EXTH-19. EVALUATING THE ANTI-TUMOR EFFECT OF A NOVEL THERAPEUTIC AGENT, MAGMAS INHIBITOR, IN MALIGNANT GLIOMA

Abstract BACKGROUNDS Glioblastoma (GBM) is an aggressive infiltrative brain tumor, and has an extremely poor prognosis despite the use of multiple treatment modalities, including surgery, radiation, and chemotherapy. Meanwhile, mitochondrial changes represent a significant part of cancer cell biology since cancer cells must survive and adapt to challenging microenvironments, specifically in conditions where tumor growth makes oxygen and glucose scarce. As GBM is characterized by extensive hypoxia-induced phenotypic changes such as abnormal vascular proliferation and necrosis, regulation of mitochondrial function could be a novel approach for treating GBM that currently lacks effective therapies. Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes for the mitochondrial import inner membrane translocase subunit Tim16. We previously demonstrated that a novel Magmas inhibitor, BT#9, significantly exerted anti-tumor effect in glioma in vitro, and may cross the blood brain barrier in vivo, indicating that Magmas inhibitor may be a new chemotherapeutic agent for the treatment of GBM. METHODS In this study, the antitumor effect of Magmas inhibitor BT#9 was tested in an orthotopic xenograft model of human GBM. The molecular mechanism of BT#9 was investigated using glioma cell lines. RESULTS The mice were tolerated to BT#9, and there was no statistical difference in the weight of animals between the control and MTD (Maximum-tolerated Dose, 50mg/kg) groups. The immunocompromised mice, intracranially implanted with human D-54 GBM xenografts, survived significantly longer than the controls (P< 0.5) when treated with BT#9 at MTD. In vitro study showed that the MAP kinase pathways are involved in BT#9-induced tumor suppression. DISCUSSION This is the first study on the role of Magmas in glioma in vivo. Our findings suggested that Magmas plays a key role in glioma survival and targeting Magmas by Magmas inhibitor has the potential to become a therapeutic strategy in glioma patients.

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OM-RCA-01, an FGFR1 specific humanized antibody for the treatment of renal cell carcinoma (RCC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3070 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3070-3070

Author(s):

Ilya Tsimafeyeu ◽

Elina Zaveleva ◽

Walter Low

Keyword(s):

Renal Carcinoma ◽

Xenograft Model ◽

Body Weight Loss ◽

In Vitro Study ◽

Growth Delay ◽

Fgf Receptor ◽

Specific Igg ◽

Set Up

3070 Background: Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a potential therapeutic target for the treatment of metastatic RCC. We investigated the preclinical activity of OM-RCA-01, a novel therapeutic humanized anti-FGFR1 antibody with high affinity (Kd of 1.59 nM), in RCC. Methods: To assess the effect of anti-FGFR1 antibody on FGF-mediated signaling, the human renal carcinoma Caki-1 FGFR1-expressing cells were dosed with OM-RCA-01 at 100, 10, and 1 mcg/ml. Control wells were left untreated. Three hours after dosing, bFGF was added at a concentration of 50 ng/ml. Additional control wells were treated with OM-RCA-01 without FGF-stimulation. Cell growth inhibition was determined using Promega’s Cell Titer-Glo assay. CR female NCr nu/nu mice were set up with 1 mm3 Caki-1 tumor fragments sc in flank. Tumor sizes were measured in a blind fashion twice a week with a vernier caliper. Mice with established tumors were randomly divided into vehicle, non-specific IgG or OM-RCA-01 groups per 10 animals in group. Endpoint was significant differences in tumor growth delay. Results: In vitro study showed that bFGF increased proliferation of the human FGFR1-expressing renal carcinoma cells (p=0.011). OM-RCA-01 antibody significantly inhibits FGF-triggered cell proliferation in comparison with control. In vivo, the tumors in untreated mice or mice treated with non-specific IgG continued their aggressive growth to reach the size of 2000 cm3, at which point the mice were killed. In contrast, treatment with OM-RCA-01 not only significant arrested further growth of the tumors (p=0.006) but also demonstrated differences in tumor volume compared with vehicle already on Day 13. A similar anti-tumor activity of OM-RCA-01 was observed when the antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (p=0.917). Administration of 10 mg/kg antibody for up to 35 days resulted in minimal body weight loss and no observations of gross toxicity were made. Conclusions: Targeting FGFR1 blocks FGF/FGFR1 pathway in RCC. Monoclonal antibody OM-RCA-01 has significant early anti-tumor efficacy in Caki-1 xenograft model. Isolated blocking of FGFR1 by low-dose antibody could be safe and effective.

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Dkk-3, a Secreted Wnt Antagonist, Suppresses Tumorigenic Potential and Pulmonary Metastasis in Osteosarcoma

Sarcoma ◽

10.1155/2013/147541 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 23

Author(s):

Carol H. Lin ◽

Yi Guo ◽

Samia Ghaffar ◽

Peter McQueen ◽

Jonathan Pourmorady ◽

...

Keyword(s):

Cell Lines ◽

Negative Impact ◽

Xenograft Model ◽

Pulmonary Nodules ◽

Cellular Motility ◽

Control Vector ◽

Orthotopic Xenograft Model ◽

Tumorigenic Potential

Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the past 2 decades. Dickkopf-3 protein (Dkk-3/REIC) has been known to inhibit canonical Wnt/β-catenin pathway, and its expression has been shown to be downregulated in OS cell lines. Usingin vivoandin vitrostudies, we demonstrated that Dkk-3-transfected 143B cells inhibited tumorigenesis and metastasis in an orthotopic xenograft model of OS. Inoculation of Dkk-3-transfected 143B cell lines into nude mice showed significant decreased tumor growth and less metastatic pulmonary nodules (88.7%) compared to the control vector.In vitroexperiments examining cellular motility and viability demonstrated less anchorage-independent growth and decreased cellular motility for Dkk-3-transfected 143B and SaOS2 cell lines compared to the control vector. Downstream expressions of Met, MAPK, ALK, and S1004A were also downregulated in Dkk-3-transfected SaOS2 cells, suggesting the ability of Dkk-3 to inhibit tumorigenic potential of OS. Together, these data suggest that Dkk-3 has a negative impact on the progression of osteosarcoma. Reexpressing Dkk-3 in Dkk-3-deficient OS tumors may prove to be of benefit as a preventive or therapeutic strategy.

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Prevalence of 5-Lipoxygenase Expression in Canine Osteosarcoma and the Effects of a Dual 5-Lipoxygenase/Cyclooxygenase Inhibitor on Osteosarcoma Cells In Vitro and In Vivo

Veterinary Pathology ◽

10.1177/0300985811432350 ◽

2012 ◽

Vol 49 (5) ◽

pp. 802-810 ◽

Cited By ~ 5

Author(s):

R. C. Goupil ◽

J. J. Bushey ◽

J. Peters-Kennedy ◽

J. J. Wakshlag

Keyword(s):

Cell Proliferation ◽

Xenograft Model ◽

Eicosatetraenoic Acid ◽

Treatment Modalities ◽

Nuclear Staining ◽

Lipoxygenase Inhibitors ◽

Canine Osteosarcoma ◽

Area Of Interest

Canine osteosarcoma is an insidious disease with few effective treatment modalities; therefore, use of pharmacologic intervention to improve mortality or morbidity is constantly sought. The use of cyclooxygenase enzyme inhibitors has been an area of interest with limited efficacy based on retrospective examination of tumor expression and in vivo cell proliferation models. Recently, examination of dual cyclooxygenase and 5-lipoxygenase inhibitors in human and canine oncology suggests that 5-lipoxygenase inhibitors may be an effective approach in vitro and during tumor induction in rodent models. Therefore, the authors decided to examine 5-lipoxygenase expression in primary canine osteosarcoma samples and have shown that approximately 65% of osteosarcomas label positive for cytoplasmic 5-lipoxygenase. Further examination of a cell culture and xenograft model shows similar 5-lipoxygenase expression. Surprisingly, a canine 5-lipoxygenase inhibitor (tepoxalin) significantly reduced cell proliferation at physiologic doses in vitro and diminished xenograft tumor growth in nude mice, suggesting that further investigation is needed. Traditionally, 5-lipoxygense leads to production of lipid mediators, such as leukotriene B4 and 5-oxo-eicosatetraenoic acid, which, when added back to the media of tepoxalin-treated cells, did not recover cell proliferation. The lack of nuclear staining in primary and xenografted tumors and the lack of response to eicoasanoids suggest that lipid mediator production is not the primary means by which tepoxalin acts to alter proliferation. Regardless of the mechanisms involved in retarding cell proliferation, future investigation is warranted.

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Enhanced Anti-Tumor Effect of Folate-Targeted FA-AMA-hyd-DOX Conjugate in a Xenograft Model of Human Breast Cancer

Molecules ◽

10.3390/molecules26237110 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7110

Author(s):

Tian-tian Liao ◽

Jiang-fan Han ◽

Fei-yue Zhang ◽

Ren Na ◽

Wei-liang Ye

Keyword(s):

Breast Cancer ◽

Nude Mice ◽

Folate Receptor ◽

Xenograft Model ◽

Maximum Tolerated Dose ◽

Therapeutic Drug ◽

Antitumor Effects ◽

Tumor Bearing

Folate-aminocaproic acid-doxorubicin (FA-AMA-hyd-DOX) was firstly synthesized by our group. It was indicated that FA-AMA-hyd-DOX was pH-responsive, and had strong cytotoxicity on a folate receptor overexpressing cell line (KB cells) in vitro. The aim of our study was to further explore the potential use of FA-AMA-hyd-DOX as a new therapeutic drug for breast cancer. The cellular uptake and the antiproliferative activity of the FA-AMA-hyd-DOX in MDA-MB-231 cells were measured. Compared with DOX, FA-AMA-hyd-DOX exhibited higher targeting ability and cytotoxicity to FR-positive tumor cells. Subsequently, the tissue distribution of FA-AMA-hyd-DOX was studied, and the result confirmed that DOX modified by FA can effectively increase the selectivity of drugs in vivo. After determining the maximum tolerated dose (MTD) of FA-AMA-hyd-DOX in MDA-MB-231 tumor-bearing nude mice, the antitumor effects and the in vivo safety of FA-AMA-hyd-DOX were systematically evaluated. The data showed that FA-AMA-hyd-DOX could effectively increase the dose of DOX tolerated by tumor-bearing nude mice and significantly inhibit MDA-MB-231 tumor growth in vivo. Furthermore, FA-AMA-hyd-DOX treatment resulted in almost no obvious damage to the mice. All the positive data suggest that FA-targeted FA-AMA-hyd-DOX is a promising tumor-targeted compound for breast cancer therapy.

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STEM-15. SerpinB3 DRIVES CANCER STEM CELL SURVIVAL IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.089 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi24-vi24

Author(s):

Adam Lauko ◽

Soumya M Turaga ◽

Josephine Volovetz ◽

Defne Bayik ◽

Shideng Bao ◽

...

Keyword(s):

Cell Death ◽

Protease Inhibitor ◽

Cysteine Protease ◽

Xenograft Model ◽

Standard Of Care ◽

Therapeutic Interventions ◽

Cysteine Protease Inhibitor ◽

Orthotopic Xenograft Model

Abstract Despite therapeutic interventions for glioblastoma (GBM), self-renewing, therapy-resistant populations of cells referred to as cancer stem cells (CSCs) drive recurrence. Previously, we identified the unique expression of junctional adhesion molecule-A (JAM-A) on CSCs and demonstrated that JAM-A is both necessary and sufficient for self-renewal and tumor growth. Moreover, we determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcription factor activity; however, the entire signaling network has yet to be fully elucidated. To further delineate this pathway, we immunoprecipitated JAM-A from patient-derived GBM CSCs and performed mass spectrometry to determine JAM-A binding proteins. This led to the identification of the cysteine protease inhibitor SerpinB3 as a putative JAM-A binding partner. Using in vitro CSC functional assays, we show that SerpinB3 is necessary for CSC maintenance and survival. In an in vivo orthotopic xenograft model, knockdown of SerpinB3 extended survival. Mechanistically, knockdown of SerpinB3 led to decreased expression of TGF-β, Myc, WNT, and Notch signaling, known regulators of the CSC state. Additionally, knockdown of SerpinB3 increases susceptibility to radiation therapy. SerpinB3 is essential for buffering cells against cathepsin-mediated cell death, and we found that elevated lysosomal membrane permeability after radiation leads to cathepsin release into the cytoplasm. As a result, SerpinB3 knockdown cells have a diminished capacity to inhibit cathepsin-driven cell death after radiation. The addition of the cathepsin inhibitor E64D partially rescues the SerpinB3 knockdown, however, SerpinB3 mutants that are unable to inhibit cathepsins fail to do the same. Taken together, our findings, identify a novel GBM CSC-specific survival mechanism involving a previously uninvestigated cysteine protease inhibitor, SerpinB3, and provide a potential target to increase the efficacy of standard of care GBM therapies against therapy-resistant CSCs.

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OS6.2 Loss of CYP46A1 directs altered cholesterol homeostasis and opens therapeutic opportunities for glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/noz126.040 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii12-iii12

Author(s):

M Han ◽

S Wang ◽

X Li ◽

J Wang ◽

R Bjerkvig

Keyword(s):

Tumour Growth ◽

Cholesterol Metabolism ◽

Ectopic Expression ◽

Xenograft Model ◽

Cholesterol Homeostasis ◽

Normal Brain ◽

Genomic Databases ◽

Orthotopic Xenograft Model

Abstract BACKGROUND Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol through conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. MATERIAL AND METHODS Molecular and clinical data was obtained from publicly genomic databases. Immunohistochemistry was applied to assess protein levels of CYP46A1 in primary GBM samples. Lentiviral constructs expressing CYP46A1 were transduced into LN229, LN18 and primary GBM GSCs for functional assays carried out in vitro and in vivo in an orthotopic xenograft model. RNA-seq was performed to identify downstream targets of 24OHC. RESULTS CYP46A1 was significantly decreased in GBM samples compared to normal brain tissue. Reduced CYP46A1 expression was associated with increasing tumour grade and poor prognosis in GBM patients. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. Treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz (EFV), an activator of CYP46A1 with BBB penetration, inhibited GBM growth in vivo. CONCLUSION Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.

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Ribosomal Protein S27-Like is overexpressed in glioma cells and inhibition of RPS27L expression suspends the tumorigenesis

10.21203/rs.3.rs-49193/v2 ◽

2020 ◽

Author(s):

Zhongzheng Sun ◽

Hao Xue ◽

Yan Wei ◽

Shaobo Wang ◽

Jianye Xu ◽

...

Keyword(s):

Ribosomal Protein ◽

Xenograft Model ◽

Glioma Cells ◽

Tumor Grade ◽

Migration And Invasion ◽

Normal Brain ◽

Orthotopic Xenograft Model ◽

High Expression Group

Abstract Background: Ribosomal Protein S27-Like is an evolutionarily conserved ribosomal protein and the role of RPS27L influencing the malignance of several cancers has been reported. However, its effects on glioma were still unknown. This investigation aims to characterize the clinical significance and the biological functions of RPS27L in gliomas.Methods: TCGA databases were explored to analyze the correlation between RPS27L expression and the clinical characteristics of glioma patients. Immunohistochemical staining was performed on glioma cases and normal brain tissues. The function of RPS27L in glioma was further explored using U87MG and A172 cell lines and a orthotopic xenograft model of nude mice.Results: Data obtained from TCGA database showed higher expression of RPS27L in glioma than normal, and the overall survival was lower in the high expression group. Immunohistochemistry showed the expression levels of RPS27L were increased with the tumor grade rising in gliomas. Functional assays showed knockdown of RPS27L inhibited proliferation, cell cycle transition, migration and invasion, while promoted apoptosis. Data of western blot indicated that knockdown of RPS27L increased the level of p21，Bax and Cleaved Caspase-3 while decreased the level of CDK4, cyclinD1, cyclinE1, Bcl-2 and MMP2, MMP9 in glioma cells. In vivo, the growth of orthotopic glioma xenografts was suppressed by expression of RPS27L shRNA, and the tumors with RPS27L shRNA showed less aggressiveness and reduced expression of Ki67, Bcl-2 and MMP2. Conclusions: RPS27L is overexpressed in glioma cells. Knockdown of RPS27L could inhibit the proliferation, migration and invasion while promote apoptosis of glioma cells in vitro and in vivo. RPS27L might be a potential prognostic biomarker and possible target for future therapy in glioma.

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Ribosomal Protein S27-Like is overexpressed in glioma cells and inhibition of RPS27L expression suspends the tumorigenesis

10.21203/rs.3.rs-49193/v1 ◽

2020 ◽

Author(s):

Zhongzheng Sun ◽

Hao Xue ◽

Yan Wei ◽

Shaobo Wang ◽

Jianye Xu ◽

...

Keyword(s):

Ribosomal Protein ◽

Xenograft Model ◽

Glioma Cells ◽

Tumor Grade ◽

Migration And Invasion ◽

Normal Brain ◽

Orthotopic Xenograft Model ◽

High Expression Group

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Targeted Radioimmunotherapy Using Anti-CD45 Antibody-Mediated Delivery Of An In Vivo Nanoparticle-Based Alpha Generator In a Xenograft Model Of Human Leukemia

Blood ◽

10.1182/blood.v122.21.2908.2908 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2908-2908

Author(s):

Aimee L. Kenoyer ◽

Alexandra H. Hernandez ◽

Mazyar Shadman ◽

Mark McLaughlin ◽

David Robertson ◽

...

Keyword(s):

Hematopoietic Cell Transplantation ◽

Xenograft Model ◽

Treatment Modalities ◽

Human Leukemia ◽

Malignant Cells ◽

The Core ◽

Nanoparticle Core ◽

Α Particles

Abstract Introduction Acute Myeloid Leukemia (AML) relapse rates remain high despite treatment with combination chemotherapy and hematopoietic cell transplantation. New targeted treatment modalities including radioimmunotherapy (RIT) have been developed to reduce relapse. However, minimally toxic means of targeting AML cells for delivery of radionuclides may not be optimal for all therapeutically favorable isotopes. Alpha (α) particles have a higher linear energy transfer and shorter path length in contrast to beta (β) particles, thus leading to the promising exploration of α-particle RIT for AML. Treatment efficacies may be further improved by the use of in vivo α-generators such as 225Ac, which emits a total of 4 α-particles upon decay. However, targeted therapy utilizing traditional 225Ac chelates poses a challenge since the α-emitting daughter radionuclides while short-lived, are difficult to retain near the targeted malignant cells and may be released into circulation, leading to unwanted non-specific toxicities such as to the renal or hepato-biliary systems. Methods To improve the therapeutic potential of 225Ac-based RIT for AML and reduce toxicities we have developed an anti-CD45 antibody (Ab)-conjugated gold-coated lanthanide phosphate nanoparticle that contains multiple gadolinium (Gd) shells designed to sequester 225Ac in the core and retain the α-daughters within the nanoparticle. Previous work demonstrated the in vivo retention of the 221Fr daughter radionuclide of over 90% for at least 3 weeks past the core nanoparticle synthesis. In this work the nanoparticle core was first synthesized using LaCl3 and GdCl3 using 177Lu as a radioactive surrogate for 225Ac. Four consecutive GdPO4 layers were added to the lanthanide core, followed by NaAuCl4 to form a metallic gold coat. Anti-human CD45 Ab (BC8) was separately labeled with 125I and then conjugated to the gold coat of the nanoparticle via a polyethylene glycol linker. This dual-labeled approach allowed for verification of stability of the Ab-nanoparticle. A competitive binding flow cytometry assay was used to measure the efficiency of the Ab conjugation to the nanoparticle and determine the concentration of Ab in solution. In vivo targeting of the Ab-nanoparticle was initially tested in athymic nude mice bearing human AML xenografts by injection with 50 µCi 177Lu-anti-CD45 Ab-nanoparticle at 100 µg per dose of Ab injected. Results Nanoparticle-BC8 dual-labeled with 177Lu and 125I bound effectively in vitro to human AML cells (HEL) with an increase in mean fluorescence index (MFI) of 9.2-fold compared to non-binding isotype control. Labeled nanoparticle-BC8 also effectively bound to human Burkitt’s lymphoma Ramos and Raji cells with an increased MFI of 86- and 36-fold compared to control, respectively. A 96-well plate-based assay for cell binding to test radioactive conjugates was also employed to verify that anti-CD45 Ab-nanoparticle remained stable in vitro. Non-conjugated BC8 effectively blocked binding of 125I-BC8-conjugated 177Lu-nanoparticle to Ramos cells in comparison with control with a reduction in binding by 21.3 % with respect to 125I-BC8 (p = 0.016) and 20.2 % with respect to the 177Lu-NP core (p = 0.026). 125I-labeled nanoparticle-BC8 conjugate bound effectively in vivo to human leukemia xenografts. Favorable targeting to sites of disease was seen by 4 hours post-injection, with 18.0 ±2.9 % injected dose per gram of targeting Ab in the tumor. Conclusion Combined nanoparticle-antibody therapy is a promising, novel approach to target malignant cells. Antibody-mediated delivery of α-particle generators represents a potential solution for the difficulties of safe and effective targeting using 225Ac, largely nonspecific toxicities due to dispersal of α-particle daughters. We have shown that 177Lu is a useful surrogate for 225Ac for preliminary characterization assays, and that 177Lu is retained over time in the nanoparticle core. We have shown in vitro targeting of leukemia and lymphoma cells and have made strides towards obtaining a favorable biodistribution in a model of human AML. However, challenges remain as liver uptake by nanoparticles cleared through the reticuloendothelial system is unfavorable and may cause dose-limiting toxicities. Future work will further characterize nanoparticle-Ab conjugates and progress toward studies involving 225Ac for AML therapy. Disclosures: Press: Genentech, inc.: Consultancy, Research Funding.

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KYP-2047, an Inhibitor of Prolyl-Oligopeptidase, Reduces GlioBlastoma Proliferation through Angiogenesis and Apoptosis Modulation

Cancers ◽

10.3390/cancers13143444 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3444

Author(s):

Sarah Adriana Scuderi ◽

Giovanna Casili ◽

Alessio Ardizzone ◽

Stefano Forte ◽

Lorenzo Colarossi ◽

...

Keyword(s):

Xenograft Model ◽

In Vitro Study ◽

Potential Effect ◽

Tumor Burden ◽

Vitro Study ◽

Prolyl Oligopeptidase ◽

Reduce Tumor Burden ◽

Apoptosis Pathways

Glioblastoma (GB) is the most aggressive tumor of the central nervous system (CNS), characterized by excessive proliferation, necrosis and invasiveness. The survival rate for patients with GB still remains low. Angiogenesis and apoptosis play a key role in the development of GB. Thus, the modulation of angiogenesis and apoptosis processes represent a possible strategy to counteract GB progression. This study aimed to investigate the potential effect of KYP-2047, an inhibitor of the prolyl-oligopeptidase (POP), known to modulate angiogenesis, in an in vivo U87-xenograft model and in an in vitro study on human GB cells. Our results showed that KYP-2047 at doses of 2.5 mg/kg and 5 mg/kg was able to reduce tumor burden in the xenograft-model. Moreover, KYP-2047 significantly reduced vascular endothelial-growth-factor (VEGF), angiopoietins (Ang) and endothelial-nitric-oxide synthase (eNOS) expression. In vitro study revealed that KYP-2047 at different concentrations reduced GB cells’ viability. Additionally, KYP-2047 at the concentrations of 50 µM and 100 µM was able to increase the pro-apoptotic protein Bax, p53 and caspase-3 expression whereas Bcl-2 expression was reduced. Thus, KYP-2047 could represent a potential therapeutic treatment to counteract or reduce GB progression, thanks its abilities to modulate angiogenesis and apoptosis pathways.

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