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1.
Nat Commun ; 12(1): 5314, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493727

RESUMO

Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells. As anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. Here, we demonstrate a post-ACT conditioning regimen that involves transient anti-CD4 treatment (CD4post). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTXpre), CD4post, and ex vivo primed tumor-reactive CD8+ T-cell infusion is presented. CTXpre/CD4post increases tumor suppression and host survival by accelerating the proliferation and differentiation of ex vivo primed CD8+ T cells and endogenous CD8+ T cells. Endogenous CD8+ T cells enhance effector profile and tumor-reactivity, indicating skewing of the TCR repertoire. Notably, enrichment of polyfunctional IL-18Rαhi CD8+ T cell subset is the key event in CTXpre/CD4post-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rαhi subset is mediated by IL-18 signaling and TCR-MHC I interaction. This study highlights the clinical relevance of CD4post in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8+ T cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos Alquilantes/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ciclofosfamida/farmacologia , Subunidade alfa de Receptor de Interleucina-18/genética , Melanoma Experimental/terapia , Neoplasias Cutâneas/terapia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Imunoterapia Adotiva/métodos , Interleucina-18/genética , Interleucina-18/imunologia , Subunidade alfa de Receptor de Interleucina-18/agonistas , Subunidade alfa de Receptor de Interleucina-18/imunologia , Ativação Linfocitária , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR4/genética , Receptores CCR4/imunologia , Receptores CCR8/genética , Receptores CCR8/imunologia , Receptores Histamínicos H4/genética , Receptores Histamínicos H4/imunologia , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/transplante , Carga Tumoral/efeitos dos fármacos
2.
Nutrients ; 13(8)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34444860

RESUMO

Cyclophosphamide (CTX) is widely applied in cancer treatment. However, the outcome is often compromised by lymphopenia, myelosuppression, and gut dysbiosis. Here, we used jujube powder to enhance CTX efficiency through nurturing gut microbiota in order to facilitate favorable metabolisms. It was observed that the oral administration of jujube powder enriched CD8+ T cells in mouse MC38 colon tumor microenvironment and increased the diversity of gut microbiota and the abundance of Bifidobacteriales, which is helpful to the production of butyrate in the cecum content. The application of jujube powder also stimulated the production of white blood cells, especially CD8+ T cells in peripheral and bone marrow, while inhibiting the growth of eosinophils in peripheral blood and the production of IL-7 and GM-CSF in serum. All these are conductive to the significant inhibition of the tumor growth, suggesting the high potential of nurturing gut microbiota with natural products for improving the efficiency of chemotherapy.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ciclofosfamida/farmacologia , Frutas , Ziziphus , Animais , Medula Óssea/metabolismo , Terapia Combinada , Modelos Animais de Doenças , Eosinofilia , Microbioma Gastrointestinal/efeitos dos fármacos , Contagem de Leucócitos , Leucócitos/efeitos dos fármacos , Camundongos , Pós , Microambiente Tumoral/efeitos dos fármacos
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445656

RESUMO

Neuroblastoma (Nb), the most common extracranial tumor in children, exhibited remarkable phenotypic diversity and heterogeneous clinical behavior. Tumors with MYCN overexpression have a worse prognosis. MYCN promotes tumor progression by inducing cell proliferation, de-differentiation, and dysregulated mitochondrial metabolism. Cyclophosphamide (CFF) at minimum effective oral doses (metronomic therapy) exerts beneficial actions on chemoresistant cancers. Molecular iodine (I2) in coadministration with all-trans retinoic acid synergizes apoptosis and cell differentiation in Nb cells. This work analyzes the impact of I2 and CFF on the viability (culture) and tumor progression (xenografts) of Nb chemoresistant SK-N-BE(2) cells. Results showed that both molecules induce dose-response antiproliferative effects, and I2 increases the sensibility of Nb cells to CFF, triggering PPARγ expression and acting as a mitocan in mitochondrial metabolism. In vivo oral I2/metronomic CFF treatments showed significant inhibition in xenograft growth, decreasing proliferation (Survivin) and activating apoptosis signaling (P53, Bax/Bcl-2). In addition, I2 decreased the expression of master markers of malignancy (MYCN, TrkB), vasculature remodeling, and increased differentiation signaling (PPARγ and TrkA). Furthermore, I2 supplementation prevented loss of body weight and hemorrhagic cystitis secondary to CFF in nude mice. These results allow us to propose the I2 supplement in metronomic CFF treatments to increase the effectiveness of chemotherapy and reduce side effects.


Assuntos
Biomarcadores Tumorais/metabolismo , Ciclofosfamida/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Iodo/farmacologia , Neuroblastoma/tratamento farmacológico , Animais , Anti-Infecciosos Locais/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Diferenciação Celular , Proliferação de Células , Quimioterapia Combinada , Humanos , Masculino , Camundongos , Camundongos Nus , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nutrients ; 13(8)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34444776

RESUMO

Cyclophosphamide (CP)-which is used to treat autoimmune diseases and cancer-is related to gonadotoxicity attributed to oxidative stress. As phycobiliproteins (PBPs) are strong antioxidants that are unexplored as protective agents against male gonadotoxicity, our work aimed to investigate the effects of PBP crude extract on testicular damage and sperm parameter alterations caused by CP in mice. Three doses of PBP (50, 100, and 200 mg/kg) were tested in the experimental groups (n = 8 per group), administered concomitantly with 100 mg/kg CP. After 42 days receiving PBP daily and CP weekly, body and relative testicular weights, serum testosterone levels, testicular lipoperoxidation and antioxidant enzyme activity levels, and testicular histology and sperm parameter alterations were assessed. The results showed that PBP crude extract at 200 mg/kg prevented testosterone serum reduction, body weight loss, lipoperoxidation and enzyme activity increments, and sperm parameter alterations and partially ameliorated relative testicular weight reductions and histological damage in CP-treated mice. In conclusion, we showed that PBP crude extract (200 mg/kg) mitigated oxidative damage in the testes and ameliorated alterations in sperm parameters in mice treated with CP (100 mg/kg); therefore, PBP extract could be considered as a potential protective agent against CP toxicity.


Assuntos
Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Ficobiliproteínas/toxicidade , Animais , Antioxidantes/farmacologia , Peso Corporal , Modelos Animais de Doenças , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/patologia , Testosterona/sangue
5.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298975

RESUMO

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization-despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.


Assuntos
Fator 3 Ativador da Transcrição/fisiologia , Ciclofosfamida/toxicidade , Neoplasias Pulmonares/secundário , Macrófagos/fisiologia , Neoplasias Mamárias Experimentais/genética , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Estresse Fisiológico/genética , Macrófagos Associados a Tumor/fisiologia , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/genética , Linhagem Celular Tumoral , Ciclofosfamida/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Genótipo , Humanos , Neoplasias Pulmonares/metabolismo , Ativação de Macrófagos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Terapia Neoadjuvante/efeitos adversos , Metástase Neoplásica/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transplante de Neoplasias/métodos , Células-Tronco Neoplásicas/patologia , Migração Transendotelial e Transepitelial , Microambiente Tumoral , Macrófagos Associados a Tumor/efeitos dos fármacos
6.
Transfus Apher Sci ; 60(5): 103197, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34175195

RESUMO

High-dose chemotherapy followed by autologous stem cell transplantation is a major component in the treatment of patients with multiple myeloma. As a prerequisite, the successful collection of a sufficient number of viable peripheral blood hematopoietic CD34+ cells is critical. A common standard protocol for mobilization is currently not defined and critically discussed especially in German-speaking Europe. In times of the Covid-19 pandemic, safe and effective strategies have to be chosen to minimize hospitalization times and severe courses. In this single-center retrospective analysis, safety and efficacy of cyclophosphamide plus etoposide (CE) and growth-factor support (n = 33) was compared to cyclophosphamide mono treatment and growth-factor support (n = 49) in 82 patients with multiple myeloma at first diagnosis. CE was superior to cyclophosphamide mono with a significantly higher number of collected CD34+ cells (15.46 × 106 CD34+ cells/kg vs. 9.92 × 106 CD34+ cells/kg), significantly faster engraftment of granulocytes after stem cell transplantation (day 10.5 vs. day 11.6), shorter duration of the inpatient stay (17.47 days vs. 19.16 days) and significantly less transfusions (8.82 % vs. 30.61 % patients receiving transfusions). The safety profile was comparable in both groups and in line with published data. We conclude that CE is a safe and highly effective mobilization protocol in patients with multiple myeloma at first diagnosis and appears to be superior to the commonly used cyclophosphamide mono regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Etoposídeo/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , COVID-19 , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Proteínas do Mieloma/análise , Pandemias , Estudos Retrospectivos , SARS-CoV-2 , Transplante Autólogo
7.
J Hematol Oncol ; 14(1): 76, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941226

RESUMO

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) using a mismatched unrelated donor (MMUD) and cord blood transplantation (CBT) are valid alternatives for patients without a fully human leukocyte antigen (HLA)-matched donor. Here, we compared the allo-HCT outcomes of CBT versus single-allele-mismatched MMUD allo-HCT with post-transplant cyclophosphamide (PTCy) in acute myeloid leukemia. METHODS: Patients who underwent a first CBT without PTCy (N = 902) or allo-HCT from a (HLA 9/10) MMUD with PTCy (N = 280) were included in the study. A multivariate regression analysis was performed for the whole population. A matched-pair analysis was carried out by propensity score-based 1:1 matching of patients (177 pairs) with known cytogenetic risk. RESULTS: The incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 6 months was 36% versus 32% (p = 0.07) and 15% versus 11% (p = 0.16) for CBT and MMUD cohorts, respectively. CBT was associated with a higher incidence of graft failure (11% vs. 4%, p < 0.01) and higher 2-year non-relapse mortality (NRM) (30% vs. 16%, p < 0.01) compared to MMUD. In the multivariate analysis, CBT was associated with a higher risk of, NRM (HR = 2.09, 95% CI 1.46-2.99, p < 0.0001), and relapse (HR = 1.35, 95% CI 1-1.83, p = 0.05), which resulted in worse leukemia-free survival (LFS) (HR = 1.68, 95% CI 1.34-2.12, p < 0.0001), overall survival (OS) (HR = 1.7, 95% CI 1.33-2.17, p < 0.0001), and GVHD-free, relapse-free survival (GRFS) (HR = 1.49, 95% CI 1.21-1.83, p < 0.0001) compared to MMUD. The risk of grade II-IV acute GVHD (p = 0.052) and chronic GVHD (p = 0.69) did not differ significantly between the cohorts. These results were confirmed in a matched-pair analysis. CONCLUSIONS: CBT was associated with lower LFS, OS, and GRFS due to higher NRM, compared to MMUD allo-HCT with PTCy. In the absence of a fully matched donor, 9/10 MMUD with PTCy may be preferred over CBT.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Ciclofosfamida/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores não Relacionados , Adulto Jovem
8.
J Microbiol Biotechnol ; 31(5): 726-732, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33820888

RESUMO

In this study, we evaluated the immune-enhancing activity of kimchi-derived Lactobacillus plantarum 200655 on immune suppression by cyclophosphamide (CP) in ICR mice. Animals were fed distilled water or 1×109 colony-forming unit/kg B.W. 200655 or Lactobacillus rhamnosus GG as a positive control for 14 days. An in vivo model of immunosuppression was induced using CP 150 and 100 mg/kg B.W. at 7 and 10 days, respectively. Body weight, spleen index, spleen weight, and gene expression were measured to estimate the immune-enhancing effects. The dead 200655 (D-200655) group showed an increased spleen weight compared to the sham control (SC) group. Similarly, the spleen index was significantly higher than that in the CP-treated group. The live 200655 (L-200655) group showed an increased mRNA expression of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in splenocytes. Also, the iNOS and COX-2 mRNA expression was upregulated in the L-200655 group compared to the CP-only (SC) group. The phosphorylation of ERK and MAPK was also upmodulated in the L-200655 group. These results indicate that L. plantarum 200655 ameliorated CP-induced immune suppression, suggesting that L. plantarum 200655 may have the potential to enhance the immune system.


Assuntos
Alimentos e Bebidas Fermentados/microbiologia , Hospedeiro Imunocomprometido/efeitos dos fármacos , Lactobacillus plantarum , Probióticos/farmacologia , Alanina Transaminase/sangue , Animais , Ciclofosfamida/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hospedeiro Imunocomprometido/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Lactobacillus plantarum/isolamento & purificação , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Probióticos/administração & dosagem , República da Coreia , Baço/efeitos dos fármacos , Baço/imunologia
9.
Theranostics ; 11(12): 6033-6043, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897897

RESUMO

Immune checkpoint blockade therapies, especially those targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have achieved impressive clinical responses in multiple types of cancers. To optimize the therapeutic effect of the checkpoint antibodies, many strategies including targeting delivery, controlled release, and cellular synthesis have been developed. However, within these strategies, antibodies were attached to drug carriers by chemical bonding, which may affect the steric configuration and function of the antibodies. Herein, we prepared cluster of differentiation 64 (CD64), a natural catcher of the fragment crystalline (Fc) of monomeric immunoglobulin G (IgG), and over-expressed it on the cell membrane nanovesicles (NVs) as PD-L1 antibody delivery vehicle (CD64-NVs-aPD-L1), which was employed to disrupt the PD-1/PD-L1 immunosuppressive signal axis for boosting T cell dependent tumor elimination. Meanwhile, chemical immunomodulatory drug cyclophosphamide (CP) was also encapsulated in the vesicle (CD64-NVs-aPD-L1-CP), to simultaneously restrain the regulatory T cells (Tregs) and invigorate Ki67+CD8+ T cells, then further enhance their anti-tumor ability. Methods: The cell membrane NVs overexpressing CD64 were incubated with PD-L1 antibody and chemotherapeutic agent CP to prepare CD64-NVs-aPD-L1-CP. Results: The CD64-NVs-aPD-L1-CP could simultaneously interrupt the immunosuppressive effect of PD-L1 and decrease the inhibition of Tregs, leading to tumor growth suppression and survival time extension. Conclusion: CD64-NVs are charismatic carriers to achieve both checkpoint blockade and immunomodulatory drugs for combined cancer immunotherapy.


Assuntos
Anticorpos/imunologia , Portadores de Fármacos/química , Neoplasias/imunologia , Neoplasias/terapia , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Ciclofosfamida/farmacologia , Engenharia Genética/métodos , Células HEK293 , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Imunoglobulina G/metabolismo , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL
10.
BMC Cancer ; 21(1): 358, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823836

RESUMO

BACKGROUND: A classification tree was used to analyze background factors for granulocyte colony-stimulating factor (G-CSF) preparation selection for febrile neutropenia (FN) prophylaxis in Japanese patients with non-Hodgkin B-cell lymphoma receiving the first R-CHOP cycle. METHODS: This was a subanalysis of the retrospective observational study STOP FN in NHL 2 (UMIN000029534). Patient characteristics, changes in neutrophil count, incidence and severity of neutropenia, and risk factors for dose reduction/delay of R-CHOP were assessed by G-CSF formulation. RESULTS: Among 234 patients in cycle 1, 25.6% received no G-CSF preparation, 52.1% received daily G-CSF, and 22.2% received pegfilgrastim. Pegfilgrastim use was most frequent among patients aged ≥ 80 years, while that of daily G-CSF was most frequent in patients with lymphocyte count (LC) < 1000 cells/µL. Changes in neutrophil count were more marked with pegfilgrastim compared with daily G-CSF and no G-CSF. Relevant factors for G-CSF preparation selection in the first R-CHOP cycle were age ≥ 80 years and LC < 1000 cells/µL; for chemotherapy dose reduction were FN onset in cycle 1 and female sex; and for dose delay was hemoglobin (< 12 g/dL). After cycle 2 and onward, pegfilgrastim use increased markedly (72.6%) compared with cycle 1 (22.2%), with significantly greater proportions continuing pegfilgrastim use and switching from daily G-CSF. CONCLUSION: Relevant factors for G-CSF preparation selection were age ≥ 80 years and LC < 1000 cells/µL. The use of pegfilgrastim increased markedly after cycle 2. These results may be useful for selecting appropriate G-CSF preparations in the first R-CHOP cycle. TRIAL REGISTRATION: UMIN000029534; registered on 13 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033733 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neutropenia Febril/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/farmacologia , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab/farmacologia , Rituximab/uso terapêutico , Vincristina/farmacologia , Vincristina/uso terapêutico
11.
Food Chem Toxicol ; 151: 112131, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33737110

RESUMO

Camel Urine (CU) is composed of components that have antitumor properties and other therapeutic benefits. Regardless of short-term preliminary CU genotoxicity is reported, comprehensive genotoxic studies are limited. In this study, sensitive in vitro and in vivo genotoxic bioassays such as mitotic index (MI), chromosomal aberrations (CA), micronucleated polychromatic erythrocytes (MPE), and analysis of primary spermatocytes were employed. The adventitious roots of Allium cepa L. and mice (Mus musculus), as an experimental mammalian system, were employed to assess the MI and CA of CU induced by sodium nitrate and cyclophosphamide respectively. In contrast, other clastogenic assays were studied in mice (Mus musculus). Twenty-eight days of four repeated doses (2.5, 5, 25, and 50 mL/kg BW) of CU were tested and compared with three doses (10, 25, and 50 mg/kg BW) cyclophosphamide as a positive control and deionized water as the negative control. The results proved that cytological examination of CU was cytotoxic since a decrease in mitotic activity (16.8-1.1) was observed, since the significant reduction in cell proliferation in A. cepa L. and also in mice bone marrow cells. On the other hand, CU did not induce a clastogenic effect since no significant stickiness, fragment, multinucleoli were observed compared to the control group. Additionally, the data showed that CU decreased the CA when mice had received cyclophosphamide (25 mg BW) followed by CU doses. CU was found to be cytotoxic but no clastogenic effect. Furthermore, it possesses anticlastogenic properties. The observed results suggest that CU in whole or the metabolites present in CU could be a potent drug target. Further research is warranted to study the complete metabolites profiling and to study the molecular mechanisms.


Assuntos
Mutagênicos/toxicidade , Urina , Animais , Antineoplásicos/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Camelus , Ciclofosfamida/farmacologia , Sistemas de Liberação de Medicamentos , Camundongos
12.
Oncoimmunology ; 10(1): 1859263, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33552684

RESUMO

Multiple Myeloma (MM) is a malignant disorder of plasma cells which, despite significant advances in treatment, remains incurable. Daratumumab, the first CD38 directed monoclonal antibody, has shown promising activity alone and in combination with other agents for MM treatment. Daratumumab is thought to have pleiotropic mechanisms of activity including natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). With the knowledge that CD38-expressing NK cells are depleted by daratumumab, we sought to investigate a potential mechanism of enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) by combining daratumumab with cyclophosphamide (CTX). Cyclophosphamide's immunomodulatory function was investigated by conditioning macrophages with tumor cell secretome collected from cyclophosphamide treated MM cell lines (CTX-TCS). Flow cytometry analysis revealed that CTX-TCS conditioning augmented the migratory capacity of macrophages and increased CD32 and CD64 Fcγ receptor expression on their cell surface. Daratumumab-specific tumor clearance was increased by conditioning macrophages with CTX-TCS in a dose-dependent manner. This effect was impeded by pre-incubating macrophages with Cytochalasin D (CytoD), an inhibitor of actin polymerization, indicating macrophage-mediated ADCP as the mechanism of clearance. CD64 expression on macrophages directly correlated with MM cell clearance and was essential to the observed synergy between cyclophosphamide and daratumumab, as tumor clearance was attenuated in the presence of a FcγRI/CD64 blocking agent. Cyclophosphamide independently enhances daratumumab-mediated killing of MM cells by altering the tumor microenvironment to promote macrophage recruitment, polarization to a pro-inflammatory phenotype, and directing ADCP. These findings support the addition of cyclophosphamide to existing or novel monoclonal antibody-containing MM regimens.


Assuntos
Mieloma Múltiplo , ADP-Ribosil Ciclase 1 , Anticorpos Monoclonais/farmacologia , Ciclofosfamida/farmacologia , Humanos , Macrófagos , Mieloma Múltiplo/tratamento farmacológico , Fagocitose , Microambiente Tumoral
13.
Sci Rep ; 11(1): 407, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431979

RESUMO

Gonadotoxic chemotherapeutics, such as cyclophosphamide, can cause early menopause and infertility in women. Earlier histological studies showed ovarian reserve depletion via severe DNA damage and apoptosis, but others suggested activation of PI3K/PTEN/Akt pathway and follicle 'burn-out' as a cause. Using a human ovarian xenograft model, we performed single-cell RNA-sequencing on laser-captured individual primordial follicle oocytes 12 h after a single cyclophosphamide injection to determine the mechanisms of acute follicle loss after gonadotoxic chemotherapy. RNA-sequencing showed 190 differentially expressed genes between the cyclophosphamide- and vehicle-exposed oocytes. Ingenuity Pathway Analysis predicted a significant decrease in the expression of anti-apoptotic pro-Akt PECAM1 (p = 2.13E-09), IKBKE (p = 0.0001), and ANGPT1 (p = 0.003), and reduced activation of PI3K/PTEN/Akt after cyclophosphamide. The qRT-PCR and immunostaining confirmed that in primordial follicle oocytes, cyclophosphamide did not change the expressions of Akt (p = 0.9), rpS6 (p = 0.3), Foxo3a (p = 0.12) and anti-apoptotic Bcl2 (p = 0.17), nor affect their phosphorylation status. There was significantly increased DNA damage by γH2AX (p = 0.0002) and apoptosis by active-caspase-3 (p = 0.0001) staining in the primordial follicles and no change in the growing follicles 12 h after chemotherapy. These data support that the mechanism of acute follicle loss by cyclophosphamide is via apoptosis, rather than growth activation of primordial follicle oocytes in the human ovary.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Apoptose/efeitos dos fármacos , Oócitos/metabolismo , Reserva Ovariana/efeitos dos fármacos , Transcriptoma , Adulto , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/genética , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacologia , Dano ao DNA , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Oócitos/química , Oócitos/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Oogênese/genética , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Reserva Ovariana/genética , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/transplante , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Célula Única/métodos , Transcriptoma/efeitos dos fármacos , Transcriptoma/fisiologia , Adulto Jovem
14.
Cancer Lett ; 501: 133-146, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33387641

RESUMO

Chemotherapies can cause germ cell depletion and gonadal failure. When injected post-chemotherapy, mesenchymal stromal cells (MSCs) from various sources have been shown to have regenerative effects in rodent models of chemotherapy-induced gonadal injury. Here, we evaluated two properties of a novel source of MSC, first trimester (FTM) human umbilical cord perivascular cells (HUCPVCs) (with increased regenerative potential compared to older sources), that may render them a promising candidate for chemotherapeutic gonadal injury prevention. Firstly, their ability to resist the cytotoxic effects of cyclophosphamide (CTX) in vitro, as compared to term HUCPVCs and bone marrow cells (BMSCs); and secondly, whether they prevent gonadal dysfunction if delivered prior to gonadotoxic therapy in vivo. BMSC, FTM HUCPVC, term HUCPVC, and control NTERA2 cells were treated with moderate (150 µmol/L) and high (300 µmol/L) doses of CTX in vitro. Viability, proliferative capacity, mesenchymal cell lineage markers and differentiation capacity, immunogenicity, and paracrine gene expression were assessed. CTX was administered to Wistar rats 2 days following an intra-ovarian injection of FTM HUCPVC. HUCPVC survival and ovarian follicle numbers were assessed using histological methods. We conclude that FTM HUCPVC maintain key regenerative properties following chemotherapy exposure and that pre-treatment with these cells may prevent CTX-induced ovarian damage in vivo. Therefore, HUCPVCs are promising candidates for fertility preservation.


Assuntos
Ciclofosfamida/farmacologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Regeneração/fisiologia , Cordão Umbilical/citologia , Cordão Umbilical/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Preservação da Fertilidade , Humanos , Ovário/efeitos dos fármacos , Ratos , Ratos Wistar , Regeneração/efeitos dos fármacos , Cordão Umbilical/transplante
15.
Mol Cell Biochem ; 476(3): 1467-1475, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33389495

RESUMO

The enzyme betaine aldehyde dehydrogenase (BADH EC 1.2.1.8) catalyzes the synthesis of glycine betaine (GB), an osmolyte and osmoprotectant. Also, it participates in several metabolic pathways in humans. All BADHs known have cysteine in the active site involved in the aldehyde binding, whereas the porcine kidney enzyme (pkBADH) also has a neighborhood cysteine, both sensitive to oxidation. The antineoplastic and immuno-suppressant pre-drug cyclophosphamide (CTX), and its bioactivation products, have two highly oxidating chlorine atoms. This work aimed to analyze the effect of CTX in the activity of porcine kidney betaine aldehyde dehydrogenase. PkBADH was incubated with varying CTX concentration (0 to 2.0 mM) at 25 °C and lost 50 % of its activity with 2.0 mM CTX. The presence of the coenzyme NAD+ (0.5 mM) decreased 95% the activity in 2.0 mM CTX. The substrate betaine aldehyde (0.05 and 0.4 mM, and the products NADH (0.1-0.5 mM) and GB (1 and 10 mM) did not have an effect on the enzyme inactivation by CTX. The reducing agents, dithiothreitol and ß-mercaptoethanol, reverted the pkBADH inactivation, but reduced glutathione (GSH) was unable to restore the enzyme activity. Molecular docking showed that CTX could enter at the enzyme active site, where its chlorine atoms may interact with the catalytic and the neighboring cysteines. The results obtained show that CTX inactivates the pkBADH due to oxidation of the catalytic cysteine or because it oxidizes catalytic and neighborhood cysteine, forming a disulfide bridge with a concomitant decrease in the activity of the enzyme.


Assuntos
Betaína-Aldeído Desidrogenase/metabolismo , Ciclofosfamida/farmacologia , Rim/metabolismo , Animais , Betaína/análogos & derivados , Catálise , Domínio Catalítico , Cloro/química , Ciclofosfamida/química , Cisteína/química , Dissulfetos , Ditiotreitol/química , Escherichia coli/metabolismo , Cinética , Ligantes , Mercaptoetanol/química , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Oxirredução , Oxigênio/química , Preparações Farmacêuticas/metabolismo , Conformação Proteica , Substâncias Redutoras/química , Suínos
16.
Res Vet Sci ; 135: 96-105, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33461120

RESUMO

The purpose of the study was to evaluate the protective effects of polygonatum sibiricum polysaccharide (PP), an important component of rhizome polygonatum, on cyclophosphamide (CY) induced immunosuppressed chickens. Four hundred and eighty one-day-old Erlang mountainous chickens were randomly allocated into four treatments. The main factors consisted of dietary supplement (PP at 0 or 800 mg/kg of diet) and immunosuppressive challenge (birds challenged with CY or treated with sterile saline). The results showed that PP enhanced chickens' growth performance via elevating daily weight gain (DWG), serum protein production, and decreasing feed conversion ratio (FCR). Moreover, physical measurements revealed that PP accelerated recovery of relative weights of immune organs and maintained their structure and function. Biochemical analysis indicated that PP significantly stimulated immunoglobulin and antioxidant indexes in serum, and improved the proliferation of peripheral blood T lymphocytes. In addition, PP promoted immune organs cells to enter into S and G2/M phases as well as inhibited the apoptosis in the spleen, thymus, and bursa of Fabricius. PP up regulated the expression of IL-2, IL-6 and IFN-γ genes. Therefore, PP performs a profile in antagonizing Cy-induced immunosuppression in chickens, and it seems that PP can be used as a potential immunostimulant agent.


Assuntos
Galinhas , Ciclofosfamida/farmacologia , Fatores Imunológicos/farmacologia , Imunossupressão/veterinária , Imunossupressores/farmacologia , Polygonatum/química , Polissacarídeos/farmacologia , Doenças das Aves Domésticas/prevenção & controle , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/metabolismo , Masculino , Polissacarídeos/administração & dosagem , Polissacarídeos/metabolismo , Distribuição Aleatória
17.
Carbohydr Polym ; 255: 117370, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436203

RESUMO

Natural polysaccharides have attracted considerable interests due to diverse biological activities. Succinoglycan is an extracellular polysaccharide produced by most Agrobacterium strains. Here, we confirmed riclin was a typical succinoglycan by NMR and methylation analysis, and investigated the antitumor effects of riclin in sarcoma 180 tumor-bearing mice. The results showed that riclin inhibited the tumor growth significantly as well as cyclophosphamide (CTX). While CTX caused serious damage to spleen structure, riclin increased the spleen index and promoted lymphocytes proliferation in peripheral blood, spleen and lymph nodes. Riclin decreased splenocytes apoptosis as evidenced by alterations of B-cell lymphoma-2 family proteins and Cleaved Caspase-3 protein. Moreover, 1H nuclear magnetic resonance (NMR)-based metabolomics analysis revealed that riclin partially altered the metabolic profiles of splenocytes. In conclusion, riclin is a succinoglycan that performed strong immunogenicity and suppressed sarcoma growth in mice. Succinoglycan riclin could be a potential antitumor agent for functional food and pharmaceutical purpose.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Fatores Imunológicos/farmacologia , Linfócitos/efeitos dos fármacos , Polissacarídeos Bacterianos/farmacologia , Sarcoma 180/tratamento farmacológico , Agrobacterium/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/genética , Sequência de Carboidratos , Caspase 3/genética , Caspase 3/imunologia , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/farmacologia , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/patologia , Linfócitos/imunologia , Linfócitos/patologia , Masculino , Metaboloma/imunologia , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/isolamento & purificação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Sarcoma 180/genética , Sarcoma 180/imunologia , Sarcoma 180/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Carga Tumoral/efeitos dos fármacos
18.
BMC Cancer ; 21(1): 37, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413214

RESUMO

BACKGROUND: Our previous studies demonstrated that the administration of crude Polysaccharide from Panax notoginseng (CPPN) can effectively prolong the lifespan of tumor-bearing mice via boosting the host immune system as well as weak cytotoxicity against hepatocellular carcinoma (HCC). In the present study, Neutral Polysaccharide (NPPN) were further purified from crude polysaccharide isolated from panax notoginseng. The effects of NPPN on the immune function and hematopoietic function of mice with low immunity and myelosuppression induced by cyclophosphamide (CTX) were investigated. The effect of NPPN combined with CTX on the tumor inhibition rate of the H22 tumor-bearing mice and the impact of NPPN on the proliferation of H22 liver cancer cells in vitro were investigated. METHODS: CPPN was obtained by water extraction and alcohol precipitation method, and further purified by DEAE Sepharose Fast Flow ion exchange resin column. NPPN was added to the immunosuppressed with myelosuppression mice induced by CTX. Thymus index, spleen index, lymphocyte proliferation stimulation index by adding of concanavalin A, determination of serum hemolysin, NK cell activity assay, mice carbon clearance experiment, blood count tests were detected. The tumor inhibition rate of the H22 tumor-bearing mice treated with NPPN combined with CTX was recorded. RESULTS: NPPN and 4 kinds of acid polysaccharide from Panax notoginseng (APPN) were successfully isolated from the CPPN by DEAE Sepharose Fast Flow ion exchange resin column. NPPN inhibited the growth of H22 cells and significantly increase the tumor inhibition rate of the H22 tumor-bearing mice combined with CTX. The elevation of the cellular and humoral immunity levels as well as a variety of blood count tests indicators of immunosuppressive with myelosuppression mice may contribute to the antitumor activity of NPPN. CONCLUSION: NPPN has a potential antitumor activity for the treatment of liver cancer combined with cyclophosphamide.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Ciclofosfamida/farmacologia , Sinergismo Farmacológico , Panax notoginseng/química , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Carcinoma Hepatocelular/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Am J Pathol ; 191(4): 631-651, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33385344

RESUMO

Cyclophosphamide may cause hemorrhagic cystitis and eventually bladder urothelial cancer. Genetic determinants for poor outcomes are unknown. We assessed actions of fibroblast growth factor receptor (FGFR) 2 in urothelium after cyclophosphamide exposure. Conditional urothelial deletion of Fgfr2 (Fgfr2KO) did not affect injury severity or proliferation of keratin 14+ (KRT14+) basal progenitors or other urothelial cells 1 day after cyclophosphamide exposure. Three days after cyclophosphamide exposure, Fgfr2KO urothelium had defective regeneration, fewer cells, larger basal cell bodies and nuclei, paradoxical increases in proliferation markers, and excessive replication stress versus controls. Fgfr2KO mice had evidence of pathologic basal cell endoreplication associated with absent phosphorylated ERK staining and decreased p53 expression versus controls. Mice with conditional deletion of Fgfr2 in urothelium enriched for KRT14+ cells reproduced Fgfr2KO abnormalities after cyclophosphamide exposure. Fgfr2KO urothelium had defects up to 6 months after injury versus controls, including larger basal cells and nuclei, more persistent basal and ectopic lumenal KRT14+ cells, and signs of metaplasia (attenuated E-cadherin staining). Mice missing one allele of Fgfr2 also had (less severe) regeneration defects and basal cell endoreplication 3 days after cyclophosphamide exposure versus controls. Thus, reduced FGFR2/ERK signaling apparently leads to abnormal urothelial repair after cyclophosphamide exposure from pathologic basal cell endoreplication. Patients with genetic variants in FGFR2 or its ligands may have increased risks of hemorrhagic cystitis or urothelial cancer from persistent and ectopic KRT14+ cells.


Assuntos
Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Regeneração/fisiologia , Bexiga Urinária/metabolismo , Urotélio/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/farmacologia , Cistite/induzido quimicamente , Cistite/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos , Músculo Liso/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/efeitos dos fármacos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Regeneração/efeitos dos fármacos , Regeneração/genética , Risco , Bexiga Urinária/lesões , Bexiga Urinária/patologia , Urotélio/patologia
20.
Cancer Invest ; 39(4): 333-348, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33474992

RESUMO

This study investigates the anticancer potential of methanolic extract of A. subulatum dry fruits (MEAS) in Dalton's Lymphoma Ascites (DLA) cells in vitro and on DLA induced ascitic and solid tumor-bearing mice. MEAS induced apoptosis in DLA cells and MEAS administration effectively reduced tumor burden, and increased life span via modulating pro-inflammatory cytokines and regulating NF-κB pathway. MEAS seemed to be much safer than the standard drug cyclophosphamide, as the latter was associated with adverse effects such as body weight loss, depletion of hemoglobin level and hepatotoxicity, suggesting A. subulatum as a potential nutraceutical against cancer.


Assuntos
Amomum , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Ascite/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Extratos Vegetais/farmacologia , Amomum/química , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Ascite/sangue , Ascite/patologia , Linhagem Celular Tumoral , Ciclofosfamida/farmacologia , Citocinas/sangue , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Linfoma de Células T/sangue , Linfoma de Células T/patologia , Masculino , Camundongos Endogâmicos BALB C , Extratos Vegetais/isolamento & purificação , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos
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