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Polo-like kinase 1 (PLK1), which is crucial in cell cycle regulation, is considered a promising anticancer drug target. Herein, we present the N-degron pathway-based proteolysis targeting chimera (PROTAC) for PLK1 degradation, targeting the Polo-box domain (PBD). We identified DD-2 as the most potent PROTAC that selectively induces PLK1 degradation in cancer cells, including HeLa and nonsmall cell lung cancer (NSCLC), through the N-degron pathway. DD-2 exhibited significant in vitro anticancer effects, inducing G2/M arrest and apoptosis in HeLa and NSCLC cell lines. DD-2 showed significant tumor growth inhibition in a xenograft mouse model using HeLa and NSCLC cell lines, highlighting its potential in cancer treatment. Furthermore, the combination of DD-2 with tyrosine kinase inhibitor (TKI), osimertinib, effectively suppressed tumor growth in double-mutated H1975 cell lines, emphasizing DD-2's potential in combination cancer therapies. Collectively, this study demonstrates the potential of the N-degron pathway, especially using DD-2, for targeted cancer therapies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular , Quimera de Direcionamento de Proteólise , Proteínas Serina-Treonina Quinases , Quinase 1 Polo-Like , Apoptose , Degrons , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pontos de Checagem da Fase G2 do Ciclo Celular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
The immunogenicity of a heterologous vaccination regimen consisting of ChAdOx1 nCoV-19 (a chimpanzee adenovirus-vectored vaccine) followed by mRNA-1273 (a lipid-nanoparticle-encapsulated mRNA-based vaccine) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), specifically the omicron variant (B.1.1.529), is poorly studied. The aim of this study was to evaluate the neutralizing antibody activity and immunogenicity of heterologous ChAdOx1 nCoV-19 and mRNA-1273 prime-boost vaccination against wild-type (BetaCoV/Korea/KCDC03/2020), alpha, beta, gamma, delta, and omicron variants of SARS-CoV-2 in Korea. A 50% neutralizing dilution (ND50) titer was determined in serum samples using the plaque reduction neutralization test. Antibody titer decreased significantly at 3 months compared with that at 2 weeks after the 2nd dose. On comparing the ND50 titers for the above-mentioned variants of concerns, it was observed that the ND50 titer for the omicron variant was the lowest. This study provides insights into cross-vaccination effects and can be useful for further vaccination strategies in Korea.
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Introduction: The effect of tixagevimab/cilgavimab (Evusheld™; AstraZeneca, UK) should be evaluated in the context of concurrent outbreak situations. Methods: For serologic investigation of tixagevimab/cilgavimab during the BA.5 outbreak period, sera of immunocompromised (IC) hosts sampled before and one month after tixagevimab/cilgavimab administration and those of healthcare workers (HCWs) sampled one month after a 3rd shot of COVID-19 vaccines, five months after BA.1/BA.2 breakthrough infection (BI), and one month after BA.5 BI were investigated. Semi-quantitative anti-spike protein antibody (Sab) test and plaque reduction neutralizing test (PRNT) against BA.5 were performed. Results: A total of 19 IC hosts (five received tixagevimab/cilgavimab 300 mg and 14 received 600 mg) and 41 HCWs (21 experienced BA.1/BA.2 BI and 20 experienced BA.5 BI) were evaluated. Baseline characteristics did not differ significantly between IC hosts and HCWs except for age and hypertension. Sab significantly increased after tixagevimab/cilgavimab administration (median 130.2 BAU/mL before tixagevimab/cilgavimab, 5,665.8 BAU/mL after 300 mg, and 10,217 BAU/mL after 600 mg; both P < 0.001). Sab of one month after the 3rd shot (12,144.2 BAU/mL) or five months after BA.1/BA.2 BI (10,455.8 BAU/mL) were comparable with that of tixagevimab/cilgavimab 600 mg, while Sab of one month after BA.5 BI were significantly higher (22,216.0 BAU/mL; P < 0.001). BA.5 PRNT ND50 significantly increased after tixagevimab/cilgavimab administration (median ND50 29.6 before tixagevimab/cilgavimab, 170.8 after 300 mg, and 298.5 after 600 mg; both P < 0.001). The ND50 after tixagevimab/cilgavimab 600 mg was comparable to those of five months after BA.1 BI (ND50 200.9) while ND50 of one month after the 3rd shot was significantly lower (ND50 107.6; P = 0.019). The ND50 of one month after BA.5 BI (ND50 1,272.5) was highest among tested groups, but statistical difference was not noticed with tixagevimab/cilgavimab 600 mg. Conclusion: Tixagevimab/cilgavimab provided a comparable neutralizing activity against the BA.5 with a healthy adult population who were vaccinated with a 3rd shot and experienced BA.1/BA.2 BI.
Assuntos
Infecções Irruptivas , COVID-19 , Adulto , Humanos , Vacinas contra COVID-19RESUMO
Gold nanoparticles (AuNPs) have been widely used as nanocarriers in drug delivery to improve the efficiency of chemotherapy treatment and enhance early disease detection. The advantages of AuNPs include their excellent biocompatibility, easy modification and functionalization, facile synthesis, low toxicity, and controllable particle size. This study aimed to synthesize a conjugated citraconic anhydride link between morphologically homogeneous AuNPs and doxorubicin (DOX) (DOX-AuNP). The carrier was radiolabeled for tumor diagnosis using positron emission tomography (PET). The systemically designed DOX-AuNP was cleaved at the citraconic anhydride linker site under the mild acidic conditions of a cancer cell, thereby releasing DOX. Subsequently, the AuNPs aggregated via electrostatic attraction. HeLa cancer cells exhibited a high uptake of the radiolabeled DOX-AuNP. Moreover, PET tumor images were obtained using radiolabeled DOX-AuNP in cancer xenograft mouse models. Therefore, DOX-AuNP is expected to provide a valuable insight into the use of radioligands to detect tumors using PET.
Assuntos
Ouro/química , Concentração de Íons de Hidrogênio , Nanopartículas Metálicas/química , Neoplasias do Colo do Útero/diagnóstico por imagem , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/uso terapêutico , Feminino , Ouro/metabolismo , Células HeLa , Humanos , Camundongos , Tomografia por Emissão de Pósitrons , Ensaio Radioligante , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Polo-like kinase-1 (Plk1) plays a key role in mitosis and has been identified as an attractive anticancer drug target. Plk1 consists of two drug-targeting sites, namely, N-terminal kinase domain (KD) and C-terminal polo-box domain (PBD). As KD-targeting inhibitors are associated with severe side effects, here we report on the pyrazole-based Plk1 PBD inhibitor, KBJK557, which showed a remarkable in vitro anticancer effect by inducing Plk1 delocalization, mitotic arrest, and apoptosis in HeLa cells. Further, in vivo optical imaging analysis and antitumorigenic activities in mouse xenograft models demonstrate that KBJK557 preferentially accumulates in cancer cells and selectively inhibits cancer cell proliferation. Pharmacokinetic profiles and partition coefficients suggest that KBJK557 was exposed in the blood and circulated through the organs with an intermediate level of clearance (t1/2, 7.73 h). The present investigation offers a strategy for specifically targeting cancer using a newly identified small-molecule inhibitor that targets the Plk1 PBD.
Assuntos
Antineoplásicos/uso terapêutico , Barbitúricos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Barbitúricos/síntese química , Barbitúricos/metabolismo , Barbitúricos/farmacocinética , Carbocianinas/química , Proteínas de Ciclo Celular/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HeLa , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Estrutura Molecular , Neoplasias/diagnóstico , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase 1 Polo-LikeRESUMO
Polo-like kinase 1 (Plk1) regulates cell cycle and cell proliferation, and is currently considered a potential biomarker in clinical trials for many cancers. A characteristic feature of Plks is their C-terminal polo-box domain (PBD). Pro-Leu-His-Ser-pThr (PLHS[pT])-the phosphopeptide inhibitor of the PBD of Plk1-induces apoptosis in cancer cells. However, because of the low cell membrane-penetration ability of PLHS[pT], new approaches are required to overcome these drawbacks. We therefore developed a vitamin E (VE) conjugate that is biodegradable by intracellular redox enzymes as an anticancer drug-delivery system. To ensure high efficiency of membrane penetration, we synthesized VE-S-S-PLHS[pT]KY (1) by conjugating PLHS[pT] to VE via a disulfide bond. We found that 1 penetrated cancer cell membranes, blocked cancer cell proliferation, and induced apoptosis in cancer cells through cell cycle arrest in the G2/M phase. We synthesized a radiolabeled peptide (124I-1), and the radioligand was evaluated in in vivo tumor uptake using positron emission tomography. This study shows that combination conjugates are an excellent strategy for specifically targeting Plk PBD. These conjugates have a dual function, with possible uses in anticancer therapy and tumor diagnosis.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/metabolismo , Fosfopeptídeos/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Vitamina E/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Citometria de Fluxo , Células HeLa , Humanos , Mitose/efeitos dos fármacos , Quinase 1 Polo-LikeRESUMO
Considering the emergence of bacterial resistance and low proteolytic stability of antimicrobial peptides (AMPs), herein we developed a series of ultra-short triazine based amphipathic polymers (TZP) that are connected with ethylene diamine linkers instead of protease sensitive amide bond. The most potent oligomers, TZP3 and TZP5 not only displayed potent antibacterial action on various drug-resistant pathogens but also exhibited a strong synergic antibacterial activity in combination with chloramphenicol against multidrug-resistant Pseudomonas aeruginosa (MDRPA). Since most of atopic dermatitis (AD) infections are caused by bacterial colonization, we evaluated the potency of TZP3 and TZP5 on AD in vitro and in vivo. In vitro AD analysis of these two polymers showed significant inhibition against the release of ß-hexosaminidase and tumor necrosis factor (TNF-α) from RBL-2H3 cells. In AD-like skin lesions in BALB/c mice model, these two polymers displayed significant potency in suppressing dermal and epidermal thickness, mast cell infiltration and pro-inflammatory cytokines expression. Moreover, these polymers exhibited remarkable efficacy over the allergies caused by the imbalance of Th1/Th2 by regulating total IgE and IgG2a. Finally, the impact of treatment effects of these polymers was examined through analyzing the weights and sizes of spleen and lymph node of AD-induced mice.
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Antibacterianos/farmacologia , Polímeros/farmacologia , Tensoativos/farmacologia , Triazinas/farmacologia , Animais , Antibacterianos/química , Bactérias/efeitos dos fármacos , Citocinas/metabolismo , Dermatite Atópica/sangue , Dermatite Atópica/patologia , Modelos Animais de Doenças , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Estabilidade Enzimática/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise , Interações Hidrofóbicas e Hidrofílicas , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Mediadores da Inflamação/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Mastócitos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Peptídeo Hidrolases/metabolismo , Polímeros/química , Ovinos , Pele/efeitos dos fármacos , Pele/patologia , Baço/efeitos dos fármacos , Baço/patologia , Triazinas/químicaRESUMO
In the last decade, drug delivery systems using biologically active molecules for cellular uptake of therapeutic targets have been studied for application and testing in clinical trials. For instance, the transactivator of transcription (TAT) peptide, or cell-penetrating peptide, was shown to deliver a variety of cargoes, including proteins, peptides, and nucleic acids. Polo-like kinase 1 (Plk1) plays key roles in the regulation of cell cycle events (e.g., mitotic progression). Plk1 was also shown to be activated and highly expressed in proliferating cells such as tumor cells. Amongst these phosphopeptides, Pro-Leu-His-Ser-p-Thr (PLHSpT), which is the minimal sequence for polo-box domain (PBD) binding, was shown to have an inhibitory effect and to induce apoptotic cell death. However, the phosphopeptide showed low cell membrane penetration. Thus, in our study, we synthesized Plk1 inhibitor TAT-PLHSpT to improve agent internalization into cells. TAT-PLHSpT was shown to internalize into the nucleus. The conjugation of TAT with PLHSpT inhibited cancer cell growth and survival. Moreover, it showed an increase in cellular uptake and inhibition of Plk1 kinase activity. Further studies are needed for biological evaluation of the new peptide in tumor-bearing animal models (in vivo). Our results prove that TAT-PLHSpT is a good candidate for specific PBD binding of Plk1 as a therapeutic agent for humans.
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Antineoplásicos/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Portadores de Fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/química , Laranja de Acridina/química , Apoptose , Sítios de Ligação , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Proliferação de Células , Sobrevivência Celular , Relação Dose-Resposta a Droga , Produtos do Gene tat/química , Células HeLa , Humanos , Microscopia de Fluorescência , Mitose , Neoplasias/química , Peptídeos/química , Ligação Proteica , Estrutura Terciária de Proteína , Quinase 1 Polo-LikeRESUMO
Oleanolic acid (OA) is a pentacyclic triterpenoid found in various plant species. Triterpenoid compounds have been shown to inhibit tumor proliferation and to induce apoptosis in cancer cells. We synthesized an OA derivative and evaluated its inhibitory effects on cell proliferation in human colon cancer. Radioisotope-labeled OA was prepared for noninvasive monitoring of tumor progression in vitro and in vivo. The OA derivative decreased cell survival in a concentration-dependent manner and increased apoptosis in HT-29 cells. Furthermore, it induced downregulation of cyclin D1, Cox-2, Bcl-2 and Bcl-xL mRNA expression and upregulation of the mRNA expression of the anti-apoptotic Bax protein in HT29 cells. NF-κB p65 and IκB expression also decreased, whereas expression of the apoptosis marker, the cleaved form of PARP-1, significantly increased in OA derivative-treated HT-29 cells. Radioisotope-labeled OA (68Ga-NOTA-OA) showed significantly high tumor uptake, as assessed by biodistribution and positron emission tomography imaging analyses, at 1 h post-injection in the human colon cancer xenograft model. Our results demonstrate that the OA derivative has promising properties as an anticancer drug and as an imaging tool for tumor targeting.
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Research into multifunctional nanoparticles is focused on creating an agent for use in an all-in-one multimodal imaging system that includes diagnostic imaging, drug delivery, and therapeutic monitoring. We designed a new dual-modality tumor-targeting agent with a new tumor-targeting molecule, oleanolic acid (OA), which is derived from a natural compound and coupled with a macrocyclic chelating agent such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), iron oxide nanoparticles (IONP), and radiolabeling components such as (68)Ga for dual-modality positron emission tomography (PET)/magnetic resonance imaging (MRI). We attempted to obtain fusion PET/MR images with the (68)Ga-NOTA-OA-IONP hybrid tumor-targeting imaging agent using colon cancer (HT-29) xenograft mice models. The HT-29 cancer cells showed high uptake of (68)Ga-NOTA-OA-IONP, which also had an inhibitory effect on the cells. Moreover, we obtained PET and MRI tumor images as well as fusion PET/MRI images of the tumors using (68)Ga-NOTA-OA-IONP. Therefore, the dual-modality cancer-targeting radiolabeled nanoparticle reported here is a potent imaging agent that is suitable for PET, MRI, and PET/MRI-based diagnosis of tumors; it also has the advantage of not only detecting tumor functionality, but also simultaneously aiding in tumor resolution.
Assuntos
Compostos Férricos/química , Imageamento por Ressonância Magnética/métodos , Nanopartículas/química , Ácido Oleanólico/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/diagnóstico , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Nus , Nanopartículas/uso terapêuticoRESUMO
Peptides are ideal candidates for developing therapeutics. Polo-like kinase 1 is an important regulatory protein in the cell cycle and contains a C-terminal polo-box domain, which is the hallmark of this protein family. We developed a peptide inhibitor of polo-like kinase 1 that targets its polo-box domain. This new phosphopeptide, cRGDyK-S-S-CPLHSpT, preferentially penetrates the cancer cell membrane mediated by the integrin receptor, which is expressed at high levels by cancer cells. In the present study, using high performance liquid chromatography and mass spectroscopy, we determined the stability of cRGDyK-S-S-CPLHSpT and its cleavage by glutathione under typical conditions for cell culture. We further assessed the ability of the peptide to inhibit the proliferation of the U87MG glioma cell line. The phosphorylated peptide was stable, and the disulfide bond of cRGDyK-S-S-CPLHSpT was cleaved in 50 mM glutathione. This peptide inhibited the growth of cancer cells and changed their morphology. Therefore, we conclude that the phosphopeptide shows promise as a prodrug and has a high potential to act as an anticancer agent by inhibiting polo-like kinase 1 by binding its polo-box domain. These findings indicate the therapeutic potential of PLHSpT and peptides similarly targeted to surface receptors of cancer cells and to the functional domains of regulatory proteins.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Glioma/fisiopatologia , Fosfopeptídeos/farmacologia , Pró-Fármacos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glioma/tratamento farmacológico , Glioma/enzimologia , Glioma/metabolismo , Humanos , Estrutura Molecular , Fosfopeptídeos/química , Pró-Fármacos/química , Quinase 1 Polo-LikeRESUMO
PURPOSE: Vascular endothelial growth factor receptors (VEGFRs) are associated with tumor growth and induction of tumor angiogenesis and are known to be overexpressed in various human tumors. In the present study, we prepared and evaluated (68)Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid-benzyl (NOTA)-VEGF(121) as a positron emission tomography (PET) radioligand for the in vivo imaging of VEGFR expression. METHODS: (68)Ga-NOTA-VEGF(121) was prepared by conjugation of VEGF(121) and p-SCN-NOTA, followed by radiolabeling with (68)GaCl(3) and then purification using a PD-10 column. Human aortic endothelial cell (HAEC) binding of (68)Ga-NOTA-VEGF(121) was measured as a function of time. MicroPET and biodistribution studies of U87MG tumor xenografted mice were performed at 1, 2, and 4 h after injection of (68)Ga-NOTA-VEGF(121). The tumor tissues were then sectioned and subjected to immunostaining. RESULTS: The decay-corrected radiochemical yield of (68)Ga-NOTA-VEGF(121) was 40 ± 4.5 % and specific activity was 243.1 ± 104.6 GBq/µmol (8.6 ± 3.7 GBq/mg). (68)Ga-NOTA-VEGF(121) was avidly taken up by HAECs in a time-dependent manner, and the uptake was blocked either by 32 % with VEGF(121) or by 49 % with VEGFR2 antibody at 4 h post-incubation. In microPET images of U87MG tumor xenografted mice, radioactivity was accumulated in tumors (2.73±0.32 %ID/g at 2 h), and the uptake was blocked by 40 % in the presence of VEGF(121). In biodistribution studies, tumor uptake (1.84±0.14 %ID/g at 2 h) was blocked with VEGF(121) at a similar level (52 %) to that of microPET images. Immunostaining analysis of U87MG tumor tissues obtained after the microPET imaging showed high levels of VEGFR2 expression. CONCLUSION: These results demonstrate that (68)Ga-NOTA-VEGF(121) has potential for the in vivo imaging of VEGFR expression. In addition, our results also suggest that the in vivo characteristics of radiolabeled VEGF depend on the properties of the radioisotope and the chelator used.
Assuntos
Radioisótopos de Gálio/farmacologia , Compostos Heterocíclicos/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Calibragem , Linhagem Celular Tumoral , Quelantes/farmacologia , Ciclotrons , Diagnóstico por Imagem/métodos , Células Endoteliais/citologia , Compostos Heterocíclicos com 1 Anel , Humanos , Imuno-Histoquímica/métodos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neovascularização Patológica , Peptídeos/química , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica , Fatores de TempoRESUMO
PURPOSE: HMOX1, which is highly expressed in various solid tumors, has an important role in rapid tumor growth. We investigated the relationship between HMOX1 expression and clinicopathological parameters in patients with NMIBC. MATERIALS AND METHODS: We analyzed 211 primary NMIBC tissue specimens by real-time PCR and compared the results with clinicopathological parameters. Kaplan-Meier survival curves and multivariate Cox regression analysis were used to assess the prognostic value of HMOX1 in NMIBC cases. RESULTS: HMOX1 mRNA expression was significantly higher in patients with higher grade and multiple tumors than in those with lower grade and single tumors (each p <0.05, respectively). Kaplan-Meier estimates showed HMOX1 expression was significantly associated with recurrence and progression (log rank test p = 0.010 and <0.001, respectively). A multivariate Cox regression model revealed that HMOX1 mRNA expression was an independent predictor of recurrence (HR 1.832, p = 0.017) and progression (HR 5.241, p = 0.001) in patients with NMIBC. CONCLUSIONS: Analysis of HMOX1 expression in 211 NMIBC tissue specimens revealed its potential usefulness as a marker to predict the NMIBC prognosis.