scholarly journals Application of hydroxyapatite nanoparticles in tumor-associated bone segmental defect

2019 ◽  
Vol 5 (8) ◽  
pp. eaax6946 ◽  
Author(s):  
Kun Zhang ◽  
Yong Zhou ◽  
Cong Xiao ◽  
Wanlu Zhao ◽  
Hongfeng Wu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Bone Repair ◽  
Osteolytic Lesion ◽  
Tumor Model ◽  
Antitumor Agent ◽  
Porous Titanium ◽  
Suppressive Effect ◽  
Segmental Defect ◽  
Segmental Bone

Hydroxyapatite (HA) has been widely applied in bone repair because of its superior biocompatibility. Recently, a proliferation-suppressive effect of HA nanoparticles (n-HA) against various cancer cells was reported. This study was aimed at assessing the translational value of n-HA both as a bone-regenerating material and as an antitumor agent. Inhibition of tumor growth, prevention of metastasis, and enhancement of the survival rate of tumor-bearing rabbits treated with n-HA were demonstrated. Activated mitochondrial-dependent apoptosis in vivo was confirmed, and we observed that a stimulated immune response was involved in the n-HA–induced antitumor effect. A porous titanium scaffold loaded with n-HA was fabricated and implanted into a critical-sized segmental bone defect in a rabbit tumor model. The n-HA–releasing scaffold not only showed a prominent effect in suppressing tumor growth and osteolytic lesion but also promoted bone regeneration. These findings provide a rationale for using n-HA in tumor-associated bone segmental defects.

scholarly journals Andrographolide Suppresses the Growth and Metastasis of Luminal-Like Breast Cancer by Inhibiting the NF-κB/miR-21-5p/PDCD4 Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Junchen Li ◽  
Lixun Huang ◽  
Zinan He ◽  
Minggui Chen ◽  
Yi Ding ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Model ◽  
Antitumor Agent ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Tumor Growth And Metastasis

Tumor growth and metastasis are responsible for breast cancer-related mortality. Andrographolide (Andro) is a traditional anti-inflammatory drug used in the clinic that inhibits NF-κB activation. Recently, Andro has been found in the treatment of various cancers. Andro inhibits breast cell proliferation and invasion and induces apoptosis via activating various signaling pathways. Therefore, the underlying mechanisms with regard to the antitumor effects of Andro still need to be further confirmed. Herein, a MMTV-PyMT spontaneous luminal-like breast cancer lung metastatic transgenic tumor model was employed to estimate the antitumor effects of Andro on breast cancer in vivo. Andro significantly inhibited tumor growth and metastasis in MMTV-PyMT mice and suppressed the cell proliferation, migration, and invasion of MCF-7 breast cancer cells in vitro. Meanwhile, Andro significantly inhibited the expression of NF-κB, and the downregulated NF-κB reduced miR-21-5p expression. In addition, miR-21-5p dramatically inhibited the target gene expression of programmed cell death protein 4 (PDCD4). In the current study, we demonstrated the potential anticancer effects of Andro on luminal-like breast cancer and indicated that Andro inhibits the expression of miR-21-5p and further promotes PDCD4 via NF-κB suppression. Therefore, Andro could be an antitumor agent for the treatment of luminal-like breast cancer in the clinic.

scholarly journals Knockdown of LncRNA LINC00958 Inhibits the Proliferation and Migration of NSCLC Cells by MiR-204-3p/KIF2A Axis

2021 ◽  
Vol 30 ◽  
pp. 096368972110255
Author(s):  
Qing Wang ◽  
Kai Li ◽  
Xiaoliang Li
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Model ◽  
Luciferase Reporter ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence suggests that long non-coding RNAs (lncRNAs) function in the tumorigenesis of NSCLC. LINC00958, a newly identified lncRNA, has been reported to be closely linked to tumorigenesis in several cancers. However, its specific role in NSCLC remains unclear. In this study, we determined the expression of LINC00958 in NSCLC by RT-qPCR analysis and evaluated cell proliferation and migration by CCK-8 and transwell assays, respectively. We established a xenograft tumor model to examine the effect of LINC00958 on tumor growth in vivo. Luciferase reporter assays were performed to determine the interaction between LINC00958 and miR-204-3p and the interaction between miR-204-3p and KIF2A. We found that LINC00958 was up-regulated in NSCLC tissues and cell lines. Down-regulation of LINC00958 inhibited cell proliferation and migration in vitro and suppressed tumor growth in vivo. Besides, miR-204-3p was identified as a target of LINC00958 and miR-204-3p inhibitor could reverse the inhibitory effect of LINC00958 knockdown on proliferation and migration of NSCLC cells. We also validated that KIF2A, a direct target of miR-204-3p, was responsible for the biological role of LINC00958. KIF2A antagonized the effect of miR-204-3p on NSCLC cell proliferation and migration and was regulated by LINC00958/miR-204-3p. Taken together, these data indicate that the LINC00958/miR-204-3p/KIF2A axis is critical for NSCLC progression, which might provide a potential therapeutic target of NSCLC.

scholarly journals Micro-MRI at 11.7 T of a Murine Brain Tumor Model Using Delayed Contrast Enhancement

2003 ◽  
Vol 2 (3) ◽  
pp. 153535002003031
Author(s):  
Rex A. Moats ◽  
Sendhil Velan-Mullan ◽  
Russell Jacobs ◽  
Ignacio Gonzalez-Gomez ◽  
David J. Dubowitz ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Tumor Growth ◽  
Intraperitoneal Administration ◽  
Three Dimensional ◽  
Tumor Model ◽  
Qualitative Assessment ◽  
Response To Treatment ◽  
Simple Method ◽  
Serial Measurement

In vivo imaging methodologies allow for serial measurement of tumor size, circumventing the need for sacrificing mice at given time points. In orthotopically transplanted murine models of brain tumors, cross-section micro-MRI allows for visualization and measurement of the physically inaccessible tumors. To allow for long resident times of a contrast agent in the tumor, intraperitoneal administration was used as a route of injection for contrast-enhanced micro-MRI, and a simple method for relative tumor volume measurements was examined. A strategy for visualizing the variability of the delayed tumor enhancement was developed. These strategies were applied to monitor the growth of brain tumors xenotransplanted into nude mice and either treated with the antiangiogenic peptide EMD 121974 or an inactive control peptide. Each mouse was used as its own control. Serial imaging was done weekly, beginning at Day 7 after tumor cell implantation and continued for 7 weeks. Images obtained were reconstructed on the MRI instrument. The image files were transferred off line to be postprocessed to assess tumor growth (volume) and variability in enhancement (three-dimensional [3-D] intensity models). In a small study, tumor growth and response to treatment were followed using this methodology and the high-resolution images displayed in 3-D allowed for straightforward qualitative assessment of variable enhancement related to vascular factors and tumor age.

scholarly journals Radiographic Assessment of Implant Failures of Titanium 3.5 LCP vs. 4.5 LCP Used for Flexible Bridging Osteosynthesis of Large Segmental Femoral Diaphyseal Defects in a Miniature Pig Model

2010 ◽  
Vol 79 (4) ◽  
pp. 599-606 ◽  
Author(s):  
Alois Nečas ◽  
Pavel Proks ◽  
Lucie Urbanová ◽  
Robert Srnec ◽  
Ladislav Stehlík ◽  
...  
Keyword(s):  
Bone Defect ◽  
Implant Failure ◽  
Radiographic Examination ◽  
Femoral Diaphysis ◽  
Proximal Fragment ◽  
Segmental Defect ◽  
Miniature Pig ◽  
Segmental Bone ◽  
Transplantation Experiments

The study describes types, absolute and relative numbers of implant failures in flexible bridging osteosynthesis using a six-hole 3.5 mm titanium Locking Compression Plate (n = 9) or a five-hole LCP 4.5 mm titanium (n = 40) selected for the fixation of segmental ostectomy of femoral diaphysis in the miniature pig used as an in vivo model in a study on the healing of a critically sized bone defect using transplantation of mesenchymal stem cells combined with biocompatible scaffolds within a broader research project. Occasional implant failure was evaluated based on radiographic examination of femurs of animals 2, 4, 8, 12 and 16 weeks after surgery. When bone defect was stabilized using 3.5 mm LCP, in 6 cases (66.7%) the screw was broken/lost in the proximal fragment of the femur 2 weeks after implantation (n = 4) and 4 weeks after implantation (n = 2). In 4 cases of these, the implant failure was accompanied also by loosening of the screw in position 3 in the proximal fragment of the femur. During ostectomy stabilization with 4.5 mm LCP, in 3 cases (7.5%) LCP was broken at the place of the empty central plate hole (without inserted screw) at the level of the segmental bone defect. Compared to the six-hole 3.5 mm LCP, the five-hole titanium 4.5 mm LCP is more suitable implant for flexible bridging osteosynthesis of a critically sized segmental defect of femoral diaphysis in the miniature pig. The results of this study will allow reducing implant failures in time- and cost-demanding transplantation experiments focused on bone healing.

Anti-Tumor Activity of the Aurora a Inhibitor MLN8237 in Diffuse Large B-Cell Lymphoma Preclinical Models.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1592-1592 ◽  
Author(s):  
Jessica J Huck ◽  
Mengkun Zhang ◽  
Marc L Hyer ◽  
Mark G Manfredi
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Model ◽  
B Cell Lymphoma ◽  
Tumor Growth Inhibition ◽  
Aurora A ◽  
Hct 116 ◽  
Xenograft Models

Abstract Aurora A kinase is a serine/threonine protein kinase that is essential for normal transit of cells through mitosis. In many tumor types the Aurora A gene is amplified and/or the protein is over-expressed. The Aurora A small-molecule inhibitor MLN8237 demonstrated robust tumor growth inhibition in xenograft models of solid tumors grown subcutaneously (S.C.) in immunocompromised mice. Here we explored the antitumor activity of MLN8237 in models of diffuse large B-cell lymphoma (DLBCL) both in vitro and in vivo. In vivo three established DLBCL xenograft models (OCI-Ly7, OCI-Ly19, and WSU-DLCL2; all cells expressing luciferase) and a primary DLBCL tumor model PHTX-22-06 were tested using MLN8237 at different doses. Rituximab, an anti-CD20 monoclonal antibody that is active against CD20+ malignant B cells and is a standard of care agent was used for comparison. Using these model systems, tumor cells were injected either I.V. (to evaluate disseminated disease), or S.C. in severe combined immunodeficient mice (SCID). Animals were dosed orally for 21 days with MLN8237 (QD or BID) at various doses, or Rituximab dosed at 10mg/kg IV (once/week) and tumor growth inhibition was monitored using either bioluminescent imaging for the disseminated models or vernier calipers for the S.C. models. Tumor growth inhibition by MLN8237 was dose dependent with 20 mg/kg bid being the most efficacious dose (TGI>100% in both disseminated OCI-Ly19 and WSU models). All animals in the OCI-Ly19 disseminated model 20 mg/kg BID treatment group demonstrated regressions and remained disease free until the end of the study, day 65. In this study the Rituximab treated animals were euthanized on day 31 due to a high level of tumor burden. In the primary tumor model, PHTX-22-06, MLN8237 dosed at 20 mg/kg BID was also the most efficacious with a TGI of 95%. Moreover, tumor growth inhibition was durable as determined by prolonged tumor growth delay (>50 days). Significant efficacy was achieved in all models tested, whether grown as disseminated or subcutaneous models. A noted increase in durability of response was observed with MLN8237 treatment when compared with previous data from solid tumor models. In vitro, MLN8237 treatment increased levels of apoptosis in the OCI-Ly19 cells in comparison to the solid tumor cell line HCT-116 (colon). Greater Annexin V positive cells and greater cleaved PARP and Caspase-3 signals were detected in the MLN8237 treated OCI-Ly19 cells when compared to HCT-116 cells. The demonstration of robust and durable anti-tumor activity in preclinical models treated with MLN8237 provides the basis for its clinical evaluation as a treatment option for DLBCL. MLN8237 is currently in multiple Phase I clinical trials.

scholarly journals Kruppel-like factor 6 suppresses growth and invasion of hepatocellular carcinoma cells in vitro and in vivo

2016 ◽  
Vol 29 (4) ◽  
pp. 666-675 ◽  
Author(s):  
Pei-Hao Wen ◽  
Dong-Yu Wang ◽  
Jia-Kai Zhang ◽  
Zhi-Hui Wang ◽  
Jie Pan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Model ◽  
Carcinoma Cells ◽  
Tumor Suppressive Function ◽  
Xenograft Tumor Growth ◽  
Hcc Cells

Kruppel-like factor 6 (KLF6) as a novel tumor suppressive gene participates in multiple biological behaviors and plays an important role in regulating tumor cell growth and invasion. However, the functions of KLF6 in hepatocellular carcinoma (HCC) remain poorly understood. The expression level of KLF6 was examined by immunohistochemical assay in human HCC tissues, and KLF6-overexpressed HCC cells (SMCC-7721 and HepG2) were used for evaluating cell proliferation and invasion by MTT and Transwell assays. A subcutaneous HCC tumor model was established for assessing tumor growth in vivo. Our results showed that the expression of KLF6 was significantly downregulated in HCC tissues compared with the adjacent non-cancerous tissues (50.0% vs. 72.0%, P = 0.034) and negatively associated with the lymph-vascular space invasion (LVSI) in HCC patients ( P = 0.003). Furthermore, overexpression of KLF6 reduced cell proliferation and weakened the cell invasive potential followed with the decreased expression of PCNA and MMP-9 in HCC cells. The in vivo experiment indicated that KLF6 overexpression suppressed the xenograft tumor growth. Therefore, our findings show that KLF6 suppresses growth and invasion of HCC cells in vitro and in vivo, suggesting a tumor suppressive function in HCC and provides the potential therapeutic target for the treatment of HCC.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ARREST CELL CYCLE IN G0/G1 PHASE AND INDUCE CELL DEATH IN OSTEOBLAST-ENRICHED CULTURES

2001 ◽  
Vol 05 (04) ◽  
pp. 279-289 ◽  
Author(s):  
MEI-LING HO ◽  
JE-KEN CHANG ◽  
HSIU-TING TSAI ◽  
MING-HSUANG CHO ◽  
GWO-JAW WANG
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Bone Remodeling ◽  
Bone Repair ◽  
Suppressive Effect ◽  
Osteoblastic Cell ◽  
Cytotoxic Effects ◽  
Inflammatory Drugs ◽  
Enriched Cultures

Nonsteroidal anti-inflammatory drugs have been widely prescribed for orthopaedic patients to relieve pain and chronic inflammation. However, it has been demonstrated that NSAIDs suppress bone repair and remodeling in vivo. We have reported that ketorolac inhibits bone repair in vivo and its critical effective timing is at the early stage of endochondral ossification. Our previous results showed that ketorolac and indomethacin inhibit osteoblast proliferation in vitro, suggesting that this effect may be one of the mechanisms contributing to the suppressive effect of NSAIDs on bone remodeling. Cell proliferation and death of osteoblasts should be well regulated through some relative apoptotic and mitotic factors during normal bone remodeling process. Accordingly, we proposed that the induction of osteoblastic cell death of NSAIDs might be one of the mechanisms involving their suppressive effect on bone remodeling in vivo. In this study, we investigated whether NSAIDs arrest osteoblastic cell cycle and/or induce cell death. Whether the mechanism was mediated through prostaglandin (PG) pathway. We tested the effects of ketorolac, indomethacin, diclofenac, piroxicam on cell cycle kinetics, cytotoxicity, and cell death pattern in osteoblast-enriched cultures derived from fetal rat calvaria. Our results showed that ketorolac and indomethacin arrested cell cycle at G0/G1 phase. All the 4 NSAIDs had cytotoxic effects and these effects were concentration dependent. The sequence of the cytotoxic effects of these four NSAIDs at 10-4 M were indomethacin > diclofenac > ketorolac > piroxicam. Both PGE1 and PGE2 (10-10 -10-8 M) also significantly elevated the LDH leakage of osteoblasts, while PGF2α had no significant effect. These results revealed that the cytotoxic effects of NSAIDs on osteoblasts might not be through inhibiting prostaglandin synthesis. They may be through PG-independent pathways. The results from flow cytometry followed by AnnexinV-FITC and propidium iodide double staining showed that 24 hours treatment of all the 4 NSAIDs (10-6 and 10-4 M) significantly induced both apoptosis (p<0.01) and necrosis (p<0.01, or p<0.05) in osteoblast cultures. These effects of NSAIDs on cell cycle arrest and cell death induction in osteoblasts may be one of the important mechanisms contributing to their suppressive effect on bone repair and bone remodeling in vivo.

scholarly journals Targeting MYC and HDAC8 with a Combination of siRNAs Inhibits Neuroblastoma Cells Proliferation In Vitro and In Vivo Xenograft Tumor Growth

2021 ◽  
Author(s):  
Nagindra Prashad
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Cellular Differentiation ◽  
Tumor Model ◽  
Significant Inhibition ◽  
Luciferase Reporter Plasmid ◽  
Combination Of Sirnas ◽  
Proliferation In Vitro

HDAC8, c MYC and MYCN are involved in the tumorigenesis of neuroblastoma. A mouse Neuroblastoma (NB) tumor model was used to understand the role of miRNA, miR-665 in NB tumorigenesis and cellular differentiation. During cellular differentiation of NB cells there is an up regulated miRNA-665. We found that HDAC 8, c MYC and MYCN are the direct targets of mimic miR-665 which was validated by luciferase reporter plasmid with 3’ UTR and ELISA. Mimic miR-665 inhibited cell proliferation, arrested cells in G1 stage and decreased S Phase in cell cycle. miR-665 increased the acetylation of histones and activated Caspase 3. This is the first report to recognize miRNA 665 as a suppressor miRNA of NB. The effects of miR-665 were confirmed with the transfection of siRNA for HDAC8 and siRNA for MYC. Individual siRNA- HDAC8 or siRNA-MYC inhibited 40–50% of cell proliferation in vitro, however, the treatment with the combination of both siRNA-MYC + siRNA- HDAC8 inhibited 86% of cell proliferation. Indicating that both the targets c MYC and HDAC 8 should be reduced to obtain a significant inhibition of cell proliferation. Intratumoral treatment of xenograft tumors in mice with the combination of siRNA-MYC + siRNA- HDAC8 reduced the levels of target c-MYC protein by 64% and target HDAC 8 protein by 85% and the average tumor growth reduced by 80% compared to control tumors treated with NC-siRNA. Our results suggest the potential therapeutic effect of suppressor miR-665 and the combination of siRNA-MYC + siRNA-HDAC8 for neuroblastoma treatment.

scholarly journals Adhesion of Platelets to Colon Cancer Cells Is Necessary to Promote Tumor Development in Xenograft, Genetic and Inflammation Models

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4243
Author(s):  
Marica Cariello ◽  
Elena Piccinin ◽  
Roberta Zerlotin ◽  
Marilidia Piglionica ◽  
Claudia Peres ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Tumor Development ◽  
Tumor Model ◽  
Cell Interaction ◽  
Colorectal Carcinogenesis ◽  
Intestinal Tumorigenesis

Platelets represent the linkage between tissue damage and inflammatory response with a putative role in tumorigenesis. Given the importance of the microenvironment in colon cancer development, we elucidated the eventual role of platelets-cancer cells crosstalk in in vivo colon cancer models. To evaluate the involvement of platelets in intestinal tumorigenesis, we first analyzed if the ablation of β-integrin P-selectin that drives platelets-cell adhesion, would contribute to platelets-colon cancer cell interaction and drive cancer progression. In a xenograft tumor model, we observed that when tumors are inoculated with platelets, the ablation of P-selectin significantly reduced tumor growth compared to control platelets. Furthermore, in genetic models, as well as in chronic colitis-associated colorectal carcinogenesis, P-selectin ablated mice displayed a significant reduction in tumor number and size compared to control mice. Taken together, our data highlights the importance of platelets in the tumor microenvironment for intestinal tumorigenesis. These results support the hypothesis that a strategy aimed to inhibit platelets adhesion to tumor cells are able to block tumor growth and could represent a novel therapeutic approach to colon cancer treatment.

scholarly journals Wireless implantable sensor for non-invasive, longitudinal quantification of axial strain across rodent long bone defects

2017 ◽  
Author(s):  
Brett S. Klosterhoff ◽  
Keat Ghee Ong ◽  
Laxminarayanan Krishnan ◽  
Kevin M. Hetzendorfer ◽  
Young-Hui Chang ◽  
...  
Keyword(s):  
Bone Repair ◽  
Ex Vivo ◽  
Axial Strain ◽  
Element Model ◽  
Tissue Mechanics ◽  
Long Bone ◽  
Segmental Defect ◽  
Non Invasive ◽  
Technical Requirements

AbstractBone development, maintenance, and regeneration are remarkably sensitive to mechanical cues. Consequently, mechanical stimulation has long been sought as a putative target to promote endogenous healing after fracture. Given the transient nature of bone repair, tissue-level mechanical cues evolve rapidly over time after injury and are challenging to measure non-invasively. The objective of this work was to develop and characterize an implantable strain sensor for non-invasive monitoring of axial strain across a rodent femoral defect during functional activity. Herein, we present the design, characterization, and in vivo demonstration of the device’s capabilities for quantitatively interrogating physiological dynamic strains during bone regeneration. Ex vivo experimental characterization of the device showed that it exceeded the technical requirements for sensitivity, signal resolution, and electromechanical stability. The digital telemetry minimized power consumption, enabling long-term intermittent data collection. Devices were implanted in a rat 6 mm femoral segmental defect model and after three days, data were acquired wirelessly during ambulation and synchronized to corresponding radiographic videos, validating the ability of the sensor to non-invasively measure strain in real-time. Lastly, in vivo strain measurements were utilized in a finite element model to estimate the strain distribution within the defect region. Together, these data indicate the sensor is a promising technology to quantify local tissue mechanics in a specimen specific manner, facilitating more detailed investigations into the role of the mechanical environment in dynamic skeletal healing and remodeling.

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