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1.
Ultrasound Med Biol ; 45(11): 2984-2992, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31405605

RESUMO

Metastasis is a major dilemma of cancer therapy. It frequently occurs in breast cancer, which is the leading form of malignant tumor among females worldwide. Although there are therapies that provide a possible method for this challenge, such as chemotherapy, the tumoral metabolic pathway is unconventional and favors metastasis and proliferation. This magnifies the difficulty of treating breast cancer. In this study, we identified 2-deoxyglucose (2 DG) as an important glycolysis suppressor that can potentiate sonodynamic therapy (SDT) to inhibit migration and invasion. In addition, disruptions of the cell membrane microstructure were captured by a scanning electron microscope in cells treated with the co-therapy. Similarly, we detected blockages of the cell cycle process, using flow cytometry. Of note, we observed that hexokinase II (HK2), the rate-limiting enzyme of glycolysis, was notably uncoupled from the mitochondria in SDT + 2 DG co-therapy group. Furthermore, there was altered expression of HK2 and Glut1, which control glycolysis. Simultaneously, the in vivo results revealed that pulmonary metastasis was also seriously suppressed by SDT + 2 DG co-therapy. These results demonstrate this co-therapy is a promising strategy for breast cancer inhibition through metastasis and proliferation.

2.
J Transl Med ; 17(1): 191, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171000

RESUMO

BACKGROUND: Elevated protein expressions of CD markers such as IL2RA/CD25, CXCR4/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML). However, the prognostic value of mRNA expressions of these CD markers in AML remains unclear. Through our pilot evaluation, IL2RA mRNA expression appeared to be the best candidate as a prognostic biomarker. Therefore, the aim of this study is to characterize the prognostic value of IL2RA mRNA expression and evaluate its potential to refine prognostification in AML. METHODS: In a cohort of 239 newly diagnosed AML patients, IL2RA mRNA expression were measured by TaqMan realtime quantitative PCR. Morphological, cytogenetics and mutational analyses were also performed. In an intermediate-risk AML cohort with 66 patients, the mRNA expression of prognostic biomarkers (BAALC, CDKN1B, ERG, MECOM/EVI1, FLT3, ID1, IL2RA, MN1 and WT1) were quantified by NanoString technology. A TCGA cohort was analyzed to validate the prognostic value of IL2RA. For statistical analysis, Mann-Whitney U test, Fisher exact test, logistic regression, Kaplan-Meier and Cox regression analyses were used. RESULTS: In AML cohort of 239 patients, high IL2RA mRNA expression independently predicted shorter relapse free survival (RFS, p < 0.001) and overall survival (OS, p < 0.001) irrespective of age, cytogenetics, FLT3-ITD or c-KIT D816V mutational status. In core binding factor (CBF) AML, high IL2RA mRNA expression correlated with FLT3-ITD status (p = 0.023). Multivariable analyses revealed that high IL2RA expression (p = 0.002), along with c-KIT D816V status (p = 0.013) significantly predicted shorter RFS, whereas only high IL2RA mRNA expression (p = 0.014) significantly predicted shorter OS in CBF AML. In intermediate-risk AML in which multiple gene expression markers were tested by NanoString, IL2RA significantly correlated with ID1 (p = 0.006), FLT3 (p = 0.007), CDKN1B (p = 0.033) and ERG (p = 0.030) expressions. IL2RA (p < 0.001) and FLT3 (p = 0.008) expressions remained significant in predicting shorter RFS, whereas ERG (p = 0.008) and IL2RA (p = 0.044) remained significant in predicting shorter OS. Similar analyses in TCGA intermediate-risk AML showed the independent prognostic role of IL2RA in predicting event free survival (p < 0.001) and OS (p < 0.001). CONCLUSIONS: High IL2RA mRNA expression is an independent and adverse prognostic factor in AML and specifically stratifies patients to worse prognosis in both CBF and intermediate-risk AML.

3.
Lasers Surg Med ; 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30277589

RESUMO

OBJECTIVES: Compared to normal cells, malignant cells have a high degree of aerobic glycolysis, also known as the Warburg effect. Therefore, supplementing photodynamic therapy (PDT), an established cancer therapy, with metabolic inhibitors can augment the mitochondrial damage by depleting ATP. To assess the combined impact of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and PDT on apoptosis and autophagy in human breast cancer cells, and examine the molecular basis. METHODS: Calcium-AM/PI double staining was used to evaluate cell viability. Reactive oxygen species (ROS), mitochondria membrane potential (MMP), nuclear morphology, and autophagosomes were measured using specific fluorescent markers. In addition, translocation of the apoptosis inducing factor (AIF) from the mitochondria to nucleus was imaged by confocal laser scanning microscopy, and DNA fragmentation was measured using PI staining and comet assay. PGC-1α expression, oxidative phosphorylation, ATP levels, and autophagy related proteins were detected by qRT-PCR, seahorse bioscience XFP extracellular flux analyzer, and Western blotting, respectively. RESULTS: Compared to with either monotherapy, 2-DG+PDT resulted in significantly higher cytotoxicity in the three breast cancer cell lines (MDA-MB-231, MCF-7, and 4T1), which was consistent with tumor growth regression trends seen in the 4T1 xenograft model. A synergistic augmentation of mitochondrial dysfunction (in terms of ROS generation, MMP loss, and PGC-1α down-regulation) and ATP depletion was seen in cells receiving 2-DG and PDT. In addition, nuclear translocation of AIF and the subsequent DNA damage indicated that the cytotoxic effects were mediated by a caspase-independent mechanism, which was relieved by the ROS scavenger N-acetylcysteine. Autophagy via the AMP-activated protein kinase (AMPK) was also observed following 2-DG+PDT, and reversed upon pre-treatment with the autophagy inhibitor 3-methyladenine. CONCLUSIONS: The anti-cancer effects of 2-DG+PDT are mediated by both mitochondria triggered apoptosis and AMPK-mediated autophagy. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc.

4.
Photodiagnosis Photodyn Ther ; 24: 198-205, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30268863

RESUMO

BACKGROUND: Esophageal cancer is a common gastrointestinal cancer. About 300,000 people die from esophageal cancer every year in the world. Photodynamic therapy (PDT) has attracted attention as a feasible cancer therap for this diagnosis. Sinoporphyrin sodium (DVDMs) is a novel sensitizer isolated from photofrin. In this study, we aimed to investigate the effects of DVDMs mediated photodynamic therapy and the possible mechanism on human esophageal cancer Eca-109 cells. METHODS: Cell viability was measured by MTT assay and cell apoptosis was determined by Annexin V-PE/7-AAD and western blot. MDC staining and western blot were used to evaluate cell autophagy. The production of intracellular reactive oxygen species (ROS) was detected by flow cytometry. The expression of MAPK and HO-1 were detected by western blot. RESULTS: DVDMs-PDT decreased cell viability and induced cell apoptosis and autophagy. Autophagy inhibition reduced cell apoptosis triggered by DVDMs-PDT in Eca-109 cells. Generation of ROS was detected in DVDMs-PDT group. p38MAPK, JNK and HO-1 were activated after PDT treatment and the activation were reversed by adding ROS scavenger NAC. CONCLUSIONS: Our studies demonstrated that DVDMs-PDT induced apoptosis and autophagy in Eca-109 cells. DVDMs-PDT induced ROS generation in Eca-109 cells, and the generation of ROS activated p38MAPK and JNK. Activation of p38MAPK and JNK may be involved in PDT-induced apoptosis.

5.
In Vitro Cell Dev Biol Anim ; 54(8): 545-548, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30083840

RESUMO

Research of epithelial cells in musk gland is lacking. There are no good characterized epithelial cell lines that can provide complementary in vitro models for in vivo research. We successfully cultivated epithelial cells of musk gland for the first time. The protocol described here produces epithelial cell lines from the mature secreting musk gland. Based on morphological observation, epithelial cells of musk gland were isolated and cultured in vitro. After the third passage, the musk gland-derived cells were filled with many lipid droplets and proliferated well. We used gas chromatography and mass spectrometry to explore the chemical composition of lipid droplets in the musk gland-derived cells. The main components of secreted lipid droplet were alkanes, esters, amines, alcohols, ketones, organic acids, and aldehydes. Muscone, which is the main active compound of musk, was not found. This is a new attempt in the field of animal musk to obtain naturally secreted animal musk in vitro by cloning specialized cells. In conclusion, this study provides a reference at the cellular level to further analyze the biology and physiology of the musk gland epithelium and secretion mechanism of musk deer.

6.
J Med Chem ; 61(16): 7189-7201, 2018 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-30048595

RESUMO

A photosensitizer with high phototoxicity, low dark toxicity, and good water solubility is crucial for effective photodynamic therapy (PDT). In this study, a novel class of porphyrin-based water-soluble derivative and its isomers, named photohexer-1 (P-1) and photohexer-2 (P-2), were synthesized and investigated for anticancer activity. Both of the isomers, P-1 and P-2, could be utilized as potential sensitizers for PDT not only owing to their definite constituents but predominantly due to their good absorption in the phototherapeutic window and high generation of intracellular ROS. Therein, P-2 exhibited stronger phototoxicity against breast cancer cells with weaker dark toxicity than P-1; however, both P-1 and P-2 were highly phototoxic as compared to their homologous compound, hematoporphyrin monomethyl ether (HMME). These findings were consistent with the antitumor efficacy in vivo. Moreover, P-1 and P-2 could both effectively localize in multiple subcellular organelles, triggering increased cellular apoptosis or necrosis under laser irradiation as compared to HMME. In conclusion, the findings of the study suggest that the two highly water-soluble porphyrin derivatives may serve as promising putative photosensitizers for improving the therapeutic efficiency of PDT.

7.
Ultrasound Med Biol ; 44(6): 1233-1243, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29555321

RESUMO

Inhibition of the increased aerobic glycolysis in cancer cells is a promising methodology for various malignant tumor therapies but is limited by systemic toxicity, at least in part. Recent studies suggest that dual restriction of glycolysis and mitochondrial function may overcome this issue. Sonodynamic therapy (SDT), a prospective therapeutic modality for cancers, has been reported to induce mitochondria-dependent cell damage. Here, we investigated the combined effect of SDT and 2-deoxyglucose (2DG), an anti-glycolytic agent, on breast cancer both in vitro and in vivo. In vitro, we found that, compared with a single treatment, SDT + 2DG co-treatment significantly decreased cell viability and increased cell apoptosis. Moreover, the generation of reactive oxygen species was enhanced and mitochondrial membrane potential (MMP) was reduced after SDT + 2DG co-treatment. Furthermore, the oxidative phosphorylation was also restrained after SDT + 2DG co-treatment, further to cause the blockage of ATP provision. In vivo, SDT + 2DG markedly reduced tumor volume and weight, consistent with the in vitro findings. Furthermore, toxicology tests concurrently indicated that the dosages of sinoporphyrin sodium and 2DG were comparatively tolerable. Generally, these results indicated that SDT + 2DG combination therapy may be an available, promising therapy for highly metastatic breast cancer.

8.
Nanomaterials (Basel) ; 8(2)2018 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-29462941

RESUMO

Layered double hydroxides (LDHs) have been widely used as an important subset of solid base catalysts. However, developing low-cost, small-sized LDH nanoparticles with enhanced surface catalytic sites remains a challenge. In this work, silica aerogel (SA)-supported, small-sized Mg-Al LDH nanosheets were successfully prepared by one-pot coprecipitation of Mg and Al ions in an alkaline suspension of crushed silica aerogel. The supported LDH nanosheets were uniformly dispersed in the SA substrate with the smallest average radial diameter of 19.2 nm and the thinnest average thickness of 3.2 nm, both dimensions being significantly less than those of the vast majority of LDH nanoparticles reported. The SA/LDH composites also showed large pore volume (up to 1.3 cm3·g) and pore diameter (>9 nm), and therefore allow efficient access of reactants to the edge catalytic sites of LDH nanosheets. In a base-catalyzed Henry reaction of benzaldehyde with nitromethane, the SA/LDH catalysts showed high reactant conversions and favorable stability in 6 successive cycles of reactions. The low cost of the SA carrier and LDH precursors, easy preparation method, and excellent catalytic properties make these SA/LDH composites a competitive example of solid-base catalysts.

9.
Artigo em Inglês | MEDLINE | ID: mdl-29092957

RESUMO

Pancreatic neuroendocrine tumors (PNETs) are a genomically and clinically heterogeneous group of pancreatic neoplasms often diagnosed with distant metastases. Recurrent somatic mutations, chromosomal aberrations, and gene expression signatures in PNETs have been described, but the clinical significance of these molecular changes is still poorly understood, and the clinical outcomes of PNET patients remain highly variable. To help identify the molecular factors that contribute to PNET progression and metastasis, and as part of an ongoing clinical trial at the BC Cancer Agency (clinicaltrials.gov ID: NCT02155621), the genomic and transcriptomic profiles of liver metastases from five patients (four PNETs and one neuroendocrine carcinoma) were analyzed. In four of the five cases, we identified biallelic loss of MEN1 and DAXX as well as recurrent regions with loss of heterozygosity. Several novel findings were observed, including focal amplification of MYCN concomitant with loss of APC and TP53 in one sample with wild-type MEN1 and DAXX Transcriptome analyses revealed up-regulation of MYCN target genes in this sample, confirming a MYCN-driven gene expression signature. We also identified a germline NTHL1 fusion event in one sample that resulted in a striking C>T mutation signature profile not previously reported in PNETs. These varying molecular alterations suggest different cellular pathways may contribute to PNET progression, consistent with the heterogeneous clinical nature of this disease. Furthermore, genomic profiles appeared to correlate well with treatment response, lending support to the role of prospective genotyping efforts to guide therapy in PNETs.

10.
Nanoscale Res Lett ; 12(1): 549, 2017 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-28948484

RESUMO

In this work, hydrozincite and Zn/Al-CO32- hydrotalcite supported on silica aerogel were prepared via a simple and economical process and used as adsorbents for Pb(II) removal. The supported hydrozincite and Zn/Al-CO32- hydrotalcite possess ultra-thin thickness, high surface area, and weak crystallinity. In the batch Pb(II) adsorption experiments, the adsorbents with higher Zn(II) contents showed higher Pb(II) adsorption capacities, and the adsorption data fitted well with the Langmuir isotherm model and pseudo-second-order kinetic model, indicating a mechanism of surface chemisorption. The adsorption capacities calculated based Langmuir isotherm model are 684.9 mg/g and 555.6 mg/g for the supported hydrozincite and Zn/Al-CO32- hydrotalcite, respectively, higher than the adsorption capacities of other hydrotalcite-based adsorbents and most of other inorganic adsorbents reported previously. The XRD diffraction peaks of hydrozincite and Zn/Al-CO32- hydrotalcite disappeared after the adsorption, and the Pb(II) species were uniformly dispersed in the adsorbents in form of Pb3(CO3)2(OH)2 proven by TEM, EDS mapping and XRD analysis, demonstrating the nature of the adsorption is the precipitation conversion of hydrozincite or Zn/Al-CO32- hydrotalcite into Pb3(CO3)2(OH)2. These results demonstrate the synergic Pb(II) removal effect of the CO32- and OH- derived from hydrozincite and Zn/Al-CO32- hydrotalcite together with their ultra-thin thickness and high surface area contribute the excellent properties of the adsorbents.

11.
Cureus ; 9(6): e1332, 2017 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-28698832

RESUMO

We report on a 56-year-old Caucasian female, diagnosed with locally advanced, hormone-receptor-positive, and human epidermal growth factor receptor 2 (HER2)-positive cancer of the left breast. The patient received neoadjuvant chemotherapy with adriamycin/cyclophosphamide (AC) followed by docetaxel/trastuzumab. A partial clinical and radiographical response was documented after four cycles of AC. Approximately one week after the first cycle of docetaxel and trastuzumab, the patient presented with diffuse edema, erythema, and induration involving the entire left breast. The differential diagnoses included infection, inflammatory response/reaction to docetaxel, or cancer progression. After a multidisciplinary review, the decision was made to stop the docetaxel and deliver neoadjuvant radiation treatment concurrent with trastuzumab. Approximately four weeks after radiation therapy completion, the patient underwent a left total mastectomy and axillary dissection, with pathologic complete response (pCR) in the breast and axillary nodal disease. After surgery, systemic therapy was resumed with paclitaxel and trastuzumab, with a plan to start adjuvant endocrine therapy after completion of chemotherapy. We will discuss clinical considerations in the management of the unexpected findings of acute inflammatory response in the breast and nodal regions during neoadjuvant chemotherapy. Associations between intrinsic breast cancer subtype and pCR in locally advanced breast cancer will also be reviewed.

12.
Biomaterials ; 141: 50-62, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28667899

RESUMO

Anti-microtubule therapy represents one of the most strategic cancer therapeutics. Tublin inhibitor such as paclitaxel (PTX) is well known to disturb the dynamic nature of microtubules, being considered as the first-line drug for various malignancies. However, PTX does not show favorable clinical outcomes due to serious systemic toxicities and low selectivity. The development of PTX delivery systems and combinational therapies has been conducted to enhance PTX efficacy with poorly defined mechanisms. Herein, we introduced a reactive oxygen species producible composite liposome based on a new photosensitizer sinoporphyrin sodium (DVDMS) to enhance the therapeutic effect of PTX through photochemical stimulation, and more importantly, the pivotal molecular regulation mechanisms were specifically explored. Compared with DVDMS-liposome (DL) or PTX-liposome (PL), the composite liposome DVDMS-PTX-liposome (PDL) exhibited a superior anti-tumor advantage following laser irradiation against MCF-7 breast cancer. The localized PTX release after PDL administration greatly decreased the drug dosage and laser power required, leading to much higher safety and lower costs. In vitro, the combined treatment significantly suppressed cell viability and potentiated cell apoptosis. The apoptotic central regulator Mcl-1 as a favorable target, was evaluated in association with photochemically enhanced sensitivity to anti-tubulin chemotherapeutics. Phosphorylation of Mcl-1 led to its direct degradation with the proteasome system, making it relatively unstable and potentiating cell death resulting from photochemical synergy via PDL plus laser irradiation. Further, a decrease in ATP production and glycolysis after PDL plus laser would prevent the possible energy-switch and apoptosis-escape by PTX alone treatment, thereby resulted in increased cell death in combinational therapy. Systemic administration of PDL followed by in vivo photochemotherapy achieved significantly improved therapeutic effects compared to either alone. And, the intrinsic fluorescence of DVDMS facilitated real-time imaging of PDL in tumors. Therefore, the present strategy with details at the molecular regulation could be a promising platform for antitublin chemotherapeutics.


Assuntos
Neoplasias da Mama/dietoterapia , Paclitaxel/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Lipossomos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacocinética , Porfirinas/administração & dosagem , Porfirinas/farmacocinética
13.
Oncotarget ; 7(52): 85798-85812, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-27741524

RESUMO

INTRODUCTION: This study was designed to investigate the combined influence of ATM and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes. METHODS: 532 formalin-fixed paraffin-embedded specimens of resected primary breast tumors were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using fluorescence and brightfield immunohistochemistry respectively, and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome. RESULTS: Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p = 0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02). CONCLUSIONS: These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/análise , Neoplasias da Mama/patologia , Antígeno Ki-67/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
14.
Ultrasound Med Biol ; 41(10): 2731-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26166458

RESUMO

The main objective of this study was to evaluate the efficacy of administration of doxorubicin (DOX) in combination with protoporphyrin IX (PpIX)-assisted low-level therapeutic ultrasound (US) in K562/DOX cells as a potential strategy in cancer therapy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine the cytotoxicity of different treatments. Apoptosis was analyzed using annexin V-PE/7-amino-actinomycin D staining. Changes in DNA fragmentation, intracellular reactive oxygen species production, cellular membrane permeability, P-glycoprotein expression and DOX uptake were analyzed with flow cytometry. Under optimal conditions, PpIX-US significantly aggravated DOX-induced K562/DOX cell death, compared with either monotherapy. Synergistic potentiation of DNA damage, generation of reactive oxygen species and P-glycoprotein inhibition were observed. Plasma membrane integrity changed slightly after US exposure, and DOX uptake was notably improved after PpIX-US exposure. The results indicate that PpIX-US could increase the susceptibility of tumors to antineoplastic drugs, suggesting a clinical potential method for sonodynamic therapy-mediated tumor chemotherapy.


Assuntos
Doxorrubicina/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Fotoquimioterapia/métodos , Protoporfirinas/administração & dosagem , Terapia por Ultrassom/métodos , Antibióticos Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Terapia Combinada/métodos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Células K562 , Fármacos Fotossensibilizantes/administração & dosagem
15.
Breast Cancer Res ; 17: 65, 2015 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-25935535

RESUMO

INTRODUCTION: The serine/threonine protein kinase ataxia telangiectasia mutated (ATM) is critical in maintaining genomic integrity. Upon DNA double-strand breaks, ATM phosphorylates key downstream proteins including p53 and BRCA1/2, thereby orchestrating complex signaling pathways involved in cell cycle arrest, DNA repair, senescence and apoptosis. Although sporadic mutation of ATM occurs rarely in breast cancer, the status of its protein expression and its clinical significance in breast cancer remain not well established. Our study was designed to investigate the influence of ATM protein in both tumor and cancer-associated stroma on clinical outcome in hormone-positive (HPBC) and hormone-negative (HNBC) early-stage breast cancer (EBC). METHODS: Tissue microarrays (TMAs), containing formalin-fixed, paraffin-embedded resected tumors from two cohorts of patients (HPBC cohort: n=130; HNBC cohort: n=168) diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, were analyzed for ATM protein expression using fluorescence immunohistochemistry (IHC) and automated quantitative analysis (AQUA). ATM expression levels were measured within the tumor as a whole (tATM) as indicated by pan-cytokeratin expression, tumor nuclear compartment (nATM) as indicated by both DAPI and pan-cytokeratin-positive results, and cancer-associated stroma (csATM) as indicated by vimentin-positive and pan-cytokeratin-negative results. ATM expression levels within these compartments were correlated with clinical outcome. RESULTS: While tATM and nATM were significantly lower in tumors compared to normal breast epithelial tissues, csATM was significantly higher than the corresponding normal tissue compartment. In addition, the median expression level of both tATM and nATM were two- to threefold lower (P<0.001) in HNBC than in HPBC. In both HNBC and HPBC cohorts, patients with low tATM, nATM and csATM tumors had significantly poorer survival outcomes than those with a high tATM, nATM and csATM, but this effect was more pronounced in HNBC. A multivariate analysis demonstrates that these biomarkers predict survival independent of tumor size and lymph node status, but only in the HNBC cohort (P<0.001). CONCLUSIONS: Low ATM protein expression in both malignant tumor and stromal compartments likely contributes to the aggressive nature of breast cancer and is an independent prognostic factor associated with worse survival in HNBC patients.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptores Estrogênicos/deficiência , Receptores de Progesterona/deficiência , Células Estromais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Carga Tumoral
16.
J Bioenerg Biomembr ; 47(3): 189-97, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25631472

RESUMO

Most cancer cells have the specially increased glycolytic phenotype, which makes this pathway become an attractive therapeutic target. Although glycolytic inhibitor 2-deoxyglucose (2-DG) has been demonstrated to potentiate the cytotoxicity of photodynamic therapy (PDT), the impacts on cell migration after the combined treatment has never been reported yet. The present study aimed to analyze the influence of glycolytic inhibitors 2-DG and 3-bromopyruvate (3-BP) combined with Ce6-PDT on cell motility of Triple Negative Breast Cancer MDA-MB-231 cells. As determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium-bromide-Tetraz-olium (MTT) assay, more decreased cell viability was observed in 2-DG + PDT and 3-BP + PDT groups when compared with either monotherapy. Under optimal conditions, synergistic potentiation on cell membrane destruction and the decline of cell adhesion and cells migratory ability were observed in both 2-DG + PDT and 3-BP + PDT by electron microscope observation (SEM), wound healing and trans-well assays. Besides, serious microfilament network collapses as well as impairment of matrix metalloproteinases-9 (MMP-9) were notably improved after the combined treatments by immunofluorescent staining. These results suggest that 2-DG and 3-BP can both significantly potentiated Ce6-PDT efficacy of cell migration inhibition.


Assuntos
Movimento Celular/efeitos dos fármacos , Desoxiglucose/farmacologia , Glicólise/efeitos dos fármacos , Fotoquimioterapia/métodos , Piruvatos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Imunofluorescência , Humanos , Microscopia Eletrônica de Varredura , Sais de Tetrazólio , Tiazóis , Neoplasias de Mama Triplo Negativas/radioterapia
17.
Zhongguo Zhong Yao Za Zhi ; 40(22): 4319-23, 2015 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-27097400

RESUMO

Forest musk deer is one of the large-scale farming musk deer animals with the largest population at the same time. The male musk deer can secrete valuable medicines, which has high medicinal and economic value. Due to the loss of habitat and indiscriminate hunting, the numbers of wild population specie and the distribution have been drastically reduced. Therefore, in-depth understanding of the molecular genetics progress of forest musk deer will pave a way for musk deer protection and breeding. In this review, the progress associated with the molecular marker, genetic classification, artificial breeding, musk secretion and disease in past decades were reviewed, in order to provide a theoretical basis for subsequent molecular genetic researches in forest musk deer.


Assuntos
Cervos/genética , Animais , Cruzamento , Cervos/classificação , Cervos/crescimento & desenvolvimento , Cervos/metabolismo , Ecossistema , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/metabolismo , Feminino , Masculino
18.
Ultrason Sonochem ; 23: 116-27, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25465095

RESUMO

Sono-Photodynamic therapy (SPDT), a new modality for cancer treatment, is aimed at enhancing anticancer effects by the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we investigated the antitumor effect and possible mechanisms of Chlorin e6 (Ce6) mediated SPDT (Ce6-SPDT) on breast cancer both in vitro and in vivo. MTT assay revealed that the combined therapy markedly enhanced cell viability loss of breast cancer cell lines (MDA-MB-231, MCF-7 and 4T1) compared with SDT and PDT alone. Propidium iodide/hoechst33342 double staining reflected that 4T1 cells with apoptotic morphological characteristics were significantly increased in groups given combined therapy. Besides, the combined therapy caused obvious mitochondrial membrane potential (MMP) loss at early 1 h post SPDT treatment. The generation of intracellular reactive oxygen species (ROS) detected by flow cytometry was greatly increased in 4T1 cells treated with the combination therapy, and the loss of cell viability and MMP could be effectively rescued by pre-treatment with the ROS scavenger N-acetylcysteine (NAC). Further, Ce6-SPDT markedly inhibited the tumor growth (volume and weight) and lung metastasis in 4T1 tumor-bearing mice, but had no effect on the body weight. Hematoxylin and eosin staining revealed obvious tissue destruction with large spaces in the Ce6-SPDT groups, and TUNEL staining indicated tumor cell apoptosis after treatment. Immunohistochemistry analysis showed that the expression level of VEGF and MMP were significantly decreased in the combined groups. These results indicated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, loss of MMP and generation of ROS might be involved. In addition, Ce6-mediated SPDT significantly inhibited tumor growth and metastasis in mouse breast cancer 4T1 xenograft model, in which MMP-9 and VEGF may play a crucial role.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Fotoquimioterapia , Porfirinas/farmacologia , Terapia por Ultrassom , Animais , Transporte Biológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Espaço Intracelular/efeitos da radiação , Neoplasias Pulmonares/secundário , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/efeitos da radiação , Metástase Neoplásica , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Photochem Photobiol Sci ; 13(12): 1793-803, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25363473

RESUMO

Malignant cells are highly dependent on aerobic glycolysis, which differs significantly from normal cells (the Warburg effect). Interference of this metabolic process has been considered as an innovative method for developing selective cancer therapy. A recent study demonstrated that the glycolysis inhibitor 2-deoxyglucose (2-DG) can potentiate PDT efficacy, whereas the possible mechanisms have not been carefully investigated. This study firstly proved the general potentiation of PDT efficacy by 2-DG and 3-bromopyruvate (3-BP) in human breast cancer MDA-MB-231 cells, and carefully elucidated the underlying mechanism in the process. Our results showed that both 2-DG and 3-BP could significantly promote a PDT-induced cell cytotoxic effect when compared with either monotherapy. Synergistic potentiation of mitochondria- and caspase-dependent cell apoptosis was observed, including a mitochondrial membrane potential (MMP) drop, Bax translocation, and caspase-3 activation. Besides, ROS generation and the expression of oxidative stress related proteins such as P38 MAPK phosphorylation and JNK phosphorylation were notably increased after the combined treatments. Moreover, when pretreated with the ROS scavenger N-acetylcysteine (NAC), the ROS generation, the MMP drop, cell apoptosis and cytotoxicity were differently inhibited, suggesting that ROS was vertical in the pro-apoptotic process induced by 2-DG/3-BP combined with PDT treatment. These results indicate that the combination of glycolytic antagonists and PDT may be a promising therapeutic strategy to effectively kill cancer cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/terapia , Desoxiglucose/farmacologia , Fotoquimioterapia/métodos , Piruvatos/farmacologia , Acetilcisteína/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Apoptose/efeitos da radiação , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , Feminino , Depuradores de Radicais Livres/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , MAP Quinase Quinase 4/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/fisiologia , Membranas Mitocondriais/efeitos da radiação , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Pharmazie ; 69(8): 621-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25158574

RESUMO

Protoporphyrin IX (PpIX) is an effective hematoporphyrin derivative, widely adopted in photodynamic therapy (PDT) and sonodynamic therapy (SDT). As a sensitizer, PpIX could significantly enhance laser light or ultrasound causing tumor cell damage in PDT/SDT studies. However, the biological function of PpIX itself has not been carefully defined. Recently, studies indicate that PpIX alone can inhibit Hela cell proliferation, but the potential mechanism was unclear. Therefore, in the present study it was investigated whether the proliferation inhibition effect generally occurred in human breast cancer MCF-7 and MDA-MB-231 cells. Different sensitivities and the involved mechanisms were carefully explored. Our results show that PpIX preferentially accumulated and selectively caused cell damage in human breast cancer MCF-7 and MDA-MB-231 cells compared with mouse embryonic fibroblast NIH-3T3. In vitro, PpIX induced cell viability decrease, intracellular ROS (reactive oxygen species) generation, and DNA damage in a concentration-dependent and cell-specific manner. MCF-7 was more sensitive to PpIX than MDA-MB-231 cells at the same PpIX dose. Western blots showed obvious enhancement of P53, and PUMA in a concentration dependent manner in MCF-7 cells, but not in MDA-MB-231 cells. In cell-free system, we also found that PpIX could interact with some large biological molecules, such as calf thymus DNA, and induce hyperchromic effects in spectroscopic analysis. Our findings imply that DNA might be one of the main targets of PpIX, and PpIX alone can cause significant tumor cell damage through ROS generation, while P53 status may play an important role in these processes.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/farmacologia , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Feminino , Humanos , Indicadores e Reagentes , Células MCF-7 , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , RNA Neoplásico/biossíntese , RNA Neoplásico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Espectrofotometria Ultravioleta
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