scholarly journals 5,7-Dihydroxyflavone Enhances the Apoptosis-Inducing Potential of TRAIL in Human Tumor Cells via Regulation of Apoptosis-Related Proteins

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Zhenzhen Zhang ◽  
Tingmei Ye ◽  
Xueting Cai ◽  
Jie Yang ◽  
Wuguang Lu ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Human Tumor ◽  
Tumor Burden ◽  
Tumor Xenograft ◽  
Apoptotic Protein ◽  
Dietary Flavonoid ◽  
Induced Apoptosis

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for the treatment of cancer, because it preferentially induces apoptosis in numerous cancer cells with little or no effect on normal cells. 5,7-Dihydroxyflavone is a dietary flavonoid commonly found in many plants. Here we show that the combined treatment with 5,7-dihydroxyflavone and TRAIL at subtoxic concentrations induced strong apoptotic response in human hepatocarcinoma HepG2 cells, acute leukemia Jurkat T cells, and cervical carcinoma HeLa cells. We further investigated the mechanisms by which 5,7-dihydroxyflavone augments TRAIL-induced apoptosis in HepG2 cells. 5,7-Dihydroxyflavone up-regulated the expression of pro-apoptotic protein Bax, attenuated the expression of anti-apoptotic proteins Bcl-2, Mcl-1, and IAPs, and reduced the phosphorylation levels of Akt and STAT3, weakening the anti-apoptotic signals thus facilitating the process of apoptosis. Moreover, 5,7-dihydroxyflavone and TRAIL were well tolerated in mice, and the combination of 5,7-dihydroxyflavone and TRAIL reduced tumor burdenin vivoin a HepG2 tumor xenograft model. Interestingly, 5,7-dihydroxyflavone-mediated sensitization to TRAIL-induced cell death was not observed in normal human hepatocytes L-O2. These results suggest that the 5,7-dihydroxyflavone in combination with TRAIL might be used for cancer prevention and/or therapy.

scholarly journals 18FDG, [18F]FLT, [18F]FAZA, and11C-Methionine Are Suitable Tracers for the Diagnosis andIn VivoFollow-Up of the Efficacy of Chemotherapy by miniPET in Both Multidrug Resistant and Sensitive Human Gynecologic Tumor Xenografts

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
György Trencsényi ◽  
Teréz Márián ◽  
Imre Lajtos ◽  
Zoltán Krasznai ◽  
László Balkay ◽  
...  
Keyword(s):  
Combined Treatment ◽  
Human Tumor ◽  
Multidrug Resistant ◽  
Tumor Xenograft ◽  
Human Tumor Xenograft ◽  
Tumor Xenografts ◽  
Gynecologic Tumor ◽  
Human Ovarian Carcinoma

Expression of multidrug pumps including P-glycoprotein (MDR1, ABCB1) in the plasma membrane of tumor cells often results in decreased intracellular accumulation of anticancer drugs causing serious impediment to successful chemotherapy. It has been shown earlier that combined treatment with UIC2 anti-Pgp monoclonal antibody (mAb) and cyclosporine A (CSA) is an effective way of blocking Pgp function. In the present work we investigated the suitability of four PET tumor diagnostic radiotracers including 2-[18F]fluoro-2-deoxy-D-glucose (18FDG),11C-methionine, 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT), and [18F]fluoroazomycin-arabinofuranoside (18FAZA) forin vivofollow-up of the efficacy of chemotherapy in both Pgp positive (Pgp+) and negative (Pgp−) human tumor xenograft pairs raised in CB-17 SCID mice. Pgp+and Pgp−A2780AD/A2780 human ovarian carcinoma and KB-V1/KB-3-1 human epidermoid adenocarcinoma tumor xenografts were used to study the effect of the treatment with an anticancer drug doxorubicin combined with UIC2 and CSA. The combined treatment resulted in a significant decrease of both the tumor size and the accumulation of the tumor diagnostic tracers in the Pgp+tumors. Our results demonstrate that18FDG,18F-FLT,18FAZA, and11C-methionine are suitable PET tracers for the diagnosis andin vivofollow-up of the efficacy of tumor chemotherapy in both Pgp+and Pgp−human tumor xenografts by miniPET.

Effect of treating glioblastoma with a cytokine inhibitor, ibudilast, in combination with temozolomide on survival in a patient-derived xenograft model.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2062-2062 ◽  
Author(s):  
Kerrie Leanne McDonald ◽  
Wendy Ha ◽  
Hatice Sevim ◽  
Kazuko Matsuda ◽  
Mustafa Khasraw
Keyword(s):  
Overall Survival ◽  
Xenograft Model ◽  
Tumor Burden ◽  
Survival Times ◽  
Poor Overall Survival ◽  
Methyl Transferase ◽  
Patient Derived Xenograft ◽  
Cytokine Inhibitor ◽  
Induced Apoptosis

2062 Background: Recurrence in patients with glioblastoma (GBM) is inevitable, even in patients with O-6-Methylguanine-DNA Methyl Transferase ( MGMT) methylation. We identified increased expression of the inflammatory cytokine, Macrophage Inhibitory Factor (MIF) and its receptor CD74 in patients with recurrent tumors. High levels of MIF and CD74 were associated with poor overall survival in GBM patients. This study aims to determine efficacy of Ibudliast (MN-166; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) to block MIF expression and decrease tumor burden. Ibudilast is an anti-inflammatory drug that was developed for the treatment of bronchial asthma. Methods: The patient derived cell lines (PDCLs) RN1 ( MGMT unmethylated), BAH1 ( MGMT methylated), and HW1 ( MGMT methylated) were treated in vitrowith different concentrations of ibudilast in combination with temozolomide (TMZ). Patient derived xenograft (PDX) models of GBM were developed and treated with the combination of ibudilast and TMZ. Overall survival was calculated. Results: Regardless of MGMT status, significant synergism between ibudilast and TMZ was observed in the PDCLs. Efficacy was associated with significantly decreased expression of its targets, MIF and CD74. Downstream proteins such as Src and Akt were also significantly inhibited. The combination induced apoptosis. RN1 tumors were established intracranially in Balb/c nude mice. Significant increases in survival times of the mice were recorded when treated with the combination. Conclusions: Ibudilast in combination with TMZ resulted in significant blockage of MIF expression, increased apoptosis and longer survival in vivo. A human pilot study for recurrent GBM patients is underway.

scholarly journals Comparison of the Impact of Xanthohumol and Phenethyl Isothiocyanate and Their Combination on Nrf2 and NF-κB Pathways in HepG2 Cells In Vitro and Tumor Burden In Vivo

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3000
Author(s):  
Marta Cykowiak ◽  
Violetta Krajka-Kuźniak ◽  
Robert Kleszcz ◽  
Małgorzata Kucińska ◽  
Hanna Szaefer ◽  
...  
Keyword(s):  
Generation X ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Tumor Burden ◽  
Ros Generation ◽  
Phenethyl Isothiocyanate ◽  
Induced Apoptosis ◽  
The Impact

Background: Increasing evidence suggests that combinations of phytochemicals are more efficient than single components in the modulation of signaling pathways involved in cancer development. In this study, the impact of phenethyl isothiocyanate (PEITC), indole-3-carbinol (I3C), xanthohumol, (X), and resveratrol (RES) and their combinations on the activation and expression of Nrf2 and NF-κB in human hepatocytes and HCC cells were evaluated. Methods: THLE-2 and HepG2 cells were exposed to single phytochemicals and their combinations for 24 h. The activation of Nrf2 and NF-κB, expression of their target genes, and effect on cells survival were assessed. The tumor burden was evaluated in mice carrying xenografts. Results: All phytochemicals enhanced the activation and expression of Nrf2 and its target genes SOD and NQO1 in HepG2 cells. The increased expression of NQO1 (~90%) was associated with increased ROS generation. X + PEITC downregulated NF-κB activation reducing binding of its active subunits to DNA resulting in diminished COX-2 expression. In contrast to single phytochemicals, X + PEITC induced apoptosis. Moderate reduction of tumor burden in mice carrying xenografts following X and PEITC or their combination was observed. Conclusions: Since Nrf2 is overexpressed in HCC its reduced activation together with diminished level of NF-κB by X + PEITC may be considered as a strategy to support conventional HCC therapy.

scholarly journals EXTH-23. COMBINED EFFECTS OF NICLOSAMIDE AND TEMOZOLOMIDE AGAINST HUMAN GLIOBLASTOMA TUMORSPHERES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi87-vi87
Author(s):  
Hyeong Cheol Oh ◽  
Jihwan Yoo ◽  
Jin-Kyoung Shim ◽  
Junseong Park ◽  
Ji-hyun Lee ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Human Colon ◽  
Tumor Burden ◽  
Anticancer Efficacy ◽  
Mesenchymal Transition ◽  
Orthotopic Xenograft ◽  
Related Proteins

Abstract PURPOSE Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. METHODS Effects of niclosamide and/or temozolomide on GBM TSs were evaluated. Viability, stemness, and invasive properties of GBM TSs were examined. In vivo anticancer efficacy was tested in a mouse orthotopic xenograft model. RESULTS The combination of niclsoamide and temozolomide significantly inhibited the viability, sphere formation, expression of stemness-related proteins, and invasive properties of GBM TSs. This combination significantly down-regulated the expression of epithelial mesenchymal transition-related proteins. Bioluminescence imaging further showed that compared with either agent alone, combination of niclosamide and temozolomide significantly reduced the tumor burden in orthotopic xenograft models. CONCLUSIONS The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM. KEYWORDS: Glioblastoma; Invasion; Niclosamide; Temozolomide; Tumorsphere

scholarly journals P11.32 Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii50-iii50
Author(s):  
E Kim ◽  
H Oh ◽  
J Shim ◽  
S Kang
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Human Colon ◽  
Tumor Burden ◽  
Anticancer Efficacy ◽  
Mesenchymal Transition ◽  
Orthotopic Xenograft ◽  
Related Proteins

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. MATERIAL AND METHODS Effects of niclosamide and/or temozolomide on GBM TSs were evaluated. Viability, stemness, and invasive properties of GBM TSs were examined. In vivo anticancer efficacy was tested in a mouse orthotopic xenograft model. RESULTS The combination of niclsoamide and temozolomide significantly inhibited the viability, sphere formation, expression of stemness-related proteins, and invasive properties of GBM TSs. This combination significantly down-regulated the expression of epithelial mesenchymal transition-related proteins. Bioluminescence imaging further showed that compared with either agent alone, combination of niclosamide and temozolomide significantly reduced the tumor burden in orthotopic xenograft models. CONCLUSION The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

scholarly journals Metformin-induced TRAIL Upregulation Promotes Apoptosis in Triple Negative Breast Cancer and Non-small Cell Lung Cancer Cells

2020 ◽  
Author(s):  
Shuang Liu ◽  
Erik V Polsdofer ◽  
Lukun Zhou ◽  
Sanbao Ruan ◽  
Hui Lyu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Triple Negative ◽  
Xenograft Model ◽  
Small Cell ◽  
Tumor Xenograft ◽  
Small Cell Lung ◽  
Trail Expression ◽  
Induced Apoptosis ◽  
Recombinant Trail

Abstract Background: Triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) are highly aggressive types of cancer with limited therapeutic options. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity and is well tolerated in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised in part by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Methods: Cell proliferation (MTS) and colony formation assays were performed to determine the anti-proliferative/anti-survival effects of metformin, a common drug for type II diabetes, on TNBC and NSCLC cells. A Live/Dead imaging assay and specific apoptotic ELISA analyzed cells undergoing apoptosis. Western blot analyses were used to examine protein expression and cleavage. A recombinant TRAIL-R2-Fc chimera protein was applied to block TRAIL binding to its receptors. Lentiviral vector containing shRNAs was used to specifically knockdown TRAIL expression. A tumor xenograft model was established by inoculation of H460 cells into nude mice. The tumor-bearing mice were treated with metformin to assess the drug’s antitumor activity. Immunohistochemistry was carried out to study the effects of metformin on tumor cell proliferation and induction of apoptosis and TRAIL in vivo. Results: Metformin upregulated TRAIL protein, but not mRNA expression, which correlated with increased apoptosis in TNBC and NSCLC cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-induced TRAIL was secreted into conditioned medium (CM) and functional, since the CM potently promoted apoptosis in MDA-MB-231 cells, which was effectively blocked by a recombinant TRAIL-R2-Fc chimera protein. Inhibition of TRAIL function by blockade of its binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth; it also elicited apoptosis and upregulated TRAIL expression in vivo. Conclusions: TRAIL upregulation and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL.

Induction of Apoptosis by Nano‐Synthesized Complexes of H2L and its Cu(II) Complex in Human Hepatocellular Carcinoma Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Thoria Diab ◽  
Tarek M. Mohamed ◽  
Alaa Hamed ◽  
Mohamed Gaber
Keyword(s):  
Cell Cycle ◽  
Metal Complexes ◽  
Hepg2 Cells ◽  
Therapeutic Potential ◽  
Free Ligand ◽  
Organometallic Complexes ◽  
Phase Cell ◽  
Sod Activity ◽  
Induced Apoptosis

Background: Chemotherapy is currently the most utilized treatment for cancer. Therapeutic potential of metal complexes in cancer therapy has attracted a lot of interest. The mechanisms of action of most organometallic complexes are poorly understood. Objective: This study was designed to explore the mechanisms governing the anti-proliferative effect of the free ligand N1,N6‐bis((2‐hydroxynaphthalin‐1‐yl)methinyl)) adipohydrazone (H2L) and its complexes of Mn(II), Co(II), Ni(II) and Cu(II). Methods: Cells were exposed to H2L or its metal complexes where cell viability determined by MTT assay. Cell cycle was analysed by flow cytometry. In addition, qRT-PCR was used to monitor the expression of Bax and Bcl-2. Moreover, molecular docking was carried out to find the potentiality of Cu(II) complex as an inhibitor of Adenosine Deaminase (ADA). ADA, Superoxide Dismutase (SOD) and reduced Glutathione (GSH) levels were measured in the most affected cancer cell line. Results: The obtained results demonstrated that H2L and its Cu(II) complex exhibited a strong cytotoxic activity compared to other complexes against HepG2 cells (IC50 = 4.14±0.036μM/ml and 3.2±0.02μM/ml), respectively. Both H2L and its Cu(II) complex induced G2/M phase cell cycle arrest in HepG2 cells. Additionally, they induced apoptosis in HepG2 cells via upregulation of Bax and downregulation of Bcl-2. Interestingly, the activity of ADA was decreased by 2.8 fold in HepG2 cells treated with Cu(II) complex compared to untreated cells. An increase of SOD activity and GSH level in HepG2 cells compared to control was observed. Conclusion: The results concluded that Cu(II) complex of H2L induced apoptosis in HepG2 cells. Further studies are needed to confirm its anti-cancer effect in vivo.

scholarly journals Force estimation from 4D OCT data in a human tumor xenograft mouse model

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Maximilian Neidhardt ◽  
Nils Gessert ◽  
Tobias Gosau ◽  
Julia Kemmling ◽  
Susanne Feldhaus ◽  
...  
Keyword(s):  
Deep Learning ◽  
Mouse Model ◽  
Haptic Feedback ◽  
Human Tumor ◽  
Tumor Xenograft ◽  
Human Tumor Xenograft ◽  
Force Estimation ◽  
Xenograft Mouse Model ◽  
Dead Tissue

AbstractMinimally invasive robotic surgery offer benefits such as reduced physical trauma, faster recovery and lesser pain for the patient. For these procedures, visual and haptic feedback to the surgeon is crucial when operating surgical tools without line-of-sight with a robot. External force sensors are biased by friction at the tool shaft and thereby cannot estimate forces between tool tip and tissue. As an alternative, vision-based force estimation was proposed. Here, interaction forces are directly learned from deformation observed by an external imaging system. Recently, an approach based on optical coherence tomography and deep learning has shown promising results. However, most experiments are performed on ex-vivo tissue. In this work, we demonstrate that models trained on dead tissue do not perform well in in vivo data. We performed multiple experiments on a human tumor xenograft mouse model, both on in vivo, perfused tissue and dead tissue. We compared two deep learning models in different training scenarios. Training on perfused, in vivo data improved model performance by 24% for in vivo force estimation.

scholarly journals A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuejie Gao ◽  
Bo Li ◽  
Anqi Ye ◽  
Houcai Wang ◽  
Yongsheng Xie ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Burden ◽  
High Rate ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Xenograft Mouse Model

Abstract Background Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. Methods We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. Results The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. Conclusion The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.

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.

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