scholarly journals Towards Optimized Bioavailability of 99mTc-Labeled Barbiturates for Non-invasive Imaging of Matrix Metalloproteinase Activity

2021 ◽  
Author(s):  
Lisa Honold ◽  
Melanie Austrup ◽  
Andreas Faust ◽  
Christian Paul Konken ◽  
Katrin Schwegmann ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Thyroid Tumor ◽  
Tumor Xenograft ◽  
High Signal ◽  
Renal Elimination ◽  
Papillary Thyroid ◽  
Mmp Inhibitors ◽  
Non Invasive

Abstract Introduction Dysregulated activity of matrix metalloproteinases (MMPs) drives a variety of pathophysiological conditions. Non-invasive imaging of MMP activity in vivo promises diagnostic and prognostic value. However, current targeting strategies by small molecules are typically limited with respect to the bioavailability of the labeled MMP binders in vivo. To this end, we here introduce and compare three chemical modifications of a recently developed barbiturate-based radiotracer with respect to bioavailability and potential to image MMP activity in vivo. Methods Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated in vitro and in vivo. Biodistribution and radiotracer elimination were determined in C57/BL6 mice by serial SPECT imaging. MMP activity was imaged in a MMP-positive subcutaneous xenograft model of human K1 papillary thyroid tumors. In vivo data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry. Results We prepared three new 99mTc‐labeled MMP inhibitors, bearing either a glycine ([99mTc]MEA39), lysine ([99mTc]MEA61), or the ligand HYNIC with the ionic co-ligand TPPTS ([99mTc]MEA223) yielding gradually increasing hydrophilicity. [99mTc]MEA39 and [99mTc]MEA61 were rapidly eliminated via hepatobiliary pathways. In contrast, [99mTc]MEA223 showed delayed in vivo clearance and primary renal elimination. In a thyroid tumor xenograft model, only [99mTc]MEA223 exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images. Conclusion Introduction of HYNIC/TPPTS into the barbiturate lead structure ([99mTc]MEA223) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model.

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 METTL14 promotes tumorigenesis by regulating lncRNA OIP5-AS1/miR-98/ADAMTS8 signaling in papillary thyroid cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Xiaoping Zhang ◽  
Dan Li ◽  
Chengyou Jia ◽  
Haidong Cai ◽  
Zhongwei Lv ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Papillary Thyroid ◽  
Qrt Pcr ◽  
The Relationship

Abstract Background Papillary thyroid cancer (PTC) is the most common type of cancer of the endocrine system. Long noncoding RNAs (lncRNAs) are emerging as a novel class of gene expression regulators associated with tumorigenesis. Through preexisting databases available for differentially expressed lncRNAs in PTC, we uncovered that lncRNA OIP5-AS1 was significantly upregulated in PTC tissues. However, the function and the underlying mechanism of OIP5-AS1 in PTC are poorly understood. Methods Expression of lncRNA OIP5-AS1 and miR-98 in PTC tissue and cells were measured by quantitative real-time PCR (qRT-PCR). And expression of METTL14 and ADAMTS8 in PTC tissue and cells were measured by qRT-PCR and western blot. The biological functions of METTL14, OIP5-AS1, and ADAMTS8 were examined using MTT, colony formation, transwell, and wound healing assays in PTC cells. The relationship between METTL14 and OIP5-AS1 were evaluated using RNA immunoprecipitation (RIP) and RNA pull down assay. And the relationship between miR-98 and ADAMTS8 were examined by luciferase reporter assay. For in vivo experiments, a xenograft model was used to investigate the effects of OIP5-AS1 and ADAMTS8 in PTC. Results Functional validation revealed that OIP5-AS1 overexpression promotes PTC cell proliferation, migration/invasion in vitro and in vivo, while OIP5-AS1 knockdown shows an opposite effect. Mechanistically, OIP5-AS1 acts as a target of miR-98, which activates ADAMTS8. OIP5-AS1 promotes PTC cell progression through miR-98/ADAMTS8 and EGFR, MEK/ERK pathways. Furthermore, RIP and RNA pull down assays identified OIP5-AS1 as the downstream target of METTL14. Overexpression of METTL14 suppresses PTC cell proliferation and migration/invasion through inhibiting OIP5-AS1 expression and regulating EGFR, MEK/ERK pathways. Conclusions Collectively, our findings demonstrate that OIP5-AS1 is a METTL14-regulated lncRNA that plays an important role in PTC progression and offers new insights into the regulatory mechanisms underlying PTC development.

scholarly journals Anti‐oral cancer effects of triptolide by downregulation of DcR3 in vitro, in vivo, and in preclinical patient‐derived tumor xenograft model

Head & Neck ◽  
2018 ◽  
Vol 41 (5) ◽  
pp. 1260-1269 ◽  
Author(s):  
Cheng‐Yu Yang ◽  
Chih‐Kung Lin ◽  
Cheng‐Chih Hsieh ◽  
Chang‐Huei Tsao ◽  
Chun‐Shu Lin ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Xenograft Model ◽  
Tumor Xenograft

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 Metformin reduces glycometabolism of papillary thyroid carcinoma in vitro and in vivo

2017 ◽  
Vol 58 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Chen-Tian Shen ◽  
Wei-Jun Wei ◽  
Zhong-Ling Qiu ◽  
Hong-Jun Song ◽  
Xin-Yun Zhang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Xenograft Model ◽  
Dependent Manner ◽  
Papillary Thyroid ◽  
Fdg Uptake ◽  
Dose Dependent

More aggressive thyroid cancer cells show a higher activity of glycometabolism. Targeting cancer cell metabolism has emerged as a novel approach to prevent or treat malignant tumors. Glucose metabolism regulation effect of metformin in papillary thyroid cancer was investigated in the current study. Human papillary thyroid carcinoma (PTC) cell lines BCPAP and KTC1 were used. Cell viability was detected by CCK8 assay. Glucose uptake and relative gene expression were measured in metformin (0–10 mM for 48 h)-treated cells by 18F-FDG uptake assay and western blotting analysis, respectively. MicroPET/CT imaging was performed to detect 18F-FDG uptake in vivo. After treatment with metformin at 0, 2.5, 5 and 10 mM for 48 h, the ratio of p-AMPK to total AMPK showed significant rising in a dose-dependent manner in both BCPAP and KTC1, whereas p-AKT and p-mTOR expression level were downregulated. 18F-FDG uptake reduced after metformin treatment in a dose-dependent manner, corresponding to the reduced expression level of HK2 and GLUT1 in vitro. Xenograft model of PTC using BCPAP cells was achieved successfully. MicroPET/CT imaging showed that in vivo 18F-FDG uptake decreased after treatment with metformin. Immunohistochemistry staining further confirmed the reduction of HK2 and GLUT1 expression in the tumor tissue of metformin-treated PTC xenograft model. In conclusion, metformin could reduce glucose metabolism of PTC in vitro and in vivo. Metformin, by targeting glycometabolism of cancer cells, could be a promising adjuvant therapy alternative in the treatment modality of advanced thyroid carcinoma.

scholarly journals Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Chongyang Li ◽  
Chaowei Deng ◽  
Guangzhao Pan ◽  
Xue Wang ◽  
Kui Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Xenograft Model ◽  
Resistant Cell ◽  
Tumor Xenograft ◽  
Gastric Cancer Cells ◽  
Bcl2 Family ◽  
Ubiquitin E3 Ligase ◽  
Underlying Mechanisms

Abstract Background Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment. Methods The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry). Results In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14–1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer. Conclusions The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.

Garcinol-loaded novel cationic nanoliposomes: in vitro and in vivo study against B16F10 melanoma tumor model

Nanomedicine ◽  
2019 ◽  
Vol 14 (15) ◽  
pp. 2045-2065 ◽  
Author(s):  
Brahamacharry Paul ◽  
Raghuvir H Gaonkar ◽  
Ria Mukhopadhyay ◽  
Shantanu Ganguly ◽  
Mita Chatterjee Debnath ◽  
...  
Keyword(s):  
Chromatin Condensation ◽  
Xenograft Model ◽  
Tumor Model ◽  
Tumor Xenograft ◽  
B16f10 Melanoma ◽  
Melanoma Tumor ◽  
Study Gene Expression ◽  
The Difference

Aim: Garcinol (GAR)-loaded cationic nanoliposomes were developed to achieve potential antitumor efficacy on B16F10 melanoma cells in vitro and in vivo. Materials & methods: Two different phospholipids namely, distearoyl phosphatidylcholine (DSPC) and dipalmitoyl phosphatidylcholine (DPPC) were used in formulation to elucidate the difference in cellular uptake, cytotoxicity, in vivo tumor uptake (by scintigraphic imaging after technetium-99m radiolabeling) and therapeutic efficacy. Results: Different in vitro protocols, for example, MTT assay, apoptosis study, gene expression analysis, chromatin condensation and cytoskeleton breakdown analysis in B16F10 cell lines as well as scintigraphic analysis and tumor inhibition studies (B16F10 tumor xenograft model) revealed superiority of GAR-DPPC than GAR-DSPC and free GAR in melanoma prevention. Conclusion: Cationic nanoliposomal formulations could be a future medication for skin cancer treatment.

scholarly journals Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer

2020 ◽  
Author(s):  
Chongyang Li ◽  
Chaowei Deng ◽  
Guangzhao Pan ◽  
Xue Wang ◽  
Kui Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Xenograft Model ◽  
Resistant Cell ◽  
Tumor Xenograft ◽  
Gastric Cancer Cells ◽  
Bcl2 Family ◽  
Ubiquitin E3 Ligase ◽  
Underlying Mechanisms

Abstract Background: Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment. Methods: The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry).Results: In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14-1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer. Conclusions: Together, the efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumorous compound for gastric cancer.

scholarly journals Overexpression of Long Non-Coding RNA NNT-AS1 Correlates with Tumor Progression and Poor Prognosis in Osteosarcoma

2018 ◽  
Vol 45 (5) ◽  
pp. 1904-1914 ◽  
Author(s):  
Hui Ye ◽  
Jinkuang Lin ◽  
Xuedong Yao ◽  
Yizhong Li ◽  
Xiaobin Lin ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Poor Prognosis ◽  
Significant Risk ◽  
Xenograft Model ◽  
Significant Risk Factor ◽  
Tumor Xenograft ◽  
Migration And Invasion ◽  
Mouse Xenograft Model

Background/Aims: Increasing evidence demonstrates that long non-coding RNAs (lncRNAs) play critical regulatory roles in cancers, including osteosarcoma. A previous study showed that Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1) was aberrantly expressed in several types of cancer. However, the potential biological roles and regulatory mechanisms of NNT-AS1 in osteosarcoma progression remain unknown. Methods: Quantitative RT-PCR was performed to examine the expression of NNT-AS1 in human tissues and cells. The biological functions of NNT-AS1 were determined by CCK-8, colony formation, Flow cytometry and Transwell assays in vitro. A mouse xenograft model was performed to investigate the effect of NNT-AS1 on tumor growth in vivo. Results: In this study, we found the expression of NNT-AS1 was significantly increased in tumor tissues compared to adjacent normal tissues. Furthermore, upregulated NNT-AS1 expression predicted poor prognosis and was an independent and significant risk factor for osteosarcoma patient survival. Further experiments revealed that NNT-AS1 knockdown significantly inhibited cell proliferation by inducing cell cycle arrest and promoting apoptosis in osteosarcoma cells. Moreover, NNT-AS1 silencing suppressed cell migration and invasion in vitro. In a tumor xenograft model, knockdown of NNT-AS1 suppressed tumor growth of OS-732 cells in vivo. Conclusions: Taken together, these findings indicate that NNT-AS1 functions as an oncogene in osteosarcoma and could be a novel diagnostic and therapeutic target for osteosarcoma.

scholarly journals Double-Edged Lipid Nanoparticles Combining Liposome-Bound TRAIL and Encapsulated Doxorubicin Showing an Extraordinary Synergistic Pro-Apoptotic Potential

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1948 ◽  
Author(s):  
Diego De Miguel ◽  
Ana Gallego-Lleyda ◽  
Miguel Martinez-Ara ◽  
Javier Plou ◽  
Alberto Anel ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Carcinoma Cells ◽  
Tumor Xenograft ◽  
Cytotoxic Potential ◽  
Primary Tumors ◽  
Soluble Trail

Although TRAIL (TNF-related apoptosis-inducing ligand, also known as Apo2L) was described as capable of inducing apoptosis in transformed cells while sparing normal cells, limited results obtained in clinical trials has limited its use as an anti-tumor agent. Consequently, novel TRAIL formulations with enhanced bioactivity are necessary for overcoming resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumors. Our group has generated artificial liposomes with sTRAIL anchored on their surface (large unilamellar vesicle (LUV)-TRAIL), which have shown a greater cytotoxic activity both in vitro and in vivo when compared to sTRAIL against distinct hematologic and epithelial carcinoma cells. In this study, we have improved LUV-TRAIL by loading doxorubicin (DOX) in its liposomal lumen (LUVDOX-TRAIL) in order to improve their cytotoxic potential. LUVDOX-TRAIL killed not only to a higher extent, but also with a much faster kinetic than LUV-TRAIL. In addition, the concerted action of the liposomal DOX and TRAIL was specific of the liposomal DOX and was not observed when with soluble DOX. The cytotoxicity induced by LUVDOX-TRAIL was proven to rely on two processes due to different molecular mechanisms: a dynamin-mediated internalization of the doxorubicin-loaded particle, and the strong activation of caspase-8 exerted by the liposomal TRAIL. Finally, greater cytotoxic activity of LUVDOX-TRAIL was also observed in vivo in a tumor xenograft model. Therefore, we developed a novel double-edged nanoparticle combining the cytotoxic potential of DOX and TRAIL, showing an exceptional and remarkable synergistic effect between both agents.

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