scholarly journals Lycorine exerts antitumor activity against osteosarcoma cells in vitro and in vivo xenograft model through the JAK2/STAT3 pathway

2019 ◽  
Vol Volume 12 ◽  
pp. 5377-5388 ◽  
Author(s):  
Hongzhi Hu ◽  
Shangyu Wang ◽  
Deyao Shi ◽  
Binglong Zhong ◽  
Xin Huang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Xenograft Model ◽  
Osteosarcoma Cells ◽  
Stat3 Pathway

scholarly journals LncRNA SNHG15 contributes to doxorubicin resistance of osteosarcoma cells through targeting the miR-381-3p/GFRA1 axis

2020 ◽  
Vol 15 (1) ◽  
pp. 871-883
Author(s):  
Jinshan Zhang ◽  
Dan Rao ◽  
Haibo Ma ◽  
Defeng Kong ◽  
Xiaoming Xu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Noncoding Rna ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells

AbstractBackgroundOsteosarcoma is a common primary malignant bone cancer. Long noncoding RNA small nucleolar RNA host gene 15 (SNHG15) has been reported to play an oncogenic role in many cancers. Nevertheless, the role of SNHG15 in the doxorubicin (DXR) resistance of osteosarcoma cells has not been fully addressed.MethodsCell Counting Kit-8 assay was conducted to measure the half-maximal inhibitory concentration value of DXR in osteosarcoma cells. Western blotting was carried out to examine the levels of autophagy-related proteins and GDNF family receptor alpha-1 (GFRA1). Quantitative reverse transcription-polymerase chain reaction was performed to determine the levels of SNHG15, miR-381-3p, and GFRA1. The proliferation of osteosarcoma cells was measured by MTT assay. The binding sites between miR-381-3p and SNHG15 or GFRA1 were predicted by Starbase bioinformatics software, and the interaction was confirmed by dual-luciferase reporter assay. Murine xenograft model was established to validate the function of SNHG15 in vivo.ResultsAutophagy inhibitor 3-methyladenine sensitized DXR-resistant osteosarcoma cell lines to DXR. SNHG15 was upregulated in DXR-resistant osteosarcoma tissues and cell lines. SNHG15 knockdown inhibited the proliferation, DXR resistance, and autophagy of osteosarcoma cells. MiR-381-3p was a direct target of SNHG15, and GFRA1 bound to miR-381-3p in osteosarcoma cells. SNHG15 contributed to DXR resistance through the miR-381-3p/GFRA1 axis in vitro. SNHG15 depletion contributed to the inhibitory effect of DXR on osteosarcoma tumor growth through the miR-381-3p/GFRA1 axis in vivo.ConclusionsSNHG15 enhanced the DXR resistance of osteosarcoma cells through elevating the autophagy via targeting the miR-381-3p/GFRA1 axis. Restoration of miR-381-3p expression might be an underlying therapeutic strategy to overcome the DXR resistance of osteosarcoma.

scholarly journals SHC014748M, a Novel Selective Inhibitor of PI3Kδ, Demonstrates Promising Pre-Clinical Antitumor Activity in B Cell Lymphomas and CLL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5306-5306
Author(s):  
Lei Fan ◽  
Chao Wang ◽  
Zhiqiang Wang ◽  
Xian Zhang ◽  
Lei Cao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Cell Lines ◽  
Xenograft Model ◽  
Selective Inhibitor ◽  
Lymphoma Cell ◽  
Class I ◽  
B Cell Lymphomas

Introduction : PI3Kδ, one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. Here, we comprehensively evaluated the in vitro and in vivo antitumor activity and the underlying mechanism of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Methods : Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary CLL cells, and PI3K/AKT pathway was measured by Western blot assay, Alphalisa and Elisa. Xenograft model was carried out to validate in-vivo antitumor potency of the compound. Besides, chemokines and cytokines derived from blood samples of patients were also detected. Results: SHC014748M was 125- to 306-fold more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines. We identified that SHC014748M treatment resulted in a 3.1- to 5.5-fold increase in annexin V/7-ADD staining, indicating a significant apoptosis induction. SHC014748M inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in lymphoma cells. Among the 15 primary CLL cells, the 50% inhibitory concentration (IC50) of SHC014748M varies from 850 nM to 37040 nM respectively and expression of phosphorylation AKT decreased to the normal levels in the presence of SHC014748M or positive control, Idelalisib. In-vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 derived from patients decreased sharply after SHC014748M treatment. Conclusion: According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL. Disclosures Wang: Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment. Wang:Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment. Zhang:Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment.

scholarly journals Inhibitory Effects of Targeted Regulatory LKB1 Gene on the Proliferation and Invasion of Osteosarcoma Cells

2021 ◽  
Vol 21 (01) ◽  
Author(s):  
Jie Liu
Keyword(s):  
Transcription Factor ◽  
Xenograft Model ◽  
Mtor Inhibitors ◽  
Regulatory Genes ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Inhibitory Effects ◽  
Proliferation And Invasion

In this study, Immunodeficiency Nude Mouse Osteosarcoma Xenograft Model was subjected to the drug intervention to explore the effect of bexarotene on the proliferation and invasion of osteosarcoma cell lines in vitro. The inhibitory effects of targeted regulatory genes on the proliferation and invasion of osteosarcoma cells were studied through various in vitro experiments include bioinformatics combined with tissue microarray research, transcription factor prediction combined with co-expression analysis to predict the transcription factor of targeted regulatory genes in osteosarcoma. The RXR protein family, LKB1, AMPK pathway, and mTOR are closely related to the body’s immune regulation. The oral administration of Bexarotene could inhibit the proliferation and able to up-regulate the expression of LKB1 gene in living osteosarcoma tissue. The xenograft model of immunodeficiency nude mice used in this study was reason for reduced the potential immunoregulatory effect of drug targeted LKB1 therapy to a certain extent. However, overexpression of LKB1 in vivo, and combined immunotherapy may become an important immunotherapy approach for osteosarcoma. LKB1 targeted therapy can potentially be used as one of the alternative treatments for mTOR inhibitors.

Lidocaine Induces Apoptosis and Suppresses Tumor Growth in Human Hepatocellular Carcinoma Cells In Vitro and in a Xenograft Model In Vivo

2017 ◽  
Vol 126 (5) ◽  
pp. 868-881 ◽  
Author(s):  
Wei Xing ◽  
Dong-Tai Chen ◽  
Jia-Hao Pan ◽  
Yong-Hua Chen ◽  
Yan Yan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Antitumor Activity ◽  
Hepg2 Cells ◽  
Xenograft Model ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Bax Protein

Abstract Background Recent epidemiologic studies have focused on the potential beneficial effects of regional anesthetics, and the differences in cancer prognosis may be the result of anesthetics on cancer biologic behavior. However, the function and underlying mechanisms of lidocaine in hepatocellular carcinoma both in vitro and in vivo have been poorly studied. Methods Human HepG2 cells were treated with lidocaine. Cell viability, colony formation, cell cycle, and apoptosis were assessed. The effects of lidocaine on apoptosis-related and mitogen-activated protein kinase protein expression were evaluated by Western blot analysis. The antitumor activity of lidocaine in hepatocellular carcinoma with or without cisplatin was investigated with in vitro experiments and also with animal experiments. Results Lidocaine inhibited the growth of HepG2 cells in a dose- and time-dependent manner. The authors also found that lidocaine arrested cells in the G0/G1 phase of the cell cycle (63.7 ± 1.7% vs. 72.4 ± 3.2%; P = 0.0143) and induced apoptosis (1.7 ± 0.3% vs. 5.0 ± 0.7%; P = 0.0009). Lidocaine may exert these functions by causing an increase in Bax protein and activated caspase-3 and a corresponding decrease in Bcl-2 protein through the extracellular signal-regulated kinase 1/2 and p38 pathways. More importantly, for the first time, xenograft experiments (n = 8 per group) indicated that lidocaine suppressed tumor development (P < 0.0001; lidocaine vs. control) and enhanced the sensitivity of cisplatin (P = 0.0008; lidocaine plus cisplatin vs. cisplatin). Conclusions The authors’ findings suggest that lidocaine may exert potent antitumor activity in hepatocellular carcinoma. Furthermore, combining lidocaine with cisplatin may be a novel treatment option for hepatocellular carcinoma.

scholarly journals PI3K inhibitor significantly enhances the antitumor activity of oncolytic virus in osteosarcoma

2020 ◽  
Author(s):  
Ye Wang ◽  
Xin Yang ◽  
Hong Li ◽  
Haiyang Xie
Keyword(s):  
Clinical Trials ◽  
Antitumor Activity ◽  
Oncolytic Virus ◽  
Xenograft Model ◽  
In Vitro Cytotoxicity ◽  
Pi3k Inhibitor ◽  
Oncolytic Viruses ◽  
Osteosarcoma Cell

Abstract Background: Osteosarcoma (OS) is a highly aggressive malignancy with less than 30% 5-year survival rate among patients with metastatic or recurrent cancer. However, the treatment for osteosarcoma has not been modified in the last three decades. Oncolytic viruses have shown encouraging results in pre-clinical trials, but have failed to translate into high therapeutic efficacy in clinical trials. In this study, we will determine the therapeutic effect of combining PI3K inhibitor with an oncolytic virus against osteosarcoma. Material and Methods: Osteosarcoma cell lines and xenograft model were treated with ZSTK474 and/or VSVΔ51, the tumor suppressive ability was verified by in vitro cytotoxicity experiments and in vivo antitumor activity experiments, and the antitumor mechanism was explored through the study of apoptosis-related signaling pathways. Results: ZSTK474 sensitized the osteosarcoma cells to VSVΔ51, and augmented apoptosis via endoplasmic reticulum stress. The combination treatment also showed greater in vivo tumor inhibition compared to either ZSTK474 or VSVΔ51 alone, and significantly enhanced the tumor infiltration of immune cells. Conclusion: PI3K inhibitors combined with oncolytic virus is a promising strategy against osteosarcoma.

Preclinical in vitro and in vivo study of UD-017, a novel highly selective and orally available CDK7 inhibitor, in a variety of cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14086-e14086 ◽  
Author(s):  
Kazuhiro Onuma ◽  
Yasuhiro Aga ◽  
Sayaka Ogi ◽  
Takashi Matsushita ◽  
Hidetoshi Sunamoto ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Xenograft Model ◽  
Antitumor Efficacy ◽  
Expression Levels ◽  
Oncogenic Driver ◽  
Xenograft Models

e14086 Background: Cyclin dependent kinase 7 (CDK7) modulates mRNA transcription and some oncogenes are reported to be sensitive to inhibition of transcription in certain cancer cells. CDK7 inhibitors have been considered as an intriguing approach to treat cancers that depend on transcriptional regulation of their oncogenes. We synthesized a novel highly selective CDK7 inhibitor, UD-017, and found that the compound showed antitumor potency in a variety of cancers in vitro and in vivo. We therefore explored underlying mechanisms especially focusing on an oncogenic driver, c-Myc. Methods: We examined CDK7 selectivity of UD-017 against the other CDKs and kinases. We evaluated an antiproliferative activity of UD-017 in over 200 multiple types of cancer cell lines including patients-derived cancer cells. We then investigated the correlation between c-Myc expression levels and an antiproliferative activity of UD-017 in cancer cells. Antitumor efficacy of UD-017 was assessed in multiple types of cancer xenograft models and patients-derived xenograft model. We determined whether an intratumoral c-Myc expression levels correlated with in vivo antitumor efficacy of UD-017 in xenograft models. Results: UD-017 inhibited CDK7 enzyme (IC50= 16 nM) highly selectively among the CDKs (over 300-fold) and almost mono-specifically in a panel of 313 kinases assay. In a cellular antiproliferative panel assay, UD-017 broadly inhibited the proliferation of a variety of cancer cells and c-Myc expression levels showed the good correlation with antiproliferative activity. UD-017 showed favorable PK profile and good oral absorbability and showed the potent antitumor activity in multiple types of cancer xenograft models in mice. In correlation with the PK, UD-017 reduced the intratumoral c-Myc mRNA levels time-dependently after dosing of UD-017 in the colorectal cancer xenograft model. Conclusions: We identified a highly selective and orally available CDK7 inhibitor that showed the broad in vitro and in vivo antitumor activity in a variety of cancers, modulating c-Myc as an oncogenic driver. These data support the rationale for further advancing towards clinical development.

scholarly journals Antineoplastic Evaluation of Two Mixed Chelate Copper Complexes (Casiopeínas®) in HCT-15 Xenograft Model

2017 ◽  
Vol 57 (3) ◽  
Author(s):  
María Elena Bravo-Gómez ◽  
Ana Laura Hernández de la Paz ◽  
Isabel Gracia-Mora
Keyword(s):  
Biological Activity ◽  
Antitumor Activity ◽  
Mouse Models ◽  
Copper Complexes ◽  
Xenograft Model ◽  
Colon Adenocarcinoma ◽  
Diimine Ligand ◽  
Secondary Ligand

Casiopeínas<sup>®</sup> is a family of copper complexes with the general formulae [Cu(N-N)(N-O)]NO<sub>3</sub> and [Cu(N-N)(O-O)]NO<sub>3</sub>; where N-N = substituted aromatic diimine (2,2’-bipyridine (<em>bipy</em>) or 1,10-phenanthroline (<em>phen</em>)); N-O = α-aminoacidate or a peptide; and O-O = acetylacetonate (<em>acac</em>) or salicylaldehydate. These compounds have shown antiproliferative activity in vitro and antitumor activity in several mouse models with promissory results. Efforts have been done in order to understand the role played by ligands in the biological activity. With the aim of finding out the effect of secondary ligand (N-O or O-O), two of the most active complexes <em>in vitro</em> assays were selected to perform in vivo study on HCT-15 colon adenocarcinoma xenograft model. Both complexes, [Cu(3,4,7,8-tetramethyl-1,10-phen anthroline)(glycinato)]NO<sub>3</sub> (<strong>1</strong>) and [Cu(3,4,7,8-tetramethyl-1,10-phenanthroline)(acetylacetonato)]NO<sub>3</sub> (<strong>2</strong>) share the same diimine ligand and the secondary ligand changes from glycinate (<em>gly</em>) to <em>acac</em>. Results show that 2 is effective to reduce tumor size but <strong>1</strong> does not achieve the values required according to protocols, revealing an important difference between compounds attributable to change of ligand from <em>gly</em> to <em>acac</em>.

Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenström macroglobulinemia

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4964-4972 ◽  
Author(s):  
Anne-Sophie Moreau ◽  
Xiaoying Jia ◽  
Hai T. Ngo ◽  
Xavier Leleu ◽  
Garrett O'Sullivan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Antitumor Activity ◽  
Mononuclear Cells ◽  
Xenograft Model ◽  
Parp Cleavage ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Synergistic Cytotoxicity

AbstractWaldenström macroglobulinemia (WM) is an incurable lymphoplasmacytic lymphoma with limited options of therapy. Protein kinase Cβ (PKCβ) regulates cell survival and growth in many B-cell malignancies. In this study, we demonstrate up-regulation of PKCβ protein in WM using protein array techniques and immunohistochemistry. Enzastaurin, a PKCβ inhibitor, blocked PKCβ activity and induced a significant decrease of proliferation at 48 hours in WM cell lines (IC50, 2.5-10 μM). Similar effects were demonstrated in primary CD19+ WM cells, without cytotoxicity on peripheral blood mononuclear cells. In addition, enzastaurin overcame tumor cell growth induced by coculture of WM cells with bone marrow stromal cells. Enzastaurin induced dose-dependent apoptosis at 48 hours mediated via induction of caspase-3, caspase-8, caspase-9, and PARP cleavage. Enzastaurin inhibited Akt phosphorylation and Akt kinase activity, as well as downstream p-MARCKS and ribosomal p-S6. Furthermore, enzastaurin demonstrated additive cytotoxicity in combination with bortezomib, and synergistic cytotoxicity in combination with fludarabine. Finally, in an in vivo xenograft model of human WM, significant inhibition of tumor growth was observed in the enzastaurin-treated mice (P = .028). Our studies therefore show that enzastaurin has significant antitumor activity in WM both in vitro and in vivo, providing the framework for clinical trials to improve patient outcome in WM.

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