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1.
Bioelectrochemistry ; 131: 107350, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31518962

RESUMO

Curcumin (Cur), the yellow pigment of well-known turmeric (Curcuma longa L.) is effective in multiple cancers including triple negative breast cancer (TNBC). In combination with electrical pulses (EP), enhanced effects of curcumin (Cur + EP) are observed in TNBC cells. To gain insights into the mechanisms of enhanced anticancer effects of Cur + EP, we studied the proteins involved in the anticancer activity of Cur + EP in MDA-MB-231, human TNBC cells using high-throughput global proteomics. A curcumin dose of 50 µM was applied with eight, 1200 V/cm, 100 µs pulses, the most commonly used electrochemotherapy (ECT) parameter in clinics. Results show that the Cur + EP treatment reduced the clonogenic ability in MDA-MB-231 cells, with the induction of apoptosis. Proteomic analysis identified a total of 1456 proteins, of which 453 proteins were differentially regulated, including kinases, heat shock proteins, transcription factors, structural proteins, and metabolic enzymes. Eight key glycolysis proteins (ALDOA, ENO2, LDHA, LDHB, PFKP, PGM1, PGAM1 and PGK1) were downregulated in Cur + EP from Cur. There was a switch in the metabolism with upregulation of 10 oxidative phosphorylation pathway proteins and 8 tricarboxylic acid (TCA) cycle proteins in the Cur + EP sample, compared to curcumin. These results provide novel systematic insights into the mechanisms of ECT with curcumin.


Assuntos
Antineoplásicos/uso terapêutico , Curcumina/uso terapêutico , Eletroquimioterapia/métodos , Proteínas de Neoplasias/metabolismo , Proteômica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Curcumina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Glicólise , Humanos , Fosforilação Oxidativa , Via de Pentose Fosfato/efeitos dos fármacos , Reprodutibilidade dos Testes , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
2.
Sci Rep ; 9(1): 19124, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31819154

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

3.
Sci Rep ; 9(1): 13916, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558821

RESUMO

Due to the lack of the three main receptors, triple negative breast cancer (TNBC) is refractive to standard chemotherapy. Hence, alternate therapies are needed. TNBCs utilize glycolysis, which heightens their growth, proliferation, invasiveness, chemotherapeutic resistance and poor therapeutic response. This calls for novel therapeutic strategies to target these metabolic vulnerabilities present in TNBC. Electroporation-mediated chemotherapy, known as electrochemotherapy (ECT) is gaining momentum as an attractive alternative. However, its molecular mechanisms need better understanding. Towards this, label-free quantitative proteomics is utilized to gain insight into the anticancer mechanisms of ECT using electrical pulses (EP) and Cisplatin (CsP) on MDA-MB-231, human TNBC cells. The results indicate that EP + CsP significantly downregulated 14 key glycolysis proteins (including ENO1, LDHA, LDHB, ACSS2, ALDOA, and PGK1), compared to CsP alone. EP + CsP caused a switch in the metabolism with upregulation of 34 oxidative phosphorylation pathway proteins and 18 tricarboxylic acid (TCA) cycle proteins compared to CsP alone, accompanied by the upregulation of proteins linked to several metabolic reactions, which produce TCA cycle intermediates. Moreover, EP + CsP promoted multiple pathways to cause 1.3-fold increase in the reactive oxygen species concentration and induced apoptosis. The proteomics results correlate well with cell viability, western blot, and qPCR data. While some effects were similar for EP, more comprehensive and long-lasting effects were observed for EP + CsP, which demonstrate the potential of EP + CsP against TNBC cells.

4.
Electrophoresis ; 39(17): 2262-2269, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29947027

RESUMO

Every forty minutes, one person dies in the USA due to glioblastoma multiforme; a deadly form of brain cancer with an average five-year survival rate less than 3%. The current standard of care for treatment involves surgical resection of the accessible tumor followed by radiation therapy and concomitant chemotherapy. Despite their potency, delivering chemotherapeutic agents to the brain is limited by the highly selective blood-brain barrier, which prevents molecules >500 Da from reaching the brain. Other techniques, such as convection-enhanced delivery, controlled release by drug-loaded wafers or intracerebroventricular infusion have limited clinical utility due to unpredictable targeting and volume of drug distribution. We introduce a novel drug delivery technique that can use direct current electric fields to deliver charged chemotherapeutics to the site of brain parenchyma after tumor resection. We fabricate and characterize an implantable drug delivery system using flushable electrodes to deliver the charged chemotherapeutic or doxorubicin (+1) in a brain tissue-mimic agarose gel (0.2% w/v) model by electrophoresis. The optimized capillary-embedded electrode system exhibited a sustained movement of charged doxorubicin through nearly 3.5 mm in four hours, a distance for achieving effective intratumoral concentrations.


Assuntos
Neoplasias Encefálicas , Encéfalo/cirurgia , Sistemas de Liberação de Medicamentos , Eletroforese , Glioblastoma , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Eletrodos , Eletroforese/instrumentação , Eletroforese/métodos , Azul Evans , Glioblastoma/tratamento farmacológico , Glioblastoma/cirurgia , Humanos , Modelos Biológicos , Imagens de Fantasmas
5.
BMC Complement Altern Med ; 18(1): 104, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29558998

RESUMO

BACKGROUND: Lung adenocarcinoma is the most common subtype of Non small cell lung cancer in which the PI3K/Akt cascade is frequently deregulated. The ubiquitous expression of the PI3K and the frequent inactivation of PTEN accounts for the prolonged survival, evasion of apoptosis and metastasis in cancer. This has led to the development of PI3K inhibitors in the treatment of cancer. Synthetic PI3K inhibitors undergoing clinical and preclinical studies are toxic in animals. Hence, there is a critical need to identify PI3K inhibitor(s) of natural origin. The current study aims to explore the efficacy of the red algae Gelidiella acerosaon inhibition of cell proliferation, migration and the expression of cell survival genes in lung adenocarcinoma cell line A549. METHODS: The phytoconstituents of Gelidiella acerosa were extracted sequentially with solvents of different polarity, screened qualitatively and quantitatively for secondary metabolites and characterized by GC-MS. The in-vitro studies were performed to check the efficacy of the extract on cell proliferation (MTT assay), cell invasion (scratch assay and colony formation assay), apoptosis (fluorescent, confocal microscopy and flow cytometry) and expression of apoptosis and cell survival proteins including PI3K, Akt and GSK3ß and matrix metalloproteinase MMP2 and MMP9 by Western blot method. The antitumor activity of GAE was analyzed in a tumor model of Zebrafish. RESULTS: The outcomes of the in vitro analysis showed an inhibition of cell proliferation, induction of apoptosis, inhibition of cell migration and colonization by the crude extract. The analysis of protein expression showed the activation of caspases 3 and Pro apoptotic protein Bax accompanied by decreased expression of Bcl-2 and Bcl-XL. On the other hand, subsequent activation of GSK3ß and down regulation of PI3K, Akt were observed. The decreased expression of MMP2 correlated with the antimetastatic activity of the extract. The in vivo studies showed an inhibition of tumor growth by GAE in Zebrafish. CONCLUSION: The phytoconstituents of algal extract contributed to the anticancer properties as evidenced by in vitro and in vivo studies. These phytoconstituents can be considered as a natural source of PI3K/Akt inhibitor for treatment of cancers involving the PI3K cascade.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Extratos Vegetais/farmacologia , Rodófitas/química , Células A549 , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Peixe-Zebra
6.
Biochem Biophys Res Commun ; 491(4): 1015-1020, 2017 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-28780353

RESUMO

Triple negative breast cancer (TNBC) is difficult to treat due to lack of the three receptors, commonly used for treating breast cancers. Current standard of cure is either ineffective or refractive to many patients. Thus, there is a critical need for alternate, affordable therapies for TNBC cancers. Towards this, electrical pulse-mediated chemotherapy, known as electrochemotherapy is a viable option, because it uses the synergy of electrical pulses and the anticancer properties of chemo drug. Considering the cost and the harsh side effects of various commonly administered chemo drugs, in this study, low cost, yet effective, natural phytochemical curcumin is studied for its anticancer effect on MDA-MB-231, TNBC cells. We applied eight 10 µs, 2500 V/cm or 5000 V/cm pulses with 10 µM concentration of curcumin, and measured cell viability and cytotoxicity. Results indicate that cell survival, as low as 4% was induced by 5000 V/cm pulses, after 72 h, while it was 15% after 24 h. This demonstrates the potential of this treatment for TNBC and the transfer to clinical practice.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Curcumina/administração & dosagem , Curcumina/farmacologia , Eletroquimioterapia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/uso terapêutico , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Eletroquimioterapia/efeitos adversos , Humanos , Relação Estrutura-Atividade , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas
7.
Mol Biotechnol ; 41(1): 69-82, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18821065

RESUMO

As the medical field moves from treatment of diseases with drugs to treatment with genes, safe and efficient gene delivery systems are needed to make this transition. One such safe, non-viral, and efficient gene delivery system is electroporation (electrogenetherapy). Exciting discoveries using electroporation could make this technique applicable to drug and vaccine delivery in addition to gene delivery. Typically milli and microsecond pulses have been used for electroporation. Recently, the use of nanosecond electrical pulses (10-300 ns) at very high magnitudes (10-300 kV/cm) has been studied for direct DNA transfer to the nucleus in vitro. This article reviews the work done using high-intensity nanosecond pulses, termed as nanosecond electroporation (nsEP), in electroporation gene delivery systems.


Assuntos
Eletroquimioterapia/métodos , Terapia Genética/métodos , Nanomedicina/instrumentação , Apoptose/fisiologia , Cálcio/metabolismo , Caspases/metabolismo , Membrana Celular/fisiologia , Citocromos c/metabolismo , Humanos , Sódio/metabolismo , Fatores de Tempo
8.
Methods Mol Biol ; 423: 109-28, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18370193

RESUMO

As the medical field moves from treatment of diseases with drugs to treatment with genes, safe and efficient gene delivery systems are needed to make this transition. One such safe, nonviral, and efficient gene delivery system is electroporation (electrogenetherapy). Exciting discoveries by using electroporation could make this technique applicable to drug and vaccine delivery in addition to gene delivery. Typically, milli- and microsecond pulses have been used for electroporation. Recently, the use of nanosecond electric pulses (10-300 ns) at very high magnitudes (10-300 kV/cm) has been studied for direct DNA transfer to the nucleus in vitro. This article reviews the work done using high intensity, nanopulses, termed as nanoelectroporation (nano-EP), in electroporation gene delivery systems.


Assuntos
Eletroquimioterapia/métodos , Terapia Genética/métodos , Apoptose , Sinalização do Cálcio , Caspases/metabolismo , Linhagem Celular , Citocromos c/metabolismo , DNA Recombinante/administração & dosagem , DNA Recombinante/genética , Eletroquimioterapia/instrumentação , Eletroporação/instrumentação , Eletroporação/métodos , Desenho de Equipamento , Humanos , Nanotecnologia , Neoplasias/terapia , Fosfatidilserinas/metabolismo , Sódio/metabolismo
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