Vol 5 (5) ◽

pp. eaau8857 ◽

Cited By ~ 30

Author(s):

M. Di Rienzo ◽

M. Antonioli ◽

C. Fusco ◽

Y. Liu ◽

M. Mari ◽

...

Keyword(s):

Mouse Models ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

Muscle Dystrophy ◽

Polyubiquitin Chains ◽

Autophagy Induction ◽

Atrophic Muscle ◽

Autophagic Activity

Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32’s ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.

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