Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.327
Filtrar
1.
Bull Exp Biol Med ; 167(1): 84-86, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177461

RESUMO

Rats with sarcoma M-1 were exposed to high dose rate irradiation with 169Yb source. In 25 days after introduction of a trocar with sealed capsule with 169Yb source into the tumor, complete tumor regression was observed in 70% animals. The results suggest feasibility of using 169Yb source for high-dose rate brachytherapy and development of the personalized medicine approaches.


Assuntos
Braquiterapia/métodos , Sarcoma Experimental/radioterapia , Itérbio/uso terapêutico , Animais , Área Sob a Curva , Masculino , Ratos
2.
PLoS Genet ; 15(4): e1008039, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30970016

RESUMO

The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.


Assuntos
Sarcoma Experimental/etiologia , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteína Nuclear Ligada ao X/deficiência , Proteína Nuclear Ligada ao X/genética , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Sistemas CRISPR-Cas , Carcinogênese/genética , Carcinogênese/metabolismo , Modelos Animais de Doenças , Eritropoese , Feminino , Técnicas de Inativação de Genes , Globinas/genética , Humanos , Mutação com Perda de Função , Masculino , Neurofibromina 1/deficiência , Neurofibromina 1/genética , Sarcoma Experimental/genética , Sarcoma Experimental/metabolismo , Homeostase do Telômero/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
3.
Mol Pharm ; 16(4): 1714-1722, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30860846

RESUMO

Tumor associated macrophages (TAMs) are important components residing in the tumor microenvironment. They are immunosuppressive and promote tumor progression. Targeting TAMs and reprogramming their phenotype may be a promising strategy that can restore antitumor immune responses. In this study, we developed a microRNA delivery system based on lipid-coated calcium phosphonate nanoparticles (CaP/miR@pMNPs) containing conjugated mannose and sterically shielded with a pH-responsive material. The nanocarrier could respond to the low pH in the tumor microenvironment and expose mannose to promote cellular internalization in TAMs. The carrier could reactivate TAMs and reprogram their functions, reverse the immunosuppressive tumor microenvironment, and inhibit tumor growth in a tumor-bearing mouse model. In summary, redirecting the polarization of TAMs is a potential therapeutic strategy for tumor immunotherapy.


Assuntos
Imunoterapia , Macrófagos/imunologia , MicroRNAs/administração & dosagem , Nanopartículas/administração & dosagem , Sarcoma Experimental/terapia , Microambiente Tumoral/imunologia , Animais , Apoptose , Fosfatos de Cálcio/química , Proliferação de Células , Humanos , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , MicroRNAs/química , MicroRNAs/genética , Nanopartículas/química , Sarcoma Experimental/genética , Sarcoma Experimental/imunologia , Sarcoma Experimental/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Res ; 79(8): 1938-1951, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30777853

RESUMO

Cancer induces alteration of hematopoiesis to fuel disease progression. We report that in tumor-bearing mice the macrophage colony-stimulating factor elevates the myeloid cell levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, which acts as negative regulator of the CXCR4 retention axis of hematopoietic cells in the bone marrow. NAMPT inhibits CXCR4 through a NAD/Sirtuin 1-mediated inactivation of HIF1α-driven CXCR4 gene transcription, leading to mobilization of immature myeloid-derived suppressor cells (MDSC) and enhancing their production of suppressive nitric oxide. Pharmacologic inhibition or myeloid-specific ablation of NAMPT prevented MDSC mobilization, reactivated specific antitumor immunity, and enhanced the antitumor activity of immune checkpoint inhibitors. Our findings identify NAMPT as a metabolic gate of MDSC precursor function, providing new opportunities to reverse tumor immunosuppression and to restore clinical efficacy of immunotherapy in patients with cancer. SIGNIFICANCE: These findings identify NAMPT as a metabolic gate of MDSC precursor function, providing new opportunities to reverse tumor immunosuppression and to restore clinical efficacy of immunotherapy in cancer patients.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Mamárias Experimentais/patologia , Células Supressoras Mieloides/patologia , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Sarcoma Experimental/patologia , Animais , Apoptose , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Hematopoese , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Supressoras Mieloides/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Sarcoma Experimental/genética , Sarcoma Experimental/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Invest New Drugs ; 37(5): 1044-1051, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30680583

RESUMO

Obtustatin, isolated from the Levantine Viper snake venom (Macrovipera lebetina obtusa -MLO), is the shortest known monomeric disintegrin shown to specifically inhibit the binding of the α1ß1 integrin to collagen IV. Its oncostatic effect is due to the inhibition of angiogenesis, likely through α1ß1 integrin inhibition in endothelial cells. To explore the therapeutic potential of obtustatin, we studied its effect in S-180 sarcoma-bearing mice model in vivo as well as in human dermal microvascular endothelial cells (HMVEC-D) in vitro, and tested anti-angiogenic activity in vivo using the chick embryo chorioallantoic membrane assay (CAM assay). Our in vivo results show that obtustatin inhibits tumour growth by 33%. The expression of vascular endothelial growth factor (VEGF) increased after treatment with obtustatin, but the level of expression of caspase 8 did not change. In addition, our results demonstrate that obtustatin inhibits FGF2-induced angiogenesis in the CAM assay. Our in vitro results show that obtustatin does not exhibit cytotoxic activity in HMVEC-D cells in comparison to in vivo results. Thus, our findings disclose that obtustatin might be a potential candidate for the treatment of sarcoma in vivo with low toxicity.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Sarcoma Experimental/tratamento farmacológico , Venenos de Víboras/farmacologia , Animais , Apoptose , Proliferação de Células , Embrião de Galinha , Membrana Corioalantoide , Integrina alfa1beta1/antagonistas & inibidores , Camundongos , Neovascularização Patológica/patologia , Sarcoma Experimental/irrigação sanguínea , Sarcoma Experimental/patologia , Células Tumorais Cultivadas
7.
Cancer Chemother Pharmacol ; 83(2): 361-374, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30506269

RESUMO

Macrophage-mediated drug delivery system has emerged and gained wide interest as a novel strategy for cancer treatment. Among them, RAW264.7 cell was commonly used as the macrophage model for antitumor drug loading and delivery. However, this cell line was a macrophage-like cancerous cell with both immunogenicity and pro-tumorigenic properties, which may interfere with the positive response of the host immune system to developed tumor. Thus, the safety and efficacy of the RAW264.7 cell line as a drug carrier for cancer therapy remain questionable. Here, we constructed doxorubicin-loaded RAW264.7 cells and examined its antitumor efficacy in S180 tumor-bearing mice. The bio-distribution of RAW264.7 cells was determined by in vivo imaging technique, showing a high accumulation level of RAW264.7 cells in mice livers, spleens, and thymuses. A phenomenon of accelerated tumor growth was observed in mice treated with doxorubicin-loaded RAW264.7 cells. Thereafter, the effect of frequency, dose, and viability of injected RAW264.7 cells on S180 tumor growth was further investigated. The underlying mechanism was confirmed, attributing to the immune tolerance induced by excessive RAW264.7 cells. Our findings emphasized the latent limitation of RAW264.7 cells as drug carrier in current researches, and provided an experimental basis for the clinical safety of cell-mediated drug delivery system.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Materiais Biomiméticos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Macrófagos/transplante , Sarcoma Experimental/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/farmacocinética , Apoptose , Proliferação de Células , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Humanos , Macrófagos/citologia , Masculino , Camundongos , Células RAW 264.7 , Sarcoma Experimental/patologia , Células Tumorais Cultivadas
8.
Photochem Photobiol Sci ; 18(1): 129-139, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30357250

RESUMO

Although infrared radiation (IR) represents more than 50% of the solar radiation reaching the Earth's surface, this waveband has been hardly investigated in terms of tumourigenesis. The objective of the present study was to investigate the influence of IR on ultraviolet B (UVB)-induced carcinogenesis in male and female wild type mice. For this purpose, male and female C57BL/6N mice were subjected to a long-term irradiation protocol. Mice were irradiated once neonatally and from the age of eight weeks for 36 weeks with a cumulative dose of 576 kJ m-2 UVB and/or 78 895 kJ m-2 IR. In order to resemble natural sun irradiation, exposure to physiological doses of UVB and IR was performed simultaneously. Mice were screened for arising lesions twice a week. Lesions were excised and histologically diagnosed. Kaplan-Meier analyses were carried out and lesion counts and cumulated hazard rates for the development of lesions in the UVB and IR + UVB-exposed groups in male and female mice were compared. We found that IR-exposure did not change the number of epithelial malignant tumours in UVB-exposed wild type mice. In combination with IR there was a tendency of more tumours with increased malignancy: 23 vs. seven spindle cell shaped sarcomas and seven vs. two MelanA+/S100+ tumours in groups of 35 C57BL/6 mice. IR did not influence UVB-induced carcinogenesis differently in male and female mice. However, comparing UVB and sham irradiated animals irrespective of IR exposure, UVB-induced non-epithelial tumours arose significantly earlier in male mice than in female mice.


Assuntos
Carcinogênese/efeitos da radiação , Raios Infravermelhos/efeitos adversos , Neoplasias Induzidas por Radiação/etiologia , Sarcoma Experimental/etiologia , Neoplasias Cutâneas/etiologia , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno MART-1/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas S100/análise , Sarcoma Experimental/patologia , Fatores Sexuais , Pele/patologia , Neoplasias Cutâneas/patologia
9.
Anticancer Agents Med Chem ; 19(3): 365-374, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30523769

RESUMO

OBJECTIVE: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. BACKGROUND: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. METHODS: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. RESULTS: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. CONCLUSION: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Dano ao DNA , DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Camptotecina/síntese química , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Sarcoma Experimental/tratamento farmacológico , Sarcoma Experimental/metabolismo , Sarcoma Experimental/patologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Células Tumorais Cultivadas
10.
Drug Deliv ; 25(1): 1826-1839, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30458644

RESUMO

Nanoparticles (NPs) have proven to be effective drug carriers in diagnosis and therapy of cancer. But, they faced a contradictory issue that NPs with large size appear weak tumor penetration, meanwhile small size resulted in poor tumor retention. Herein, we fabricated doxorubicin conjugated carbon dots (CDs-DOX) and indocyanine green (ICG)-loaded liposomes (ICG-LPs) named CDs-ICG-LPs using a modified reverse phase evaporation process, and with high incorporation in the aqueous core. The CDs-ICG-LPs exhibited good monodispersity, excellent fluorescence/size stability, and consistent spectra characteristics compared with free ICG or DOX. Moreover, the CDs-ICG-LPs showed higher temperature response, faster DOX release under laser irradiation. In the meantime, the fluorescence of DOX and ICG in CDs-ICG-LPs was also visualized for the process of subcellular location in vitro. In comparison with chemo or photothermal treatment alone, the combined treatment of CDs-ICG-LPs with laser irradiation synergistically induced the apoptosis and death of DOX-sensitive HepG2 cells. In vivo antitumor activities demonstrated CDs-ICG-LPs could reach higher antitumor activity compared with CDs-DOX and ICG-LPs for H22 tumor cells, and suppressed H22 tumor growth in vivo. Notably, no systemic toxicity occurrence was observed after repeated dose of CDs-ICG-LPs with laser irradiation. Hence, the well-defined CDs-ICG-LPs exhibited great potential in targeting cancer imaging and chemo-photothermal therapy.


Assuntos
Antineoplásicos/administração & dosagem , Carbono/administração & dosagem , Doxorrubicina/administração & dosagem , Verde de Indocianina/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Pontos Quânticos/administração & dosagem , Sarcoma Experimental/terapia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carbono/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Liberação Controlada de Fármacos , Quimioterapia Combinada , Células Hep G2 , Humanos , Hipertermia Induzida/métodos , Verde de Indocianina/uso terapêutico , Lipossomos , Masculino , Camundongos , Nanopartículas , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia
11.
JCI Insight ; 3(20)2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30333301

RESUMO

Cancer results from the accumulation of genetic mutations in a susceptible cell of origin. We and others have also shown that injury promotes sarcoma development, but how injury cooperates with genetic mutations at the earliest stages of tumor formation is not known. Here, we utilized dual recombinase technology to dissect the complex interplay of the timing of KrasG12D activation, p53 deletion, and muscle injury in sarcomagenesis using a primary mouse model of soft tissue sarcoma. When mutations in oncogenic Kras and p53 are separated by 3 weeks, few sarcomas develop without injury. However, the transformation potential of these tumor-initiating cells can be unmasked by muscle injury. In the absence of Kras mutations, injury of the muscle with global deletion of p53 results in sarcomas with amplification of chromosomal regions encompassing the Met or Yap1 gene. These findings demonstrate a complex interplay between the timing of genetic mutations and perturbations in the tumor microenvironment, which provides insight into the earliest stages of sarcoma development.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Musculares/etiologia , Músculo Esquelético/lesões , Sarcoma Experimental/etiologia , Ferimentos e Lesões/complicações , Animais , Linhagem Celular Tumoral , DNA Nucleotidiltransferases/genética , Modelos Animais de Doenças , Integrases/genética , Camundongos , Camundongos Transgênicos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Tempo , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética
12.
PLoS One ; 13(8): e0201220, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30080874

RESUMO

In recent years, immunogenic cell death (ICD) has emerged as a revolutionary concept in the development of novel anticancer therapies. This particular form of cell death is able, through the spatiotemporally defined emission of danger signals by the dying cell, to induce an effective antitumor immune response, allowing the immune system to recognize and eradicate malignant cells. To date, only a restricted number of chemotherapeutics can trigger ICD of cancer cells. We previously reported that a peptide, called RT53, spanning the heptad leucine repeat region of the survival protein AAC-11 fused to a penetrating sequence, selectively induces cancer cell death in vitro and in vivo. Interestingly, B16F10 melanoma cells treated by RT53 were able to mediate anticancer effects in a tumor vaccination model. Stimulated by this observation, we investigated whether RT53 might mediate ICD of cancer cells. Here, we report that RT53 treatment induces all the hallmarks of immunogenic cell death, as defined by the plasma membrane exposure of calreticulin, release of ATP and the exodus of high-mobility group box 1 protein (HMGB1) from dying cancer cells, through a non-regulated, membranolytic mode of action. In a prophylactic mouse model, vaccination with RT53-treated fibrosarcomas prevented tumor growth at the challenge site. Finally, local intratumoral injection of RT53 into established cancers led to tumor regression together with T-cell infiltration and the mounting of an inflammatory response in the treated animals. Collectively, our results strongly suggest that RT53 can induce bona fide ICD of cancer cells and illustrate its potential use as a novel antitumor and immunotherapeutic strategy.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/farmacologia , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Peptídeos Penetradores de Células/farmacologia , Proteínas Nucleares/farmacologia , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Proteínas Reguladoras de Apoptose/química , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/química , Células HL-60 , Humanos , Células Jurkat , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Peptídeos/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia , Sarcoma Experimental/tratamento farmacológico , Sarcoma Experimental/imunologia , Sarcoma Experimental/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Curr Med Sci ; 38(4): 697-703, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30128881

RESUMO

This study examined the effect of saponins from Tupistra chinensis Bak (STCB) on the growth of sarcoma S-180 cells in vitro and in mouse xenografts as well as the underlying mechanisms. Cell proliferation was assessed by MTT assay. Cell cycle distribution was determined by flow cytometry. Sarcoma S-180 tumor-bearing mice were treated with different doses of STCB with 10 µg/mL 5-fluorouracil (5-Fu) as a positive control. The activity of nuclear factor (NF)-κB was detected by gel mobility shift assay. The mRNA level of NF-κB was determined by real-time quantitative RT-PCR. The results showed that in vitro STCB inhibited the growth of S-180 cells in a concentration-dependent manner, which was accompanied by cell cycle arrest at S-phase. In vivo STCB significantly inhibited the growth of S-180 tumor mouse xenografts in a dose-dependent manner with apparent induction of cell apoptosis. Moreover, STCB inhibited the activity of NF-κB p65 and reduced the expression of NF-κB p65 mRNA in mouse xenografts. It was concluded that STCB inhibits the proliferation and cell cycle progression of S-180 cells by suppressing NF-κB signaling in mouse xenografts. Our findings suggest STCB is a promising agent for the treatment of sarcoma.


Assuntos
Antineoplásicos/uso terapêutico , Saponinas/uso terapêutico , Sarcoma Experimental/tratamento farmacológico , Fator de Transcrição RelA/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Asparagaceae/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Saponinas/farmacologia , Sarcoma Experimental/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/genética
14.
PLoS One ; 13(4): e0195667, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29630640

RESUMO

Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation (hypoxia). Tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy (RT), chemotherapy and surgery procedures, and is a hallmark of metastatic potential. In particular, the radiation therapy dose needed to achieve the same tumor control probability in hypoxic tissue as in normoxic tissue can be up to 3 times higher. Even very small tumors (<2-3 mm3) comprise 10-30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over the course of seconds to days. We investigate the potential of recently developed lipid-stabilized oxygen microbubbles (OMBs) to improve the therapeutic ratio of RT. OMBs, but not nitrogen microbubbles (NMBs), are shown to significantly increase dissolved oxygen content when added to water in vitro and increase tumor oxygen levels in vivo in a rat fibrosarcoma model. Tumor control is significantly improved with OMB but not NMB intra-tumoral injections immediately prior to RT treatment and effect size is shown to depend on initial tumor volume on RT treatment day, as expected.


Assuntos
Fibrossarcoma/radioterapia , Microbolhas/uso terapêutico , Oxigênio/uso terapêutico , Animais , Feminino , Fibrossarcoma/metabolismo , Humanos , Oxigênio/administração & dosagem , Oxigênio/metabolismo , Ratos , Ratos Endogâmicos F344 , Sarcoma Experimental/metabolismo , Sarcoma Experimental/radioterapia , Pesquisa Médica Translacional , Hipóxia Tumoral/efeitos dos fármacos
15.
Theranostics ; 8(7): 1782-1797, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29556356

RESUMO

Gold nanoparticles (AuNPs) are emerging as promising agents for both cancer therapy and computed tomography (CT) imaging. AuNPs absorb x-rays and subsequently release low-energy, short-range photoelectrons during external beam radiation therapy (RT), increasing the local radiation dose. When AuNPs are near tumor vasculature, the additional radiation dose can lead to increased vascular permeability. This work focuses on understanding how tumor vascular permeability is influenced by AuNP-augmented RT, and how this effect can be used to improve the delivery of nanoparticle chemotherapeutics. Methods: Dual-energy CT was used to quantify the accumulation of both liposomal iodine and AuNPs in tumors following AuNP-augmented RT in a mouse model of primary soft tissue sarcoma. Mice were injected with non-targeted AuNPs, RGD-functionalized AuNPs (vascular targeting), or no AuNPs, after which they were treated with varying doses of RT. The mice were injected with either liposomal iodine (for the imaging study) or liposomal doxorubicin (for the treatment study) 24 hours after RT. Increased tumor liposome accumulation was assessed by dual-energy CT (iodine) or by tracking tumor treatment response (doxorubicin). Results: A significant increase in vascular permeability was observed for all groups after 20 Gy RT, for the targeted and non-targeted AuNP groups after 10 Gy RT, and for the vascular-targeted AuNP group after 5 Gy RT. Combining targeted AuNPs with 5 Gy RT and liposomal doxorubicin led to a significant tumor growth delay (tumor doubling time ~ 8 days) compared to AuNP-augmented RT or chemotherapy alone (tumor doubling time ~3-4 days). Conclusions: The addition of vascular-targeted AuNPs significantly improved the treatment effect of liposomal doxorubicin after RT, consistent with the increased liposome accumulation observed in tumors in the imaging study. Using this approach with a liposomal drug delivery system can increase specific tumor delivery of chemotherapeutics, which has the potential to significantly improve tumor response and reduce the side effects of both RT and chemotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Vasos Sanguíneos/efeitos da radiação , Doxorrubicina/administração & dosagem , Ouro/metabolismo , Permeabilidade/efeitos da radiação , Sarcoma/tratamento farmacológico , Sarcoma/radioterapia , Animais , Ouro/administração & dosagem , Iodo/administração & dosagem , Lipossomos/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Camundongos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/metabolismo , Sarcoma/diagnóstico por imagem , Sarcoma Experimental/diagnóstico por imagem , Sarcoma Experimental/tratamento farmacológico , Sarcoma Experimental/radioterapia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
16.
Sci Rep ; 8(1): 2194, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29391414

RESUMO

A newly designed organoselenium compound, methyl substituted umbelliferone selenocyanate (MUS), was synthesized as a primary hit against the myelotoxic activity of carboplatin. MUS was administered at 6 mg/kg b.wt, p.o. in concomitant and pretreatment schedules with carboplatin (12 mg/kg b.wt, i.p. for 10 days) in female Swiss albino mouse. MUS treatment reduced (P < 0.001) the percentage of chromosomal aberrations, micronuclei formation, DNA damage and apoptosis in murine bone marrow cells and also enhanced (P < 0.001) the bone marrow cell proliferation of the carboplatin-treated mice. These activities cumulatively restored the viable bone marrow cell count towards normalcy. Myeloprotection by MUS was achieved, in part, due to a significant reduction in the ROS/RNS formation and restoration of glutathione redox pool. Additionally, MUS synergistically enhanced the cytotoxicity of carboplatin against two human cancer cell lines (MCF-7 and Colo-205). Furthermore, MUS can effectively potentiate the antitumour activity of carboplatin against two murine cancers (Dalton's Lymphoma and Sarcoma-180) in vivo. These preclinical findings clearly indicate that MUS can improve the therapeutic index of carboplatin and ensures more effective therapeutic strategy against cancer for clinical development.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/química , Desenho de Fármacos , Linfoma/tratamento farmacológico , Mielopoese/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Sarcoma Experimental/tratamento farmacológico , Animais , Antineoplásicos/química , Antioxidantes/química , Antioxidantes/farmacologia , Apoptose , Proliferação de Células , Quimioterapia Adjuvante , Aberrações Cromossômicas , Dano ao DNA/efeitos dos fármacos , Feminino , Peroxidação de Lipídeos , Linfoma/patologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Sarcoma Experimental/patologia , Células Tumorais Cultivadas
17.
Mol Cancer Ther ; 17(4): 858-868, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29437879

RESUMO

Carbon ion therapy (CIT) offers several potential advantages for treating cancers compared with X-ray and proton radiotherapy, including increased biological efficacy and more conformal dosimetry. However, CIT potency has not been characterized in primary tumor animal models. Here, we calculate the relative biological effectiveness (RBE) of carbon ions compared with X-rays in an autochthonous mouse model of soft tissue sarcoma. We used Cre/loxP technology to generate primary sarcomas in KrasLSL-G12D/+; p53fl/fl mice. Primary tumors were irradiated with a single fraction of carbon ions (10 Gy), X-rays (20 Gy, 25 Gy, or 30 Gy), or observed as controls. The RBE was calculated by determining the dose of X-rays that resulted in similar time to posttreatment tumor volume quintupling and exponential growth rate as 10 Gy carbon ions. The median tumor volume quintupling time and exponential growth rate of sarcomas treated with 10 Gy carbon ions and 30 Gy X-rays were similar: 27.3 and 28.1 days and 0.060 and 0.059 mm3/day, respectively. Tumors treated with lower doses of X-rays had faster regrowth. Thus, the RBE of carbon ions in this primary tumor model is 3. When isoeffective treatments of carbon ions and X-rays were compared, we observed significant differences in tumor growth kinetics, proliferative indices, and immune infiltrates. We found that carbon ions were three times as potent as X-rays in this aggressive tumor model and identified unanticipated differences in radiation response that may have clinical implications. Mol Cancer Ther; 17(4); 858-68. ©2018 AACR.


Assuntos
Proliferação de Células , Radioterapia com Íons Pesados , Sarcoma Experimental/radioterapia , Sarcoma/radioterapia , Animais , Apoptose , Relação Dose-Resposta à Radiação , Feminino , Masculino , Camundongos , Radiometria , Eficiência Biológica Relativa , Sarcoma/patologia , Sarcoma Experimental/patologia
18.
J BUON ; 23(6): 1904-1911, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30610820

RESUMO

PURPOSE: To examine the antitumor effects of Mebendazole (MZ) in a model of experimental fibrosarcoma induced by inoculation of BHK-21/C13 cells in Syrian golden hamster. METHODS: Hamsters were inoculated with a suspension of BHK cells by subcutaneous injection and randomly divided into 5 experimental and 2 control groups. Treatment started on the 10th day after inoculation, when the tumor grew to a diameter of 5mm. The experimental design was based on distributing the total amount of drug MZ(z) in different protocols and approaches (oral/intraperitoneal) to the 5 experimental groups. The positive control group received doxorubicin intraperitoneally. Negative control group received olive oil orally. The total amount of MZ(z) was chosen to be the highest for the animal to survive during the experiment. For antitumor effect evaluation, the main parameters were tumor size, number of mitoses, cytochrome-C immunopositivity and tumor tissue morphology incuding cytoarchitecture and percentage of preserved tumor tissue in stereologically reconstructed tumor mass. RESULTS: The results of this study showed absence of objective MZ antitumor effect on experimental fibrosarcoma. MZ does not exhibit activity similar to DNA-damaging agents on the fibrosarcoma model. CONCLUSIONS: It might be postulated that soft tissue tumors on animal models could show high level of resistance to MZ effect.


Assuntos
Proliferação de Células/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Fibrossarcoma/patologia , Mebendazol/uso terapêutico , Sarcoma Experimental/patologia , Moduladores de Tubulina/uso terapêutico , Animais , Fibrossarcoma/tratamento farmacológico , Mesocricetus , Sarcoma Experimental/tratamento farmacológico
19.
Nanomedicine ; 14(2): 289-301, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28993266

RESUMO

In order to prevent the aggregation of ICG and enhance its stability, a novel nanoplatform (TiO2:Yb,Ho,F-ß-CD@ICG/HA) was designed for NIR-induced phototherapy along with multi-mode imaging(UCL/MRI/Flu). In this nanosysytem: TiO2:Yb,Ho,F was used as upconversion materials and applied in vivo for the first time; ß-CD acted as a "protective umbrella" to load separated ICG and avoid the low phototherapy efficiency because of its aggregation; HA was the capping agent of ß-CD to prevent ICG unexpected leaking and a target to recognize CD44 receptor. The nanosystem exhibited excellent size (~200 nm) and photo- and thermal-stability, preferable reactive oxygen yield and temperature response (50.4 °C) under 808 nm laser. It could efficiently target and suppress tumor growth. The imaging ability (UCL/MRI) of TiO2:Yb,Ho,F could facilitate diagnosis of the tumor, especially for deep tissues. Altogether, our work successfully improved the phototherapy efficacy through incorporating the ICG into the cavity of ß-CD and applied TiO2:Yb,Ho,F for upconversion imaging in vivo.


Assuntos
Verde de Indocianina/metabolismo , Neoplasias Mamárias Experimentais/terapia , Imagem Multimodal/métodos , Nanopartículas/administração & dosagem , Fototerapia , Sarcoma Experimental/terapia , Animais , Apoptose , Ciclo Celular , Feminino , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Sarcoma Experimental/metabolismo , Sarcoma Experimental/patologia , Células Tumorais Cultivadas
20.
Cancer Lett ; 416: 1-10, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29104145

RESUMO

Inhibition of the VEGF/VEGF receptor (VEGFR) and angiopoietin-2 (Ang-2)/TEK receptor tyrosine kinase (Tie-2) pathway is a potential target for tumor angiogenesis. We previously showed that a peptide AS16 which dually inhibits VEGFR/Ang-2 could reduce the tumor growth and decrease the number of microvessels in tumor. However, its short circulating half-life in the serum limits its clinical applications. In this study, as an effort to prolong the short in vivo half-life of AS16, we designed a fusion protein containing peptide AS16 and an IgG Fc fragment. Pharmacokinetic study also revealed that AS16-Fc has a prolonged circulating half-life of about 231 min in rats. We examined the effects of treatment on the tumor vasculature and immune cell populations, tumor growth, in both the MCA-205 and S180 tumor models. We found that AS16-Fc dramatically reduced tumor volume, vascular density and tumor-associated macrophages. Macrophages were identified as potential novel targets following anti-angiogenic therapy, our findings imply a novel role for anti-angiogenic peptide AS16-Fc. These findings indicate that AS16-Fc could be more effective on inhibiting tumor growth angiogenesis and tumor immune microenvironment than that of peptide AS16.


Assuntos
Imunoconjugados/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neovascularização Patológica/prevenção & controle , Sarcoma Experimental/tratamento farmacológico , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Fragmentos Fc das Imunoglobulinas/química , Imunoglobulina G/química , Ativação de Macrófagos/imunologia , Macrófagos/classificação , Macrófagos/imunologia , Camundongos , Peptídeos/química , Ratos Sprague-Dawley , Sarcoma Experimental/irrigação sanguínea , Sarcoma Experimental/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA