scholarly journals Combining chloroquine with RAD001 inhibits tumor growth in a NEN mouse model

2018 ◽  
Vol 25 (6) ◽  
pp. 677-686 ◽  
Author(s):  
Shani Avniel-Polak ◽  
Gil Leibowitz ◽  
Victoria Doviner ◽  
David J Gross ◽  
Simona Grozinsky-Glasberg
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Mtor Inhibitors ◽  
Degradation Pathway ◽  
Neuroendocrine Neoplasms ◽  
Histopathological Analysis ◽  
Anti Cancer ◽  
Subcutaneous Xenograft ◽  
Rheumatic Drug

Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 in vivo by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.

scholarly journals The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Diana Spiegelberg ◽  
Andris Abramenkovs ◽  
Anja Charlotte Lundgren Mortensen ◽  
Sara Lundsten ◽  
Marika Nestor ◽  
...  
Keyword(s):  
Tumor Growth ◽  
External Beam Radiotherapy ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Control Group ◽  
A431 Cells ◽  
Anti Cancer ◽  
Client Proteins

AbstractOncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 × 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 × 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.

A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion

2010 ◽  
Vol 99 (2) ◽  
pp. 165-176 ◽  
Author(s):  
Laura M. Shelton ◽  
Purna Mukherjee ◽  
Leanne C. Huysentruyt ◽  
Ivan Urits ◽  
Joshua A. Rosenberg ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Mouse Model ◽  
Tumor Growth ◽  
Malignant Brain Tumor ◽  
Tumor Growth And Invasion

[18F]FLT Is Superior to [18F]FDG to Early Predict Response to Specific Inhibitors of NPM-ALK-Dependent Pathways In a Human ALCL Xenograft Model

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2849-2849
Author(s):  
Nicolas Graf ◽  
Zhoulei Li ◽  
Ken Herrmann ◽  
Alexandra Junger ◽  
Daniel Weh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Growth ◽  
Fdg Pet ◽  
Xenograft Model ◽  
Large Cell ◽  
Histopathological Analysis ◽  
Lymphoma Cells ◽  
Flt Pet

Abstract Abstract 2849 Purpose: The thymidine analogue [18F]fluorothymidine (FLT) has been shown to reflect proliferation of high-grade lymphoma cells both in preclinical and clinical studies. In this preclinical in vitro and in vivo study we assessed early FLT-uptake as an adequate and robust surrogate marker for response to inhibitors of Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-dependent pathways in an anaplastic large cell lymphoma (ALCL) xenotransplant model. Methods: In vitro investigations included viability assessment (MTT assay), cell cycle analysis using propidium iodide staining and western blotting to characterize response of the ALCL cell lines SUDHL-1 and Karpas299 to treatment with heat shock protein 90 (Hsp90) inhibitor NVP-AUY922, the Phosphoinositide 3-kinase (PI3K) inhibitor BGT226 or the mammalian target of rapamycin (mTOR) inhibitor RAD001. Thymidine metabolism in severe combined immunodeficient (SCID) mice bearing SUDHL-1 or Karpas 299 lymphoma xenotransplants was assessed non-invasively prior to and early in the course of therapy (48h to 7 days) by FLT and FDG positron emission tomography (FLT-PET and FDG-PET) using a dedicated small animal PET system. Tumor-to-background ratios (TBR) of FLT-PET were compared to that of PET using the standard radiotracer [18F]fluorodeoxyglucose (FDG). Reference for tumor response was local control of the tumor measured by shifting calliper and histopathological analysis of explanted lymphomas. Results: In vitro, SUDHL-1 cells were sensitive to all three inhibitors (IC50 AUY922= 50 nM; IC50 BGT266= 10 nM; IC50 RAD001= 1 nM). These cells showed a dose-dependent induction of cell-cycle arrest in G1-phase and reduction of S-Phase after 24 to 48 hours and - to a lesser extent - increase of apoptosis. Incubation of SUDHL-1 cells with NVP-AUY922 (50 nM) for 24 hours led to a 70% reduction of ALK level and a abrogation of Akt phosphorylation as determined by western blot analysis. Likewise, no phosphorylation of Akt was detectable after incubation with BGT266 (10 nM) already after 4 hours. RAD001 (0.1-1nM, 24h) completely inhibited phosphorylation of p70 S6K. In contrast, Karpas299 cells were only sensitive to RAD001-induced cell cycle arrest, but insensitive to NVP-AUY922 and BGT266. In vivo, we performed FLT- and FDG-PET scans to monitor inhibition of tumor growth in the course of therapy with NVP-AUY922. Tumor volume in treated animals bearing SUDHL-1 lymphomas showed modest increase within the first week (median increase= + 25%, range -30% to + 80%, n=8) as opposed to a 3.8-fold increase in untreated control animals. After 14 days a clear reduction of tumor mass could be observed (median= - 25%, range -40% to + 30%, n=4). Median TBR of FLT-PET decreased significantly to 40% compared to baseline as earlier as 5 days after initiation of therapy (range 32–67%, n=8, p=0,008). In contrast, the pattern of TBR in FDG-PET did not show any clear tendency (median TBR 79%, range 36%-161%, n=8, p=0,73). We then investigated the ability of FLT-PET to differentiate between sensitive and resistant lymphoma cells. Therefore, mice bearing Karpas299 lymphomas were treated with NVP-AUY922 (resistant in vitro) or RAD001 (sensitive in vitro). According to our in vitro results, no effect was seen during treatment with NVP-AUY299 as indicated by about 3-fold tumor growth on day 7 and increase of median TBR in FLT-PET to 162% (range 106–177%, p=0,008, n=8) on day 2. In contrast, mice receiving RAD001 showed a deceleration of tumor development with doubling of tumor volume within the first week (range -20% to + 320%, n=10) that remained fairly constant over the following weeks. FLT-PET imaging indicated a slight increase of TBR correctly reflecting tumor growth kinetics (median=126%, range 60–129%, no p-value). A larger cohort is currently investigated as well as histopathological analysis of explanted lymphomas. The updated data will be presented at the meeting. Conclusion: In contrast to FDG-PET, FLT-PET is able to predict response to specific inhibitors early in the course of the therapy using a anaplastic large cell lymphoma xenograft model and is able to distinguish between sensitive and resistant lymphoma cells. Disclosures: No relevant conflicts of interest to declare.

Establishment of Bioluminescence Imaging Based Leukemia In Vivo Model for Preclinical Testing

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4879-4879
Author(s):  
Myoung Woo Lee ◽  
Hye Jin Kim ◽  
Dae Seong Kim ◽  
Meong Hi Son ◽  
Soo Hyun Lee ◽  
...  
Keyword(s):  
Animal Model ◽  
Mouse Model ◽  
Drug Screening ◽  
Scid Mouse ◽  
Lymphoblastic Leukemia ◽  
Cancer Drug ◽  
Screening System ◽  
Bioluminescent Signal ◽  
Anti Cancer

Abstract Abstract 4879 Background. A hematological malignant animal model is an essential tool for evaluating efficacy of anti-cancer drugs and elucidating underlying mechanism of leukemogenesis. Intraperitoneal (IP) and intravenous (IV) xenograft of acute lymphoblastic leukemia (ALL) cells have limited capacity as in vivo anti-cancer drug screening system. Purpose. In this study, we aimed to establish an ALL animal model using NOD/SCID mouse and evaluate efficiency and sensitivity of the model as a preclinical drug screening system. Materials and Methods. Firefly luciferase (fLuc)-gene introduced ALL (ALL/fLuc) cell line and patient-originated ALL cells were transplanted into a tibia of NOD/SCID mouse. We conducted a comparative analysis of intra-bone marrow (IBMT) transplanted leukemia model with IP and IV transplantation of leukemic cells. Results. IBMT of ALL/fLuc cells effectively established a bioluminescent leukemia NOD/SCID mouse model. Upon comparison of IBMT model with IP and IV transplantation models, infusing identical number of ALL/fLuc cells into NOD/SCID mice resulted in IBMT model with evaluable bioluminescent signal, but not in IP and IV models. In IBMT model, bioluminescent signals of ALL/fLuc cells emitted from peripheral blood, tibia and infiltrated organs indicated that leukemia model was established. The changes in these signals' strength reflected dose-dependent cytotoxic effects of vincristine, which allowed leukemia model with evaluable bioluminescent signal to be utilized as a preclinical drug screening system. IBMT leukemia model was also established using primary ALL cells that can provide additional insights for the development of leukemia therapeutics. Conclusion. IBMT of ALL/fLuc cells enables development of leukemia mouse model with the greater bioluminescent sensitivity than IP and IV in NOD/SCID to evaluate candidate for development of anti-cancer drug. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Thyroxine promotes lung cancer growth in an orthotopic mouse model

2019 ◽  
Vol 26 (6) ◽  
pp. 565-574 ◽  
Author(s):  
S Latteyer ◽  
S Christoph ◽  
S Theurer ◽  
G S Hönes ◽  
K W Schmid ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Plasma Membrane ◽  
Thyroid Hormone ◽  
Mouse Model ◽  
Tumor Growth ◽  
Hormone Receptors ◽  
Cancer Growth ◽  
Orthotopic Mouse Model ◽  
Tumor Weight

Thyroid hormones are important for physiology and homeostasis. In addition to nuclear thyroid hormone receptors, the plasma membrane protein integrin αvβ3 has been recognized as a receptor for both thyroxine (T4) and triiodothyronine (T3). Here, we studied whether thyroid hormone promotes growth of murine lung cancer via αvβ3 in vivo. Murine Lewis lung carcinoma cells (3LL), stably transfected with luciferase, were injected into mouse lungs. Tumor growth in untreated mice was compared to hypothyroid mice and hypothyroid mice treated with T3 or T4 with or without the αvβ3 inhibitor 3,5,3′,5′-tetraiodothyroacetic acid (Tetrac). Tumor progression was determined by serial in vivo imaging of bioluminescence emitted from the tumor. Tumor weight was recorded at the end of the experiment. Neoangiogenesis was determined by immunohistochemistry for CD31. Tumor growth was reduced in hypothyroidism and increased by T4 treatment. Strikingly, only T4 but not T3 treatment promoted tumor growth. This T4 effect was abrogated by the αvβ3 inhibitor Tetrac. Tumor weight and neoangiogenesis were also significantly increased only in T4-treated mice. The T4 effect on tumor weight and neoangiogenesis was abolished by Tetrac. In vitro, T4 did not stimulate 3LL cell proliferation or signaling pathway activation. We conclude that T4 promotes lung cancer growth in this orthotopic mouse model. The tumor-promoting effect is mediated via the plasma membrane integrin αvβ3 and increased neoangiogenesis rather than direct stimulation of 3LL cells. These data suggest that such effects of levothyroxine may need to be considered in cancer patients on T4 substitution.

scholarly journals Combination Therapy of a Host Defense-Like Lytic Peptide and Continuous Low-Dose Doxorubicin Inhibits Tumor Growth in a Syngeneic Immunocompetent Murine Fibrosarcoma (BFS-1) Model

2020 ◽  
Author(s):  
Jan Philip Suppelna ◽  
Kamran Harati ◽  
Andrea Rittig ◽  
Ingo Stricker ◽  
Markus Lehnhardt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Cell Line ◽  
Host Defense ◽  
Low Dose ◽  
Sarcoma Cell ◽  
Fibrosarcoma Cell ◽  
Murine Fibrosarcoma

Abstract Background: The concept of a multimodality therapy in the treatment of soft tissue sarcomas (STS) has been discussed with controversy. Surgical resection with clear margins and radiation therapy remain gold standard in STS therapy. It is still questionable whether a systemic therapy with chemotherapeutics has a positive impact on the overall survival rate especially in early stages of disease, because the therapeutic effect in the treatment of STS is limited by its toxicities and its low responding rates. Treatment options are rare. As a result the search for combination therapies by using low dose approaches is of high importance. Recent studies showed the therapeutic efficiency of a designer host defense-like lytic D,L- amino acid peptide [D]-K 3 H 3 L 9 . Therefore we tested a combination of this peptide with Doxorubicin on two different sarcoma cell lines in vitro and also in a syngeneic immunocompetent murine fibrosarcoma mouse model. Methods: In vitro the human synovial sarcoma cell line SW 982 and the murine fibrosarcoma cell line BFS-1 were exposed to the oncolytic peptide [D]-K 3 H 3 L 9 , to the Anthracycline Doxorubicin and to both agents simultaneously. In vivo the murine fibrosarcoma cell line BFS-1 was injected subcutaneously into the syngeneic mice. When the tumors engrafted the oncolytic designer peptide [D]-K 3 H 3 L 9 , Doxorubicin or a combination of both was administered thrice a week for a three weeks’ follow-up. Results: The combination treatment approach using an oncolytic designer host defense peptide and Doxorubicin inhibited the in vitro sarcoma cell proliferation significantly. The single therapies, either with local intratumoral application of [D]-K 3 H 3 L 9 or with intraperitoneal application of Doxorubicin in the syngeneic mouse model, inhibited at least the tumor progression. The combination of both substances revealed a significant inhibition of tumor growth and weight. Conclusion: The in vivo low dose combination schedule inhibited the tumor growth significantly. Histological analyses of the tumor sections revealed an antiproliferative and antiangiogenic effect. So, these results demonstrate the effectiveness of combined low-dose application forms with designer host defense-like lytic peptides and chemotherapeutics.

scholarly journals Chemo-enzymatic Synthesis of Ester-Linked Docetaxel-Glycoside Conjugate and its Drug Delivery System Using Hybrid-Bio-Nanocapsules Targeted With Trastuzumab and Cetuximab

2019 ◽  
Vol 14 (6) ◽  
pp. 1934578X1985880
Author(s):  
Yuya Fujitaka ◽  
Hiroki Hamada ◽  
Hatsuyuki Hamada ◽  
Noriyoshi Masuoka ◽  
Kei Shimoda ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Tumor Growth ◽  
Drug Delivery System ◽  
Delivery System ◽  
Enzymatic Synthesis ◽  
Effective Suppression ◽  
Anti Cancer ◽  
Cancer Activity

Synthesis of ester-linked glucoside conjugate of docetaxel, 7-propionyldocetaxel 3''- O-α-D-glucopyranoside, was carried out by chemo-enzymatic procedures. The EE and LE values for hybrid-bio-nanocapsules of 7-propionyldocetaxel 3''- O-α-D-glucopyranoside were much improved rather than those of docetaxel. The hybrid-bio-nanocapsules targeted with trastuzumab and cetuximab, which contained 7-propionyldocetaxel 3''- O-α-D-glucopyranoside, showed high in vivo anti-cancer activity, ie, effective suppression of tumor growth, respectively.

scholarly journals OR06-02 TBR-760, a Chimeric Somatostatin-Dopamine Compound, Arrests Aggressive Non-Functioning Pituitary Adenoma Growth In Vivo

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Heather A Halem ◽  
Ute Hochgeschwender ◽  
Arunthi Thiagalingam ◽  
Michael D Culler
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Pituitary Adenomas ◽  
Initial Study ◽  
Mouse Tumors ◽  
Inhibition Of Tumor Growth ◽  
Null Mutant Mice ◽  
The Individual

Abstract TBR-760 is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R; EC50 0.064nM) and SST type 2 (SSTR2; EC50 1.2nM) receptors. Prior studies have demonstrated that the chimeric DA-SST compounds are more potent and effective than either individual or combinations of individual DA and/or SST analogs in inhibiting secretion from pituitary adenomas. Non-functioning pituitary adenomas (NFPA) express high levels of D2R as well as lower levels of SSTRs, including the type 2 receptor (1), and thus have an appropriate receptor profile to respond to TBR-760. The present study examines the ability of TBR-760 to inhibit tumor growth in a mouse model of aggressive NFPA. Heterozygous and null mutant mice lacking one or both copies, respectively, of the pro-opiomelanocortin (POMC) gene (POMC-KO mice)(2) spontaneously develop aggressive, non-secreting pituitary adenomas (3). The POMC-KO mouse tumors have been shown to express D2R and SSTR2 at a similar level as human NFPAs (4). In addition, merging of microarray data (Affymetrix, U133 plus_2.0 and Mouse Genome 430 2.0 arrays), reveals 154 common gene signatures between human NFPAs and the POMC-KO mouse tumors. In an initial study, heterozygous POMC-KO mice with an established pituitary tumor of approx. 10mm3 (mean volume 8.9±0.3), as determined by MRI, were treated with a range of TBR-760 doses (0.125 to 12.5mg/kg, sc, QD) for 60 days. During that time, tumors in vehicle-treated mice increased in size by 890±0.7%, whereas all doses of TBR-760 tested resulted in a nearly complete inhibition of tumor growth from treatment initiation. We then compared the effect of the TBR-760 chimera with that of its individual SST agonist (SSTA) and DA agonist (DAA) components on tumor growth in the POMC-KO mice. As in the earlier study, TBR-760 treatment (1mg/kg, sc, QD), initiated when the mice had an established tumor of approx. 10mm3, completely arrested tumor growth during the 8 weeks of treatment (final mean tumor volume of 8.5±1.3mm3 vs. 54.61±10.6mm3 in vehicle-treated mice). Treatment with equimolar or 10x-higher doses of the individual SSTA or DAA, either alone or in combination, had no significant effect on tumor growth, except in the lower dose DAA group where a modest suppression of tumor growth was observed. These data demonstrate that only the dual DA-SST chimeric compound, TBR-760, completely arrested tumor growth in the POMC-KO mouse model of NFPA. Further, despite the highly aggressive nature of the POMC-KO tumors, significant tumor shrinkage was observed in 20% of the mice treated with TBR-760. These results support the development of TBR-760 as a medical therapy to prevent or arrest the growth of NFPAs and, potentially, to induce NFPA shrinkage. References: (1) Florio et al., 2008 Endocr Relat Cancer; 15: 583-596. (2) Yaswen et al., 1999 Nat Med; 9:1066-70 (3) Karpac J et al., 2006 Cell Mol Biol; 52: 47-52.

Effect of AdipoR agonist in cholangiocarcinoma.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 323-323
Author(s):  
Khac Cuong Bui ◽  
Mai Ly Thi Nguyen ◽  
Samarpita Barat ◽  
Xi Chen ◽  
Vikas Bhuria ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Cell Lines ◽  
Colony Formation ◽  
Tumor Burden ◽  
Potential Candidate ◽  
Anti Cancer ◽  
Apoptosis Assay

323 Background: Adiponectin is the key adipokine, which plays an important role in health and disease such as obesity, diabetes, and cancer. Adiponectin is reduced in different tumor types, especially in obesity-related cancer, and recent studies showed that Adiponectin had a potential anti-cancer effect. Obesity is a risk factor for various tumor diseases including cholangiocarcinoma (CC), the second most common primary hepatic cancer. The aim of this study is to investigate for the first time the anti-cancer effect of AdipoR agonist in CC cell lines and a CC engineered mouse model. Methods: Human CC cell lines (TFK-1 and SZ-1) and CC engineered mice (Alb-Cre/KRASG12D/p53L/L) were used to investigate the anti-cancer effects of an AdipoR agonist (2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide). Cell proliferation, migration, invasion, colony formation, apoptosis assay were applied to evaluate the effect of AdipoR agonist in vitro. In addition, important cancer signalling pathways and targets were analysed by Western Blot. Mice (n = 12) were treated with AdipoR or verhicle and tumor burden and survival were monitored. Results: AdipoR agonist suppressed proliferation, migration, invasion, colony formation and apoptosis in CC cells. AdipoR agonist regulated the expression of different proteins such as EMT markers, pAMPK, pSTAT3, and PARP, which have pivotal functions in cholangiocarcinogenesis. AdipoR agonist also prolonged survival time in a CC engineered mouse model. Conclusions: Our data revealed that AdipoR agonist inhibited successfully cell proliferation, migration, invasion, colony formation and apoptosis in vitro, and prolonged mice survival in vivo through regulation of crucial signaling pathways in cholangiocarcinogenesis. These results suggested that AdipoR agonist might become a new potential candidate for CC treatment in the future.

Intra-vesical therapy using 4N1K-peptide in bladder cancer and its effects on tumor growth and angiogenesis.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 446-446
Author(s):  
Yasuyoshi Miyata ◽  
Kyohei Araki ◽  
Tsutomu Yuno ◽  
Yuichiro Nakamura ◽  
Yuji Sagara ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Morphological Characteristics ◽  
Intravesical Therapy ◽  
Transfected Cells ◽  
T24 Cells ◽  
Mouse Tissues ◽  
Anti Cancer

446 Background: The 4N1K-peptide (KRFYVVMWKK), which is derived from thrombospondins has anti-cancer activities in several cancers. We previously found that 4N1K-peptide expression was negatively associated with tumor invasion and prognosis in patients with bladder cancer (BC). The main aim of this study is to clarify whether intravesical therapy using 4N1K-peptide has anti-cancer effects in BC by in vivo and in vitro studies. Methods: Change in tumor growth and apoptosis due to transfection of 4N1K-peptide were evaluated in the BC cell line, T24 cells. Next, to clarify the anti-cancer effects of 4N1K-peptide as intra-vesical therapy, cell survival, apoptosis, and microvessel density (MVD) were investigated in chemical (BBN)-induced BC mouse model. In this study, natural saline (Ns) and 4NGG-peptide which has a similar structure to 4N1K-peptide but does not have any biological activity were used. In addition, survival analyses are performed in these mouse model. Results: In T24 cells, mean/SD of AI in 4N1K-peptide-transfected cells was 7.9/1.1%, which was remarkably higher (P < 0.001) than that in 4NGG-peptide-transfected cells (1.6 / 0.2%). In mouse model, 7 of the 20 mice treated with Ns died because of cancer-related symptoms, and invasive cancer was detected in 9/13 (69.2%). In contrast, in mice treated with 4N1K-peptide, 1 of 15 mice was died and invasive disease was observed in 1/14 (7.1%) at 24 weeks of age. Kaplan-Meier survival cures showed mice treated with 4N1K-intarvesical therapy had better prognosis compared to others (P = 0.036). In mouse tissues, apoptotic index in mice treated with 4N1K-peptide was significantly higher (P < 0.01) than that in others. In contrast, MVD in mice with 4N1K-peptide was significantly lower (P < 0.05) compared to others. In normal urothelium of mouse treated with 4N1K-peptide, change of morphological characteristics was not detected. Conclusions: 4N1K-peptide played as tumor-suppressor by regulating apoptosis and angiogenesis in BC animal model. Therefore, there is the possibility that 4N1K-peptide is a potential useful and safety therapeutic agent for intra-vesical therapy in BC patients.

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