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1.
Res Vet Sci ; 128: 86-89, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31760317

RESUMO

Chemotherapeutic drugs are given parenterally to treat various canine tumors. A limitation of parenteral administration is low drug penetration into the tumor, which reduces tumoricidal activity. Various drug carriers have been used to enhance tumor delivery, including albumin, liposomes and nanoparticles. A novel peptide-based nanofiber precursor (NFP) has been developed that is designed to take advantage of the leaky tumor neovasculature to promote drug delivery after parenteral administration. In this study, we loaded aldoxorubicin, an albumin-bound prodrug version of doxorubicin, onto NFP and tested the in vitro cytotoxicity in canine mammary carcinoma (CMT12, CMT25) and osteosarcoma (HMPOS, D-17, Abrams) cell lines. The half maximal inhibitory concentration (IC50) was determined with a luminescence-based cell viability assay. The IC50 for aldoxorubicin-loaded NFP was lower than free aldoxorubicin or doxorubicin in all cell lines, whereas non-drug loaded NFP had no cytotoxic effects. There were differences in IC50 between the osteosarcoma lines, with lower and higher IC50 for HMPOS and D-17 cells, respectively, with all drugs (aldoxorubicin-loaded NFP, free aldoxorubicin or free doxorubicin). Our results indicate that drug-loaded NFPs are cytotoxic for various canine mammary carcinoma and osteosarcoma cell lines in vitro and hold promise as a mechanism for enhancing delivery of chemotherapeutic agents to canine tumors.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doenças do Cão/tratamento farmacológico , Doxorrubicina/análogos & derivados , Hidrazonas/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Nanofibras , Osteossarcoma/veterinária , Animais , Linhagem Celular Tumoral , Cães , Doxorrubicina/farmacologia , Osteossarcoma/tratamento farmacológico
2.
Int J Nanomedicine ; 14: 6721-6732, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686805

RESUMO

Background: The early and accurate detection afforded by imaging techniques significantly reduces mortality in cancer patients. However, it is still a great challenge to achieve satisfactory performance in tumor diagnosis using any single-modality imaging method. Magnetic resonance imaging (MRI) has excellent soft tissue contrast and high spatial resolution, but it suffers from low sensitivity. Fluorescence imaging has high sensitivity, but it is limited by penetration depth. Thus, the combination of the two modes could result in synergistic benefits. Here, we design and characterize a novel dual-modality MR/near-infrared fluorescence imaging (MR/NIRFI) nanomicelle and test its imaging properties in mouse models of breast cancer. Methods: The nanomicelles were prepared by incorporating superparamagnetic iron oxide (SPIO) nanoparticles into 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] micelles to which an NIRF dye and a tumor-targeted peptide (N3-Lys-bombesin, Bom) were conjugated. The nanomicelles were characterized for particle size, zeta potential and morphology. The transverse relaxivity, targeting specificity and imaging ability of the nanomicelles for MR/NIRFI were also examined. Results: The fabricated nanomicelles displayed a well-defined spherical morphology with a mean diameter of 145±56 nm and a high transverse relaxivity (493.9 mM-1·s-1, 3.0T). In MRI, the T2 signal reduction of tumors in the Bom-targeted group was 24.1±5.7% at 4 hrs postinjection, whereas only a 0.1±3.4% (P=0.003) decrease was observed in the nontargeted group. In NIRFI, the contrast increased gradually in the targeted group, and the tumor/muscle ratio increased from 3.7±0.3 at 1 hr to 4.7±0.1 at 2 hrs and to 6.4±0.2 at 4 hrs. No significant changes were observed in the nontargeted group at any time points. Conclusion: Considering all our results, we conclude that these novel MR/NIRFI dual-modality nanomicelles could be promising contrast agents for cancer diagnosis.


Assuntos
Bombesina/farmacologia , Bombesina/uso terapêutico , Imagem por Ressonância Magnética , Nanopartículas de Magnetita/química , Animais , Bombesina/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Fluorescência , Humanos , Nanopartículas de Magnetita/ultraestrutura , Neoplasias Mamárias Animais/tratamento farmacológico , Camundongos , Micelas , Imagem Óptica , Tamanho da Partícula
3.
Colloids Surf B Biointerfaces ; 184: 110532, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590051

RESUMO

In this work, a multi-stimuli responsive drug delivery system (MCHP) was designed for combinational chemotherapy and photothermal therapy (PTT). Mesoporous carbon nanoparticles (MCN) with a high loading efficiency were used as near-infrared (NIR)-responsive drug carriers. Human serum albumin (HSA) was attached to the pore openings of MCN via disulfide bonds to serve as a gatekeeper due to its biocompatibility and appropriate molecular size. To improve the dispersity and biocompatibility, the surface of the MCN was modified with polyethylene glycol (PEG). In vitro photothermal effect results showed that MCHP exhibited a power and concentration-dependent photothermal conversion capacity and a good photothermal stability. The doxorubicin (DOX) release from the MCHP/DOX system exhibited NIR/pH/reduction-responsive release properties. A cytotoxicity assay demonstrated that, under NIR irradiation, the MCHP/DOX exhibited chemo-photothermal synergistic effects with a combination index (CI) of 0.643. The biodistribution of DOX in vivo indicated that an NIR laser can prolong the retardation time of DOX in tumor sites. In vivo antitumor experiments showed that MCHP/DOX with NIR irradiation had the highest tumor inhibition rate against 4T1 tumors in mice. This work suggested that MCHP could be explored as a multi-responsive drug release platform for combinational photothermo-chemotherapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Carbono/química , Doxorrubicina/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Nanopartículas/química , Fotoquimioterapia , Albumina Sérica Humana/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Feminino , Humanos , Injeções Subcutâneas , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Porosidade , Propriedades de Superfície
4.
Anticancer Res ; 39(10): 5483-5494, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570442

RESUMO

BACKGROUND/AIM: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs. Rivoceranib (also known as apatinib) is a novel anti-angiogenic tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor-2 (VEGFR2). The aim of this study was to disclose the antitumor effects of rivoceranib on CMGT cell lines. MATERIALS AND METHODS: The direct effects of rivoceranib on CMGT cells in vitro were analyzed by cell proliferation and migration assays. Cell-cycle distribution and apoptotic ratio were analyzed by flow cytometry. Expression levels of phosphorylated VEGFR2 were evaluated by western blot analysis. RESULTS: Rivoceranib treatment significantly reduced the proliferation and migration of CMGT cells in a dose-dependent manner. Flow cytometry results revealed significant increases in G0/G1 phase arrest and apoptosis proportional to the drug concentration used. Rivoceranib reduced the level of phosphorylated VEGFR2. CONCLUSION: We confirm that rivoceranib exerts antitumor effects on CMGT cells by inhibiting biological functions.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cães , Feminino , Fase G1/efeitos dos fármacos , Neoplasias Mamárias Animais/metabolismo , Fosforilação/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Nano Lett ; 19(9): 5844-5852, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424944

RESUMO

The majority of developed and approved anticancer nanomedicines have been designed to exploit the dogma of the enhanced permeability and retention (EPR) effect, which is based on the leakiness of the tumor's blood vessels accompanied by impeded lymphatic drainage. However, the EPR effect has been under scrutiny recently because of its variable manifestation across tumor types and animal species and its poor translation to human cancer therapy. To facilitate the EPR effect, systemically injected NPs should overcome the obstacle of rapid recognition and elimination by the mononuclear phagocyte system (MPS). We hypothesized that circulating monocytes, major cells of the MPS that infiltrate the tumor, may serve as an alternative method for achieving increased tumor accumulation of NPs, independent of the EPR effect. We describe here the accumulation of liposomal quantum dots (LipQDs) designed for active delivery via monocytes, in comparison to LipQDs designed for passive delivery (via the EPR effect), following IV administration in a mammary carcinoma model. Hydrophilic QDs were synthesized and entrapped in functionalized liposomes, conferring passive ("stealth" NPs; PEGylated, neutral charge) and active (monocyte-mediated delivery; positively charged) properties by differing in their lipid composition, membrane PEGylation, and charge (positively, negatively, and neutrally charged). The various physicochemical parameters affecting the entrapment yield and optical stability were examined in vitro and in vivo. Biodistribution in the blood, various organs, and in the tumor was determined by the fluorescence intensity and Cd analyses. Following the treatment of animals (intact and mammary-carcinoma-bearing mice) with disparate formulations of LipQDs (differing by their lipid composition, neutrally and positively charged surfaces, and hydrophilic membrane), we demonstrate comparable tumor uptake of QDs delivered by the passive and the active routes (mainly by Ly-6Chi monocytes). Our findings suggest that entrapping QDs in nanosized liposomal formulations, prepared by a new facile method, imparts superior structural and optical stability and a suitable biodistribution profile leading to increased tumor uptake of fluorescently stable QDs.


Assuntos
Lipossomos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Sistema Fagocitário Mononuclear/química , Pontos Quânticos/química , Animais , Vasos Sanguíneos/efeitos dos fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Lipídeos/química , Lipídeos/farmacologia , Lipossomos/química , Neoplasias Mamárias Animais/patologia , Camundongos , Nanomedicina , Células Neoplásicas Circulantes , Permeabilidade/efeitos dos fármacos
6.
Oncol Rep ; 42(3): 1149-1160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322257

RESUMO

While erythropoietin (EPO) regulates erythropoiesis, the erythropoietin receptor (EPOR) has been identified in many non­hematopoietic cells, including cancer. Our previous study demonstrated that overexpression of EPOR altered the cell growth and the sensitivity of RAMA 37 breast cancer cells to tamoxifen. Indeed, results of the present study uncovered the role of EPOR in the resistance of EPOR­overexpressing RAMA 37­28 cells to paclitaxel chemotherapy. In this regard, EPOR silencing in the presence of paclitaxel therapy decreased RAMA 37­28 cell proliferation, confirming its role in the sensitivity or resistance of RAMA 37­28 cells to paclitaxel. Notably, compared to parental RAMA 37 cells, RAMA 37­28 cells also showed a lower rate of apoptosis induced by paclitaxel, as monitored by caspase 3/7 activation and Annexin V by IncuCyte ZOOM system. Moreover, enhanced activation of signaling pathways mediated by pERK1/2 in RAMA 37­28 cells as detected by western blot analysis was demonstrated to be essential for paclitaxel resistance.


Assuntos
Adenocarcinoma/patologia , Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Eritropoetina/metabolismo , Neoplasias Mamárias Animais/patologia , Paclitaxel/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Apoptose , Proliferação de Células , Eritropoetina/genética , Feminino , Humanos , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Ratos , Células Tumorais Cultivadas
7.
Mol Med Rep ; 20(2): 1808-1818, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257529

RESUMO

Benzyl isothiocyanate (BITC) has been reported to exhibit antitumor properties in various cancer types; however, the underlying mechanisms of its action remain unclear. In the present study, the efficacy of BITC on murine mammary carcinoma cells was evaluated in vitro and in vivo, revealing a potential mechanism for its action. In vivo bioluminescence imaging indicated dynamic inhibition of murine mammary carcinoma cell growth and metastasis by BITC. A terminal deoxynucleotidyl transferase­mediated dUTP nick end labeling assay demonstrated that BITC also induced apoptosis. BITC further exhibited antitumorigenic activity in 4T1­Luc cells in vitro via the inhibition of cell proliferation, induction of apoptosis and cell cycle arrest, and inhibition of cell migration and invasion. Furthermore, the activity of key molecules of the adenomatous polyposis coli (APC)/ß­catenin complex was altered following treatment with BITC, which suggested a potential role for the APC/ß­catenin complex in the BITC­mediated induction of apoptosis and inhibition of metastasis in murine mammary carcinoma. BITC upregulated the activity of glycogen synthase kinase­3ß and APC proteins, whereas it downregulated ß­catenin expression. The inhibition of metastasis was accompanied with the downregulation of vimentin and upregulation of E­cadherin. Conversely, BITC did not exhibit toxicity or side effects in the normal mammary epithelial cell line MCF­10A. The present study indicated that BITC exhibited anticancer properties due to the induction of breast cancer cell apoptosis and inhibition of breast cancer cell metastasis mediated by the Wnt/ß­catenin signaling pathway.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Isotiocianatos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Movimento Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Camundongos , Metástase Neoplásica , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
8.
Vet Comp Oncol ; 17(4): 507-521, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31207004

RESUMO

Therapy of canine mammary tumours (CMTs) with classical antitumour drugs is problematic, so better therapeutic options are needed. Palbociclib (PD-0332991) is an innovative and effective anticancer drug for the treatment of breast cancer in women. Palbociclib is an inhibitor of cyclin-dependent kinase 4 (CDK4) and CDK6, which are key regulators of the cell cycle machinery and thus cell proliferation. In the present in vitro study, we investigated whether Palbociclib also represents a candidate drug to combat CMT. For this purpose, the effect of Palbociclib was analysed in P114 and CF41 cells, two CMT cell lines with an endogenous CDK4/6 co-expression. Incubation of P114 and CF41 cells with Palbociclib resulted in a dose- and time-dependent loss of phosphorylated retinoblastoma protein (pRb), a classical CDK4/6 substrate within the cell cycle machinery. Moreover, treatment of CMT cells with Palbociclib-induced cell cycle arrest affected cell viability, prevented colony formation and impaired cell migration activity. Palbociclib also inhibited the growth of P114 and CF41 cell spheroids. Immunohistochemical analysis of canine patient samples revealed a consistent expression of CDK6 in different canine mammary carcinoma types, but an individual and tumour-specific expression pattern of phosphorylated pRb independent of the tumour grade. Together, our findings let us suggest that Palbociclib has antitumour effects on CMT cells and that canine patients may represent potential candidates for treatment with this CDK4/6 inhibitor.


Assuntos
Adenocarcinoma/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Doenças do Cão/tratamento farmacológico , Neoplasias Mamárias Animais/tratamento farmacológico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Cães , Feminino
9.
Dis Model Mech ; 12(7)2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31213486

RESUMO

The Wnt gene family encodes an evolutionarily conserved group of proteins that regulate cell growth, differentiation and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed as a driver of tumorigenesis, especially in the basal-like tumor subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt-based therapeutics, however, has been slowed in part by a limited understanding of the context-dependent nature with which these aberrations influence breast tumorigenesis. We previously reported that MMTV-Wnt1 mice, an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-EarlyEx and Wnt1-LateEx Here, we extend this initial observation and show that Wnt1-EarlyEx tumors exhibit high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-EarlyEx tumors showed a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-EarlyEx tumors had primarily Cd49fpos/Epcamneg FACS profiles, but it was not possible to serially transplant these tumors into wild-type FVB female mice. Conversely, Wnt1-LateEx tumors had a bloody gross pathology, which was highlighted by the presence of 'blood lakes' identified by H&E staining. These tumors had primarily Cd49fpos/Epcampos FACS profiles, but also contained a secondary Cd49fpos/Epcamneg subpopulation. Wnt1-LateEx tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitively shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors that differ in multiple biological aspects including sensitivity to an EGFR inhibitor.


Assuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/patologia , Vírus do Tumor Mamário do Camundongo/patogenicidade , Proteína Wnt1/fisiologia , Animais , Antineoplásicos/farmacologia , Carcinogênese , Separação Celular , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Genes ras , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/virologia , Camundongos , Fenótipo , Via de Sinalização Wnt , Proteína Wnt1/metabolismo
10.
Pharmacol Res ; 146: 104330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31251988

RESUMO

Mahanine (MH), a carbazole alkaloid isolated from an edible plant (Murraya koenigii), potentially inhibits the growth of altered subtypes of breast cancer cells in vitro and significantly reduced the mammary tumor burden in N-Methyl-N-nitrosourea (MNU) induced rat. The experimental results showed that 20-25 µM of MH for 24 h of treatment was very potent to reduce the cell proliferation through apoptosis with arresting the cells in G0/G1 in both ER+/p53WT MCF-7 and triple negative/p53Mut MDA-MB-231 cells. On the other hand, 10-15 µM of MH exposure to those two cell lines, caused inhibition of mammosphere formation and reduction of CD44high/CD24low/epithelial-specific antigen-positive (ESA+) population, which ultimately led to loss of self-renewal ability of breast cancer stem cells. Further, in vivo observation indicated that intraperitoneal injection of MH for four weeks with a dose of 50 mg/kg body weight thrice in a week, significantly (P =  0.03) reduced the mammary tumor weight in MNU induced rat. In conclusion, this study provides the novel insight into the mechanism of MH mediated growth arrest in subtype irrespective breast cancer progression.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carbazóis/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Carga Tumoral/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dieta , Progressão da Doença , Feminino , Fase G1/efeitos dos fármacos , Humanos , Células MCF-7 , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Ratos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos
11.
Commun Biol ; 2: 192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123716

RESUMO

The heterogeneity of breast cancer makes current therapies challenging. Metformin, the anti-diabetic drug, has shown promising anti-cancer activities in epidemiological studies and breast cancer models. Yet, how metformin alters the normal adult breast tissue remains elusive. We demonstrate metformin intake at a clinically relevant dose impacts the hormone receptor positive (HR+) luminal cells in the normal murine mammary gland. Metformin decreases total cell number, progenitor capacity and specifically reduces DNA damage in normal HR+ luminal cells, decreases oxygen consumption rate and increases cell cycle length of luminal cells. HR+ luminal cells demonstrate the lowest levels of mitochondrial respiration and capacity to handle oxidative stress compared to the other fractions, suggesting their intrinsic susceptibility to long-term metformin exposure. Uncovering HR+ luminal cells in the normal mammary gland as the major cell target of metformin exposure could identify patients that would most benefit from repurposing this anti-diabetic drug for cancer prevention/therapy purposes.


Assuntos
Hipoglicemiantes/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metformina/farmacologia , Animais , Apoptose , Ciclo Celular , Linhagem da Célula , Separação Celular , Dano ao DNA , Feminino , Citometria de Fluxo , Camundongos , Receptores Estrogênicos/metabolismo
12.
Anticancer Res ; 39(5): 2277-2287, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092419

RESUMO

BACKGROUND: Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application. MATERIALS AND METHODS: Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified. RESULTS: Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells. CONCLUSION: Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development.


Assuntos
Neoplasias da Mama/genética , Neoplasias Mamárias Animais/genética , Proteínas de Neoplasias/genética , Neovascularização Patológica/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/patologia , Camundongos , Terapia de Alvo Molecular , Metástase Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Microambiente Tumoral/genética
13.
Oncol Res ; 27(8): 889-899, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30940289

RESUMO

The thorns of Gleditsia sinensis have been historically used in Chinese medicine and are considered one of the fundamental therapeutic herbs. Its anticancer effects are currently being explored. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and still requires the development of new drugs with higher efficiency. By using a rat HCC model implanted with cancerous Walker-256 cells, the therapeutic effects of G. sinensis extract (GSE) were assessed, as well as its regulatory effects on miRNAs. GSE significantly restored liver morphology and dramatically induced cell apoptosis in HCC rats. In addition, miR-21/181b/183 was upregulated in the HCC liver, and the elevation of these miRNAs could be alleviated by both GSE and sorafenib. PTEN/TIMP3/PDCD4 downregulation was consistent with the targets of miR-21/181b/183 in the HCC liver, and the alteration of these target genes was restored by both GSE and sorafenib. TIMP3 effects on MMP-2/9 expression were also determined. Our present findings indicate the potential of GSE in HCC treatment, and expand the understanding of miRNA-related mechanisms in the anticancer effects of GSE.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Mamárias Animais/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gleditsia/química , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , MicroRNAs/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , Extratos Vegetais/farmacologia , Ratos , Inibidor Tecidual de Metaloproteinase-3/genética
14.
Oncol Rep ; 41(6): 3155-3166, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002367

RESUMO

Baker's yeast, Saccharomyces cerevisiae, has been shown to sensitize a variety of breast cancer cell (BCC) lines to paclitaxel chemotherapy in vitro. The present study evaluated the ability of S. cerevisiae to sensitize BCCs to paclitaxel in animals bearing Ehrlich ascites carcinoma (EAC). Mice bearing EAC were intratumorally injected with dead S. cerevisiae (1x107 cells/ml) in the presence or absence of low- and high-dose paclitaxel [paclitaxel-L, 2 mg/kg body weight (BW) and paclitaxel-H, 10 mg/kg BW, respectively]. At 30 days post tumor inoculation, co-treatment with yeast plus paclitaxel-L showed improvements over paclitaxel-H alone, as measured by tumor weight (-64 vs. -53%), DNA damage (+79 vs. +62%), tumor cell apoptosis (+217 vs. +177%), cell proliferation (-56 vs. -42%) and Ki-67 marker (+95 vs. +40%). Histopathology and ultra-structural examinations showed that yeast plus paclitaxel-L enhanced apoptosis in EAC more than paclitaxel-H alone and caused comparable tumor necrosis. We conclude that baker's yeast may be used with low-dose chemotherapy to achieve the same potency as high-dose chemotherapy in mice bearing EAC. This suggests that baker's yeast may be an anticancer adjuvant and may have clinical implications for the treatment of breast cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma de Ehrlich/tratamento farmacológico , Neoplasias Mamárias Animais/tratamento farmacológico , Saccharomyces cerevisiae/química , Adenocarcinoma/patologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/genética , Carcinoma de Ehrlich/patologia , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dieta , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Animais/patologia , Camundongos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Carga Tumoral/efeitos dos fármacos
15.
Res Vet Sci ; 124: 240-247, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30947110

RESUMO

Epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties, generating metastases. Dihydroartemisinin (DHA) exhibits potent anti-cancer activities. CMTs is a potential suitable model for studies in human breast cancer research. In the present study, we separated DHA-untreated cells from CMTs cells to be a control group, the rest of the CMTs cells treated by DHA which were composed of three concentrations 5,10 as well as 20 µM. After that we cultivate the cells severally under the condition of 24, 48 and 72 h at 37 °C. CMTs cells were evaluated by Cell viability assay, Wound healing assay, Invasion assay and RT-PCR analysis for the expression of Slug, ZEB1, ZEB2 and Twist. Our results showed that DHA increased the inhibitory rate of CMTs cell and restrain TGF-ß1-induced migration and invasion of cells in a time and concentration reliant manner efficaciously. Our result also show DHA inhibits the expression of Slug, ZEB1, ZEB2 and Twist at the mRNA in vitro, the media concentration DHA (10 µM) decreased the expression level of the Slug, ZEB1, ZEB2 mRNA significantly. In conclusion, DHA inhibits canine mammary tumours cells migration and invasiveness by regulating the expression of EMT-related genes.


Assuntos
Antineoplásicos/farmacologia , Artemisininas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Mamárias Animais/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga
16.
Mol Imaging Biol ; 21(3): 436-446, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30805885

RESUMO

PURPOSE: In order to monitor the drug responses of three-dimensional mammary tumor spheroids and to elucidate the role of inter- and intra-spheroid heterogeneity in determining drug sensitivity in the spheroids, an integrated image analysis framework was developed for morphometric and metabolic characterization of the three-dimensional tumor spheroids. PROCEDURE: Three-dimensional spheroid cultures of primary mammary tumor epithelial cells isolated from freshly excised tumors from a transgenic mouse model of adenocarcinoma (MMTV-PyMT) were imaged by using vital dyes and mitochondrial membrane potential markers. Custom-developed java and python program codes facilitated image processing, numerical computation, and graphical analysis of large datasets generated from the experiments. A panel of cancer drugs (rapamycin, BEZ235, MK2206, and flavopiridol) was tested to determine the degree of drug sensitivity as well as heterogeneity in drug response. RESULTS: A new quantitative metric (growth/toxicity) was developed based on morphometric parameters that were found to track the growth and apoptotic cell populations. Further, this study identified two parameters, namely, skew and kurtosis-which report the spatial heterogeneity in mitochondrial metabolism within the spheroids. The results of this study show that three-dimensional tumor spheroids selectively respond to cancer drugs depending on the specific metabolic pathways (AKT inhibition pathway in the present study), and there exists significant heterogeneity in the untreated tumor spheroids. Drug sensitivity of the spheroids was found to be associated with significant alterations in mitochondrial heterogeneity within the spheroids. CONCLUSIONS: In conclusion, the quantitative imaging of morphometric and metabolic analysis in large image datasets can serve as an excellent tool box for characterizing tumor heterogeneity in three-dimensional tumor spheroids and potentially, in intact tumors as well.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Mamárias Animais/diagnóstico por imagem , Neoplasias Mamárias Animais/metabolismo , Esferoides Celulares/metabolismo , Animais , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Feminino , Processamento de Imagem Assistida por Computador , Neoplasias Mamárias Animais/tratamento farmacológico , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Esferoides Celulares/efeitos dos fármacos
17.
Anticancer Agents Med Chem ; 19(6): 827-839, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30648522

RESUMO

BACKGROUND: Triple Negative Breast Cancer (TNBC) tends to be more aggressive than other types of breast cancer. Resistance to chemotherapy is a major obstacle hence there is a significant need for new antineoplastic drugs with multi-target potency. Numerous Benzoisoxazole moieties have been found to possess a broad spectrum of pharmacological activities. In the present study, we have synthesized 9 novel derivatives of Benzisoxazole 7(a-i) and screened them for their biological potential. METHODS: Chemical synthesis, Mass spectrometry (HRMS), cell proliferation and cytotoxicity assay, wound healing assay, flow cytometry and nuclear staining. Angio-inhibitory activity assessed by corneal micropocket assay and in vivo peritoneal angiogenesis assay. RESULTS: The Benzisoxazole derivatives 7(a-i) were synthesized and screened for their biological potency by both in vitro and in vivo experimental models. Among the series, compound 3-(1-((3-(3(Benzyloxy)-4-methoxyphenyl)- 4,5-dihydroisoxazole-5-yl)methyl)piperidine-4-yl)6-fluorobenzo[d] isoxazole (7e) was found to be most promising, with an average IC50 value of 50.36 ± 1.7 µM in MTT assay and showed 81.3% cell death. The compound 7e also showed 60-70% inhibition on a recombinant Metastasis-Associated protein (MTA1) induced proliferation and cell migration in MDAMB-231 cells, which is known to play a major role in angiogenesis. The anti-tumour studies inferred the regression of tumour activity. This was due to inhibition of neovascularization and evoking apoptosis process as assessed by corneal vascularization, peritoneal angiogenesis and apoptotic hallmarks in 7e treated cells. CONCLUSION: These findings not only show the biological efficacy of compound 7e but it is also an effective beginning to explore the mechanism of metastasis and cancer therapy strategy targeting MTA1. The observed biological activity makes compound 7e an attractive drug candidate.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Isoxazóis/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Neoplasias Mamárias Animais/patologia , Camundongos , Estrutura Molecular , Neovascularização Patológica/patologia , Ratos , Relação Estrutura-Atividade
18.
Nano Lett ; 19(2): 997-1008, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30676760

RESUMO

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor ( S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Colágeno/metabolismo , Doxorrubicina/administração & dosagem , Neoplasias Mamárias Animais/tratamento farmacológico , Doadores de Óxido Nítrico/administração & dosagem , S-Nitrosotióis/administração & dosagem , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Feminino , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/ultraestrutura , Doadores de Óxido Nítrico/farmacologia , Proteólise/efeitos dos fármacos , S-Nitrosotióis/farmacologia , Dióxido de Silício/química , Microambiente Tumoral/efeitos dos fármacos
19.
Cancer Res ; 79(1): 159-170, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30224373

RESUMO

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the antitumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer-induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B-cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice, restored MPL/TDCM-induced protection in mice with B-cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell-produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases. SIGNIFICANCE: This work identifies a critical antitumor role for innate-like B cells localized within the peritoneal cavity and demonstrates a novel strategy to activate their tumor-killing potential.See related commentary by Tripodo, p. 5.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunidade Inata/imunologia , Imunoglobulina M/imunologia , Ativação Linfocitária/imunologia , Neoplasias Mamárias Animais/imunologia , Cavidade Peritoneal/patologia , Neoplasias Peritoneais/imunologia , Animais , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Fatores Corda/farmacologia , Feminino , Imunidade Inata/efeitos dos fármacos , Imunoglobulina M/efeitos dos fármacos , Lectinas Tipo C/agonistas , Lipídeo A/análogos & derivados , Lipídeo A/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Receptores Toll-Like/agonistas
20.
Breast Cancer Res Treat ; 173(3): 545-557, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30367332

RESUMO

PURPOSE: Exposure to the polyphenolic plant lignan secoisolariciresinol diglucoside (SDG) and its metabolite enterolactone (ENL) has been associated with reduced breast cancer progression, particularly for estrogen receptor alpha (ERα)-negative disease, and decreased preclinical mammary tumor growth. However, while preclinical studies have established that SDG and ENL affect measures of progression in models of triple-negative breast cancer (TNBC, a subset of ERα-negative disease), the molecular mechanisms underlying these effects remain unclear. METHODS: C57BL/6 mice were fed a control diet (control, 10% kcal from fat) or control diet + SDG (SDG, 100 mg/kg diet) for 8 weeks, then orthotopically injected with syngeneic E0771 mammary tumor cells (a model of TNBC); tumor growth was monitored for 3 weeks. The role of reduced NF-κB signaling in SDG's anti-tumor effects was explored in vitro via treatment with the bioactive SDG metabolite ENL. In addition to the murine E0771 cells, the in vitro studies utilized MDA-MB-231 and MCF-7 cells, two human cell lines which model the triple-negative and luminal A breast cancer subtypes, respectively. RESULTS: SDG supplementation in the mice significantly reduced tumor volume and expression of phospho-p65 and NF-κB target genes (P < 0.05). Markers of macrophage infiltration were decreased in the distal-to-tumor mammary fat pad of mice supplemented with SDG relative to control mice (P < 0.05). In vitro, ENL treatment inhibited viability, survival, and NF-κB activity and target gene expression in E0771, MDA-MB-231, and MCF-7 cells (P < 0.05). Overexpression of Rela attenuated ENL's inhibition of E0771 cell viability and survival. CONCLUSIONS: SDG reduces tumor growth in the E0771 model of TNBC, likely via a mechanism involving inhibition of NF-κB activity. SDG could serve as a practical and effective adjuvant treatment to reduce recurrence, but greater understanding of its effects is needed to inform the development of more targeted recommendations for its use.


Assuntos
Anti-Inflamatórios/farmacologia , Butileno Glicóis/farmacologia , Linho/química , Glucosídeos/farmacologia , Neoplasias Mamárias Animais/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , 4-Butirolactona/análogos & derivados , 4-Butirolactona/sangue , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Biomarcadores , Butileno Glicóis/administração & dosagem , Butileno Glicóis/química , Linhagem Celular Tumoral , Sobrevivência Celular , Citocinas/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Perfilação da Expressão Gênica , Glucosídeos/administração & dosagem , Glucosídeos/química , Imuno-Histoquímica , Lignanas/sangue , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Camundongos
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