Antitumor Effect of Cycle Inhibiting Factor Expression in Colon Cancer via Salmonella VNP20009

2020 ◽  
Vol 20 (14) ◽  
pp. 1722-1727
Author(s):  
Liang Liu ◽  
Junhua Zhang ◽  
Mingqiang Gu ◽  
Guichao Li ◽  
Jianjiao Ni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Salmonella Typhimurium ◽  
Antitumor Effect ◽  
Expression System ◽  
Xenograft Model ◽  
Sw480 Cell ◽  
Cell Cycle Regulators ◽  
Attenuated Salmonella Typhimurium

Background: Colon cancer is one of the major causes of morbidity and mortality worldwide. Cycle inhibiting factors (Cifs) have been shown to deamidate Nedd8, resulting in cell cycle arrest. Objective: To determine the antitumor effect of Cifs on colon cancer by using attenuated Salmonella typhimurium VNP20009. Methods: The VNP-SOPE2-cif and VNP-SOPE2-cif-C/A plasmids were transfected into attenuated Salmonella typhimurium VNP20009. The efficiency and specificity of the Cif promoter were validated in colon cancer SW480 cell lines. Western blotting was subsequently performed to evaluate cell cycle regulators, including P21, P27 and Wee1. In vivo, the antitumor effect of VNP20009 was evaluated in a colon cancer xenograft model. Results: Firstly, VNP-SOPE2-cif and VNP-SOPE2-cif-C/A were selectively expressed both in the bacterial and colon cancer cells. Cif expression in SW480 cells via the VNP tumor-targeted expression system induced the accumulation of Wee1, p21 and p27 expression. Moreover, tumor growth was significantly inhibited in the mice with VNP-SOPE2-cif compared to the mice with VNP with the empty construct. Conclusion: These results suggest that Cif gene delivered by VNP20009 is a promising approach for the treatment of colon cancer.

scholarly journals Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization

2017 ◽  
Vol 42 (5) ◽  
pp. 1789-1801 ◽  
Author(s):  
Jia Shen ◽  
Hailin Ma ◽  
Tiancheng Zhang ◽  
Hui Liu ◽  
Linghua Yu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Colony Formation ◽  
Xenograft Model ◽  
Small Cell ◽  
Cell Cycle Regulators ◽  
Small Cell Lung ◽  
Microtubule Polymerization

Background: The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment. Methods: Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata) on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC) cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol’s inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol’s efficacy in vivo. Results: Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo. Conclusion: These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment.

scholarly journals TAM Inhibitor ONO-7475 Combination with Sorafenib Is Effective Using in Vitro and In Vivo Models of FLT3 ITD Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2642-2642
Author(s):  
Peter P. Ruvolo ◽  
Huaxian Ma ◽  
Vivian Ruvolo ◽  
Xiaorui Zhang ◽  
Hong Mu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Xenograft Model ◽  
Cell Cycle Regulators ◽  
Flt3 Inhibitor

Abstract Background: Internal tandem duplication (ITD) mutation in Fems-like kinase 3 (FLT3) occur in ~ 25% of newly diagnosed acute myeloid leukemia (AML) patients and are associated with poor survival outcome. We recently demonstrated that highly specific AXL/MER inhibitor ONO-7475 (Ono Pharmaceutical Co, Osaka, Japan) was effective as a single agent against FLT3 ITD AML cells studied with in vitro co-culture and murine xenograft models (Ruvolo et al Haematologica, 2017). Based on expression of TAM kinases in the AML cells tested, mechanism for ONO-7475 killing in the FLT3 ITD AML cells was due to AXL inhibition. Here we report on the in vitro and in vivo effects of ONO-7475 when combined with FLT3 inhibitor Sorafenib in FLT3 ITD AML models. Methods: FLT3 ITD AML cell lines Molm13 and MV4;11 as well as Sorafenib resistant Molm13 cells were treated with varying doses of ONO-7475 in the presence and absence of FLT3 inhibitor Sorafenib and effect on cell viability and induction of apoptosis was assessed by flow cytometry using DAPI, Annexin V, and counting beads. RNA was isolated and gene expression profiling (GEP) analysis using microarray was performed on ONO-7475 treated cells. GEP results for a number of genes including CDK1, PLK1, and other cell cycle regulators were validated by qRT-PCR. The efficacy of ONO-7475 combination with Sorafenib in an in vivo AML xenograft model was tested using Molm13 cells expressing luciferase/GFP in NSG mice. Both drugs were given by oral gavage (ONO-7475 at 10 mg/kg and Sorafenib at 5 mg/kg). Drugs were given 5 days a week. Leukemia burden was assessed by IVIS imaging. Results: Molm13 and MV4;11 cells were highly sensitive to ONO-7475 combination with Sorafenib. A dose of 50 nM ONO-7475 with 25 nM Sorafenib potently induces apoptosis and eliminates > 90% of cells after 72 hours. Sorafenib resistant Molm13 cells were more resistant to either drug compared to parental cells. However, combination of 50 nM ONO-7475 with 100 nM Sorafenib potently induces apoptosis in the Sorafenib resistant cells with nearly all leukemic cells eliminated after 72 hour treatment. GEP analysis of cells treated with the AXL inhibitor revealed suppression of many genes involved in cell cycle control including various CDKs (e.g. CDK1, CDK4), Cyclins (e.g Cyclin B1), and other cell cycle regulators such as PLK1. ONO-7475 inhibition of gene expression of these genes was verified by qRT-PCR. GEP also revealed induction of genes associated with more mature myeloid cells including HLA-DR, CD114, and CD115. Finally, single agent use of ONO-7475 (10 mg/kg) or Sorafenib (5 mg/kg) had limited effect in the FLT3 ITD AML xenograft model; however, the combination of both drugs at single agent dose was effective reducing leukemia burden and significantly enhancing survival of mice bearing the Molm13 leukemia cells. Conclusions: These results suggest that ONO-7475 combination with Sorafenib is effective killing AML cells with FLT3 ITD including those that are resistant to the FLT3 inhibitor. The identification of gene expression of cell cycle regulators as novel targets of the drug suggests for the first time that AXL regulates cell cycle via a complex transcriptional mechanism. The ability of the drug to induce expression of genes associated with mature myeloid cells suggest the drug may have the potential to promote differentiation of FLT3 AML cells. Finally, combination of ONO-7475 with Sorafenib proved effective in an in vivo AML xenograft model suggesting that combination of ONO-7475 with a FLT3 inhibitor could be efficacious for therapy of AML patients with FLT3 ITD. Disclosures Yasuhiro: Ono Pharmaceutical: Employment. Tanaka:Ono Pharmaceutical: Employment. Yoshizawa:Ono Pharmaceutical: Employment. Cortes:Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Andreeff:AstraZeneca: Research Funding.

scholarly journals LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bo Jia ◽  
Junfeng Dao ◽  
Jiusong Han ◽  
Zhijie Huang ◽  
Xiang Sun ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Cell Cycle Regulators ◽  
Normal Tissues ◽  
Stat3 Signaling ◽  
Long Intergenic Noncoding Rna

Abstract Background Tongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown. Methods The effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2′-deoxyuridline (EdU) assay and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays. Results LINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo. In mechanism, LINC00958 acted as a ceRNA by competitively sponging miR-211-5p. In addition, we identified CENPK as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Furthermore, The overexpression of CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling. Conclusions Our findings suggested that LINC00958 is a potential prognostic biomarker in TSCC.

scholarly journals A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2840
Author(s):  
Dana M. Zaher ◽  
Wafaa S. Ramadan ◽  
Raafat El-Awady ◽  
Hany A. Omar ◽  
Fatema Hersi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cell ◽  
Xenograft Model ◽  
Mitochondrial Metabolism ◽  
High Dose ◽  
Anticancer Effect ◽  
Safety Margins ◽  
Wide Range

(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.

Anti-glioma Efficacy and Mechanism of Action of Tripolinolate A from Tripolium pannonicum

Planta Medica ◽  
2018 ◽  
Vol 84 (11) ◽  
pp. 786-794
Author(s):  
Weiyun Chai ◽  
Lu Chen ◽  
Xiao-Yuan Lian ◽  
Zhizhen Zhang
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Glioma Cells ◽  
Inhibitory Effect ◽  
Cell Cycle Regulators ◽  
Expression Levels ◽  
Multiple Tumor ◽  
Glioma Growth

AbstractTripolinolate A as a new bioactive phenolic ester was previously isolated from a halophyte of Tripolium pannonicum. However, the in vitro and in vivo anti-glioma effects and mechanism of tripolinolate A have not been investigated. This study has demonstrated that (1) tripolinolate A inhibited the proliferation of different glioma cells with IC50 values of 7.97 to 14.02 µM and had a significant inhibitory effect on the glioma growth in U87MG xenograft nude mice, (2) tripolinolate A induced apoptosis in glioma cells by downregulating the expressions of antiapoptotic proteins and arrested glioma cell cycle at the G2/M phase by reducing the expression levels of cell cycle regulators, and (3) tripolinolate A also remarkably reduced the expression levels of several glioma metabolic enzymes and transcription factors. All data together suggested that tripolinolate A had significant in vitro and in vivo anti-glioma effects and the regulation of multiple tumor-related regulators and transcription factors might be responsible for the activities of tripolinolate A against glioma.

An Orthotopic Colon Cancer Model for Studying the B7-H3 Antitumor Effect In Vivo

2006 ◽  
Vol 10 (5) ◽  
pp. 635-645 ◽  
Author(s):  
C LUPU ◽  
C EISENBACH ◽  
M KUEFNER ◽  
J SCHMIDT ◽  
A LUPU ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Antitumor Effect ◽  
Cancer Model

scholarly journals LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway

2021 ◽  
Author(s):  
Bo Jia ◽  
Junfeng Dao ◽  
Jiusong Han ◽  
Zhijie Huang ◽  
Xiang Sun ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Cell Cycle Regulators ◽  
Normal Tissues ◽  
Stat3 Signaling ◽  
Long Intergenic Noncoding Rna

Abstract ​ Background: Tongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown. Methods: The expression levels of LINC00958 in human TSCC tissues and adjacent normal tissues were detected. The effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2’-deoxyuridline (EdU) assay, and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays. Results: We found LINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo . In mechanism, LINC00958 acted as a competing endogenous RNA (ceRNA) by competitively sponging miR-211-5p. In addition, we identified centromere protein K (CENPK) as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Conclusion: Furthermore, CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling. Our findings suggest that LINC00958 is a potential prognostic biomarker in TSCC.

scholarly journals Antitumor Effect of a Novel Spiro-Acridine Compound is Associated with Up-Regulation of Th1-Type Responses and Antiangiogenic Action

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 29 ◽  
Author(s):  
Daiana K. Frade Silva ◽  
Sâmia S. Duarte ◽  
Thaís M. H. Lisboa ◽  
Rafael C. Ferreira ◽  
Ana Luíza de O. Lopes ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Antitumor Effect ◽  
Inflammatory Responses ◽  
Lethal Dose ◽  
Ehrlich Ascites Carcinoma ◽  
Antitumor Effects ◽  
Th2 Immune Response

Tumor cells have specific features, including angiogenesis induction, cell cycle dysregulation, and immune destruction evasion. By inducing a T helper type 2 (Th2) immune response, tumor cells may favor immune tolerance within the tumor, which allows progression of cancer growth. Drugs with potential antitumor activity are the spiro-acridines, which is a promising new class of acridine compounds. Herein, the novel spiro-acridine (E)-5′-oxo-1′-((3,4,5-trimethoxybenzylidene)amino)-1′,5′-dihydro-10H-spiro[acridine-9,2′-pyrrole]-4′-carbonitrile (AMTAC-17) was synthesized and tested for antitumor effects. Toxicity evaluation was performed in mice after acute treatment (2000 mg/kg, intraperitoneally, i.p.). The Ehrlich ascites carcinoma model was used to investigate the antitumor activity of AMTAC-17 (12.5, 25, or 50 mg/kg, i.p.) after seven days of treatment. Effects on the cell cycle, angiogenesis, and inflammatory responses were investigated. LD50 (lethal dose 50%) was estimated to be higher than 5000 mg/kg. AMTAC-17 reduced the Ehrlich tumor’s total viable cancer cells count and peritumoral micro-vessels density, and induced an increase in the sub-G1 peak. Additionally, there was an increase of Th1 cytokine profile levels (IL-1β, TNF-α, and IL-12). In conclusion, the spiro-acridine compound AMTAC-17 presents low toxicity, and its in vivo antitumor effect involves modulation of the immune system to a cytotoxic Th1 profile and a reduction of tumor angiogenesis.

Impact of protamine I on colon cancer proliferation, invasion, migration, diagnosis and prognosis

2018 ◽  
Vol 399 (3) ◽  
pp. 265-275 ◽  
Author(s):  
Zhi Chen ◽  
Chunyu Shi ◽  
Shuohui Gao ◽  
Defeng Song ◽  
Ye Feng
Keyword(s):  
Colon Cancer ◽  
Cell Invasion ◽  
Cell Apoptosis ◽  
Xenograft Model ◽  
Enzyme Linked Immunosorbent Assay ◽  
Invasion And Migration ◽  
Diagnosis And Prognosis ◽  
And Migration ◽  
Cancer Tissues

AbstractThis paper investigates protamine I (PRM1) expression and its effects on proliferation, invasion and migration of colon cancer cells as well as its function in clinical diagnosis and prognosis. Gene chips were used to screen differentially expressed genes. PRM1 expression was detected by Western blotting and quantitative real time-polymerase chain reaction (qRT-PCR). Hematoxylin and eosin (HE) staining and immunohistochemistry were utilized to compare the expression of PRM1 from multiple differentiation levels of colon cancer tissues. Cell viability, cell apoptosis and cell cycle were tested using the MTT assay and flow cytometry. Cell invasion and migration capability were tested using the Transwell assay and wound healing.In vivoeffects of PRM1 on colon cancer were explored using a xenograft model.PRM1expression in serum was detected by enzyme-linked immunosorbent assay (ELISA). The expression level of PRM1 was significantly higher in colon cancer tissues and the staining degree of PRM1 in poorly-differentiated was stronger. pcDNA3.1-PRM1 decreased cell apoptosis while it increased the proliferation, cell invasion and migration. The si-PRM1 group displayed an opposite tendency. The serum PRM1 level was significantly higher and could serve as a diagnostic biomarker for colon cancer.

scholarly journals A Tryptophan Metabolite, 8-Hydroxyquinaldic Acid, Exerts Antiproliferative and Anti-Migratory Effects on Colorectal Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1655 ◽  
Author(s):  
Katarzyna Walczak ◽  
Ewa Langner ◽  
Karolina Szalast ◽  
Anna Makuch-Kocka ◽  
Piotr Pożarowski ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Mitochondrial Activity ◽  
Cell Cycle Regulators ◽  
Migratory Activity ◽  
Colorectal Cancer Cells ◽  
Induced Changes ◽  
Ht 29

8-Hydroxyquinaldic acid, the end-metabolite of tryptophan, is well-known metal chelator; however, its role in humans, especially in cancer promotion and progression, has not been fully revealed. Importantly, 8-hydroxyquinaldic acid is the analog of kynurenic acid with evidenced antiproliferative activity towards various cancer cells. In this study, we revealed that 8-hydroxyquinaldic acid inhibited not only proliferation and mitochondrial activity in colon cancer HT-29 and LS-180 cells, but it also decreased DNA synthesis up to 90.9% for HT-29 cells and 76.1% for LS-180 cells. 8-Hydroxyquinaldic acid induced changes in protein expression of cell cycle regulators (CDK4, CDK6, cyclin D1, cyclin E) and CDKs inhibitors (p21 Waf1/Cip1, p27 Kip1), but the effect was dependent on the tested cell line. Moreover, 8-hydroxyquinaldic acid inhibited migration of colon cancer HT-29 and LS-180 cells and increased the expression of β-catenin and E-cadherin. Importantly, antiproliferative and anti-migratory concentrations of 8-hydroxyquinaldic acid were non-toxic in vitro and in vivo. We reported for the first time antiproliferative and anti-migratory activity of 8-hydroxyquinaldic acid against colon cancer HT-29 and LS-180 cells.

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