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1.
Anticancer Res ; 39(8): 4023-4030, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366484

RESUMO

BACKGROUND: Treatment options for patients with platinum-resistant ovarian cancer are generally palliative in nature and rarely have realistic potential to be curative. Because many patients with recurrent ovarian cancer receive aggressive chemotherapy for prolonged periods, sometimes continuously, therapy-related toxicities are a major factor in treatment decisions. The use of ex vivo drug sensitivity screens has the potential to improve the treatment of patients with platinum-resistant ovarian cancer by providing personalized treatment plans and thus reducing toxicity from unproductive therapy attempts. MATERIALS AND METHODS: We evaluated the treatment responses of a set of six early-passage patient-derived ovarian cancer cell lines towards a set of 30 Food and Drug Administration-approved chemotherapy drugs using drug-sensitivity testing. RESULTS: We observed a wide range of treatment responses of the cell lines. While most compounds displayed vastly different treatment responses between cell lines, we found that some compounds such as docetaxel and cephalomannine reduced cell survival of all cell lines. CONCLUSION: We propose that ex vivo drug-sensitivity screening holds the potential to greatly improve patient outcomes, especially in a population where multiple continuous treatments are not an option due to advanced disease, rapid disease progression, age or poor overall health. This approach may also be useful to identify potential novel therapeutics for patients with ovarian cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Platina/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Platina/efeitos adversos
2.
Inorg Chem ; 58(16): 11076-11084, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31393117

RESUMO

Platinum drugs including cisplatin are widely used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the major problems that lead to side effects in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In this study, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide. This LHRH-platinum(IV) conjugate is highly soluble in water and quite stable in a PBS buffer. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicities 5-8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH-platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase. In summary, we report a novel LHRH-platinum(IV) anticancer prodrug having largely improved selectivity toward LHRH receptor-positive cancer cells, relative to cisplatin.


Assuntos
Antineoplásicos/farmacologia , Platina/farmacologia , Pró-Fármacos/farmacologia , Receptores LHRH/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta à Radiação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Platina/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Receptores LHRH/metabolismo , Relação Estrutura-Atividade
3.
J Ovarian Res ; 12(1): 17, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760286

RESUMO

OBJECTIVE: Relapsed epithelial ovarian cancer (EOC) is frequently treated with pegylated liposomal doxorubicin (PLD). Unfortunately, most patients do not benefit from treatment. Prediction of response is crucial to optimize PLD use and avoid unnecessary toxicities. We aimed at assessing the value of topoisomerase II alpha (TOP2A) expression as predictive marker of response to PLD-based therapy in patients with relapsed EOCs. METHODS: We retrospectively analyzed Formalin Fixed Paraffin Embedded (FFPE) tissues from 101 patients with platinum resistant (PR) or partially platinum-sensitive (PPS) EOCs treated with PLD-based chemotherapy beyond second line in three referral cancer centers between January 2010 and June 2018. TOP2A expression was measured by immunohistochemistry (IHC): images of each sample were acquired by optical microscope and analyzed by using automatic counter software. Correlation between TOP2A expression and response to PLD was assessed. Since no cut-off for positivity has been validated yet, we dichotomized TOP2A expression based on a cut-off of 18% (mean value in this study). RESULTS: TOP2A expression beyond cut-off was not prognostic for primary platinum-free interval in our series (p = 0.77) neither for optimal cytoreduction (p = 0.9). TOP2A > 18% was associated with a longer time to progression (TTP) following PLD-treatment, although not statistically significant (p = 0.394). No difference was observed between PR and PPS patients' groups (p = 0.445 and p = 0.185, respectively). Not unexpectedly, patients with TOP2A expression > 18% treated with PLD monotherapy achieved a longer TTP compared with PLD-doublet therapy (p = 0.05). CONCLUSIONS: Our data suggest that TOP2A status might predict activity of PLD in patients with PR/PPS EOCs.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , DNA Topoisomerases Tipo II/metabolismo , Doxorrubicina/análogos & derivados , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , DNA Topoisomerases Tipo II/genética , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Platina/farmacologia , Polietilenoglicóis/uso terapêutico , Estudos Retrospectivos
4.
Int J Mol Sci ; 20(4)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769904

RESUMO

Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from Aß, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC50 values in the micromolar range. MS analysis confirms the formation of adducts between peptides and Pt(II) complexes that are also able to reduce amyloid cytotoxicity in human SH-SY5Y neuroblastoma cells. Overall data suggests that bidentate ligands based on ß-hydroxy dithiocinnamic esters can be used to develop platinum or platinoid compounds with anti-amyloid aggregation properties.


Assuntos
Peptídeos beta-Amiloides/química , Complexos de Coordenação/farmacologia , Proteínas Nucleares/química , Fatores de Terminação de Peptídeos/química , Agregação Patológica de Proteínas/tratamento farmacológico , Proteínas de Saccharomyces cerevisiae/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/síntese química , Amiloidose/tratamento farmacológico , Amiloidose/patologia , Benzotiazóis/farmacologia , Linhagem Celular , Cinamatos/química , Cinamatos/farmacologia , Dicroísmo Circular , Complexos de Coordenação/química , Humanos , Ligantes , Proteínas Nucleares/antagonistas & inibidores , Fatores de Terminação de Peptídeos/antagonistas & inibidores , Platina/química , Platina/farmacologia , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores
5.
Adv Mater ; 31(14): e1806803, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30734370

RESUMO

Electrochemical therapy (EChT), by inserting electrodes directly into tumors to kill cancer cells under direct current (DC), is clinically used in several countries. In EChT, the drastic pH variation nearby the inserted electrodes is the main cause of tumor damage. However, its limited effective area and complex electrode configuration have hindered the clinical application of EChT in treating diverse tumor types. Herein, a conceptually new electric cancer treatment approach is presented through an electro-driven catalytic reaction with platinum nanoparticles (PtNPs) under a square-wave alternating current (AC). The electric current triggers a reaction between water molecules and chloride ions on the surface of the PtNPs, generating cytotoxic hydroxyl radicals. Such a mechanism, called electrodynamic therapy (EDT), enables effective killing of cancer cells within the whole electric field, in contrast to EChT, which is limited to areas nearby electrodes. Remarkable tumor destruction efficacy is further demonstrated in this in vivo EDT treatment with PtNPs. Therefore, this study presents a new type of cancer therapy strategy with a tumor-killing mechanism different from existing methods, using nanoparticles with electrocatalytic functions. This EDT method appears to be minimally invasive, and is able to offer homogeneous killing effects to the entire tumor with a relatively large size.


Assuntos
Terapia por Estimulação Elétrica/métodos , Nanopartículas Metálicas/química , Platina/química , Platina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia por Estimulação Elétrica/instrumentação , Eletroquímica , Eletrodos , Humanos , Modelos Moleculares , Conformação Molecular , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
6.
Inorg Chem ; 58(3): 2191-2200, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30657321

RESUMO

Quinone oxidoreductase isozyme I (NQO1) is a cytoprotective two-electron-specific reductase that highly expresses in various cancer cells. Taking NQO1 as the target, we herein report three hybrid compounds from Pt(IV) complexes and a quinone propionic acid unit. The mechanism studies showed that the hybrids could be activated by both NQO1 and ascorbic acid to release the cytotoxic Pt(II) unit, exhibiting a dual stimuli-responsive character. In the pharmacological studies, complexes 2 and 3 presented higher antitumor activity than cisplatin. More importantly, the hybrid could also overcome cisplatin resistance due to the NQO1 targeting ability, improved cellular uptake, and/or different action mechanism. Significantly, complex 3 containing a coumarin moiety could be effectively activated in NQO1-overexpressed cancer cells to "turn on" fluorescence, showing a promising visual effect in cancer cells. In vivo study revealed that both 2 and 3 exhibited higher antitumor efficacy than cisplatin in the A549 xenograft mouse model at an equimolar dose to cisplatin. In all, the hybrids may serve as promising NQO1-targeting anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Compostos Organoplatínicos/farmacologia , Platina/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cisplatino/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Platina/química
7.
Mater Sci Eng C Mater Biol Appl ; 96: 693-707, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30606583

RESUMO

A facile one step green synthesis of silver (AgNP), gold (AuNP) and platinum (PtNP) nanoparticles has been attempted using the rind extract of the fruit of Garcinia mangostana L. The rind of the fruit is enriched with wide varieties of natural resources which could be conveniently exploited as alternative for synthesis of nanoparticles eliminating the need for hazardous chemical methods. The formation of gold nanoparticles occurred at room temperature within a few seconds while the formation of silver and platinum nanoparticles was obtained after heating the solution for 20 min at 80 °C. Parameters such as contact time, temperature and pH were optimized to obtain the precise nanoparticles. The green synthesized nanoparticles were characterized using several state-of-the-art techniques like UV-Vis spectroscopic, FT-IR, HR-SEM and HR-TEM, XRD analyses and zeta potential measurements. Attempt has also been made to evaluate the antibacterial activity of the metal nanoparticles before and after combining with commercially used antibiotics as well as free antibiotics against human pathogenic bacteria. The bare silver nanoparticles (AgNP) showed relatively higher antibacterial activity than AuNP and PtNP and this activity was found to be more pronounced against gram negative bacteria than gram positive ones. Interestingly, all the three metal nanoparticles combined with antibiotics showed enhanced antibacterial activity against the pathogenic bacteria which suggested synergism between the nanoparticles and antibiotics. The high point of the present investigation has been that the Bacillus sp. which is highly resistant to streptomycin becomes highly susceptible to the same antibiotic when combined with gold nanoparticles. This particular observation opens up windows for the treatment of antibiotic resistant bacteria after combining with different nanoparticles under clinical set up.


Assuntos
Antibacterianos , Bacillus/crescimento & desenvolvimento , Ouro , Nanopartículas Metálicas/química , Platina , Prata , Antibacterianos/química , Antibacterianos/farmacologia , Sinergismo Farmacológico , Frutas/química , Garcinia/química , Ouro/química , Ouro/farmacologia , Platina/química , Platina/farmacologia , Prata/química , Prata/farmacologia
8.
Int J Clin Oncol ; 24(5): 476-484, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30689078

RESUMO

BACKGROUND: Signal transducer and activator of transcription (STAT) 3 plays a vital role in carcinogenesis and drug response. Platinum-based chemotherapy is the first-line treatment for lung cancer patients, especially those in advanced stages. In the present study, we investigated the association of STAT3 polymorphism rs4796793 with lung cancer susceptibility, platinum-based chemotherapy response, and toxicity. METHODS: A total of 498 lung cancer patients and 213 healthy controls were enrolled in the study. 467 of them received at least 2-cycle platinum-based chemotherapy. Unconditional logistical regression analysis was used to assess the associations. RESULTS: STAT3 rs4769793 G allele carriers had an increased susceptibility of lung cancer [additive model: adjusted OR (95% CI) 1.376 (1.058-1.789), P = 0.017; recessive model: adjusted OR (95% CI) 1.734 (1.007-2.985), P = 0.047]. Rs4769793 was not significantly associated with platinum-based chemotherapy response in lung cancer patients. STAT3 rs4796793 was associated with an increased risk of severe overall toxicity [additive model: adjusted OR (95% CI) 1.410 (1.076-1.850), P = 0.013; dominant model: adjusted OR (95% CI) 1.638 (1.091-2.459), P = 0.017], especially hematological toxicity [additive model: adjusted OR (95% CI) 1.352 (1.001-1.826), P = 0.049]. CONCLUSIONS: STAT3 rs4796793 may be considered as a potential candidate biomarker for the prediction of susceptibility and prognosis in Chinese lung cancer patients. However, well-designed studies with larger sample sizes are required to verify the results.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Platina/farmacologia , Prognóstico , Fator de Transcrição STAT3 , Resultado do Tratamento
9.
Proc Natl Acad Sci U S A ; 116(5): 1698-1703, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30647111

RESUMO

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived "surge" of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias Ovarianas/metabolismo , Platina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia
10.
PLoS One ; 14(1): e0211268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695050

RESUMO

Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput screening assay for identification of synergistic combinations between broadly applied platinum-based chemotherapeutics and drugs from a library composed of 1280 chemically and pharmacologically diverse (mostly FDA approved) compounds. The assay was performed on chemoresistant cell lines derived from lung (A549) and pancreatic (PANC-1) carcinoma, where platinum-based combination regimens are currently applied though with limited success. The synergistic combinations identified during the screening were validated by synergy quantification using the combination index method and via high content fluorescent microscopy analysis. New promising synergistic combinations discovered using this approach include compounds currently not used as anticancer drugs, such as cisplatin or carboplatin with hycanthone and cisplatin with spironolactone in pancreatic carcinoma, and carboplatin and deferoxamine in non-small cell lung cancer. Strong synergy between cisplatin or carboplatin and topotecan in PANC-1 cells, compared to A549 cells, suggests that this combination, currently used in lung cancer treatment regimens, could be applied to pancreatic carcinoma as well. Several drugs used to treat diseases other than cancer, including pyrvinium pamoate, auranofin, terfenadine and haloprogin, showed strong cytotoxicity on their own and synergistic interactions with platinum drugs. This study demonstrates that non-obvious drug combinations that would not be selected based on complementary mechanisms can be identified via high-throughput screening.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Platina/farmacologia , Células A549 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sinergismo Farmacológico , Ensaios de Triagem em Larga Escala/métodos , Humanos , Microscopia de Fluorescência , Platina/uso terapêutico , Prognóstico
11.
Microb Pathog ; 128: 47-54, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30579946

RESUMO

Tetra-platinated(II) porphyrin hexafluorophosphate compound (4-PtTPyPor) was synthetized and along 5,10,15,20-tetrakis(4-pyridyl)porphyrin (4-TPyPor), evaluated about the antimicrobial activity and safety. The effect was evaluated with and without light exposition. The antimicrobial activity was analyzed by microdilution and growth curve method. The assays showed an increase of antimicrobial potential caused by porphyrins with light exposition comparing the treatment without light irradiation. The biocompatibility was tested by MTT, ROS production, dsDNA on culture medium and hemolysis. All platinum porphyrin concentrations showed hemolytic activity under light exposition. The ROS measurement doesn't showed statistic difference between treatments and control. The picogreen assay demonstrates a reduction of dsDNA on culture medium with cells treated with porphyrins under light irradiation. The study demonstrated that the platinated porphyrins might be promising microbial photodynamic inactivation with potential applications in wastewater treatment, biofilm control and bioremediation.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Platina/farmacologia , Porfirinas/farmacologia , Antibacterianos/química , Bactérias/crescimento & desenvolvimento , Bactérias/efeitos da radiação , Meios de Cultura , DNA Bacteriano/análise , Hemólise , Luz , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Platina/química , Porfirinas/química , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Águas Residuárias , Purificação da Água/métodos
12.
Sensors (Basel) ; 18(12)2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30563229

RESUMO

Platinum(II) complexes have been found to be effective against cancer cells. Cisplatin curbs cell replication by interacting with the deoxyribonucleic acid (DNA), reducing cell proliferation and eventually leading to cell death. In order to investigate the ability of platinum complexes to affect cancer cells, two examples from the class of polyfluorophenylorganoamidoplatinum(II) complexes were synthesised and tested on isolated DNA. The two compounds trans-[N,N'-bis(2,3,5,6-tetrafluorophenyl)ethane-1,2-diaminato(1-)](2,3,4,5,6-pentafluorobenzoato)(pyridine)platinum(II) (PFB) and trans-[N,N'-bis(2,3,5,6-tetrafluorophenyl)ethane-1,2-diaminato(1-)](2,4,6-trimethylbenzoato)(pyridine)platinum(II) (TMB) were compared with cisplatin through their reaction with DNA. Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopy was applied to analyse the interaction of the Pt(II) complexes with DNA in the hydrated, dehydrated and rehydrated states. These were compared with control DNA in acetone/water (PFB, TMB) and isotonic saline (cisplatin) under the same conditions. Principle Component Analysis (PCA) was applied to compare the ATR-FTIR spectra of the untreated control DNA with spectra of PFB and TMB treated DNA samples. Disruptions in the conformation of DNA treated with the Pt(II) complexes upon rehydration were mainly observed by monitoring the position of the IR-band around 1711 cm-1 assigned to the DNA base-stacking vibration. Furthermore, other intensity changes in the phosphodiester bands of DNA at ~1234 cm-1 and 1225 cm-1 and shifts in the dianionic phosphodiester vibration at 966 cm-1 were observed. The isolated double stranded DNA (dsDNA) or single stranded DNA (ssDNA) showed different structural changes when incubated with the studied compounds. PCA confirmed PFB had the most dramatic effect by denaturing both dsDNA and ssDNA. Both compounds, along with cisplatin, induced changes in DNA bands at 1711, 1088, 1051 and 966 cm-1 indicative of DNA conformation changes. The ability to monitor conformational change with infrared spectroscopy paves the way for a sensor to screen for new anticancer therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Técnicas Biossensoriais , DNA/química , Conformação de Ácido Nucleico , Platina/farmacologia , Animais , Bovinos , Cisplatino/química , Cisplatino/farmacologia , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de Fourier
13.
Int J Biol Sci ; 14(14): 2012-2022, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30585265

RESUMO

Background: As a major subtype of ovarian cancer, high grade FIGO stage IIIc serous ovarian carcinoma (HG3cSOC), has various prognosis due to genetic heterogeneity. Methods: The transcriptome of 401 primary FIGO IIIc serous ovarian samples was screened, seven genes based prognostic model was developed. The prognostic valueof risk score in four different cohorts (TCGA-cohort, Poland-cohort, Japan-cohort and USA-cohort) was validated. The relationship between risk score and other clinical indicators were analyzed. The guide value of risk score for platinum-taxol chemotherapy was also assayed. Tissue microenvironment difference among samples with different risk scores was investigated. Results: High-risk group (N=200, median survival months: 39.6, 95% CI: 35.9-46.3 months) had a significantly worse prognosis than low-risk group (N=201, median survival months: 52.6, 95% CI: 45.2-64.9 months;). The risk score's performance was validated in Japan-cohort (N=90, Poland-cohort (N=48) and USA-cohort (N=84). The risk score is independent from age, primary tumor size, grade and treatment methods and the performance of risk score is uniform in subgroups. Furthermore, the risk score predicted the response of HG3cSOC to platinum-based regimen after surgery, and this finding was further validated in newly collected China-cohort (N=102). Gene Set Enrichment Analysis (GSEA) and tumor infiltration analysis revealed that risk score reflected the immune infiltration and cell-cell interaction status, and the migration function of candidate genes were also verified. Conclusions: The optimized seven genes-based model is a valuable and robust model in predicting the survival of HG3cSOC, and served as a valuable marker for the response to platinum-based chemotherapy.


Assuntos
Cistadenocarcinoma Seroso/genética , Neoplasias Ovarianas/genética , Platina/farmacologia , Transcriptoma/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Humanos , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real
14.
Int J Mol Sci ; 19(7)2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30011897

RESUMO

Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl2(cis-1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1-cyclobutanedicarboxylate) analogue the antioxidant α-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds (cis,trans,cis-[Pt(CBDCA)(ALA)2(cis-1,4-DACH)], 2, and cis,trans,cis-[PtCl2(ALA)2(cis-1,4-DACH)], 3), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters.


Assuntos
Mitocôndrias/metabolismo , Compostos Organoplatínicos/metabolismo , Platina/metabolismo , Pró-Fármacos/metabolismo , Ácido Tióctico/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/metabolismo , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Estrutura Molecular , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Platina/química , Platina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ácido Tióctico/química , Ácido Tióctico/farmacologia
15.
Int J Nanomedicine ; 13: 3295-3310, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29910616

RESUMO

Background: Although the diverse biological properties of nanoparticles have been studied intensively, research into their mechanism of action is relatively rare. In this study, we investigated the molecular mechanisms of the anticancer activity of heterometallic Au@Pt-nanoseeds (NSs) against bladder cancers. Materials and methods: Mode of action of Au@Pt-NSs was investigated through MTT assay, flow cytometry analysis, Western immunoblots, real-time qPCR, wound-healing migration and invasion assays, zymography, and electrophoretic mobility shift assay (EMSA). Results: Treatment with Au@Pt-NSs significantly inhibited the proliferation of EJ cells in a dose-dependent manner by inducing G1 phase cell cycle arrest. Among the regulators associated with the G1 cell cycle phase, CDK2, CDK4, cyclin D1, cyclin E, and p21WAF1 were shown to participate in the inhibitory pathways of Au@Pt-NSs. In addition, treatment with Au@Pt-NSs led to upregulation of phospho-p38 MAPK and downregulation of phospho-AKT in EJ cells. Interestingly, Au@Pt-NSs inhibited the migratory and invasive potential of the cells, which was attributed to the suppression of the enzymatic activity of matrix metalloproteinase-9 (MMP-9). Using MMP-9-specific oligonucleotides, we showed that transcription factors such as NF-κB and Sp-1 were responsible for the MMP-9-mediated metastatic potential of EJ cells. Conclusion: Au@Pt-NSs significantly limited the progression, migration, and invasion of bladder cancer EJ cells. Our data represent a novel insight into developing cisplatin-like chemotherapeutic reagents with fewer side effects and provide useful information on molecular markers to monitor patients under Au@Pt-NSs-based chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Ouro/farmacologia , Platina/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Ouro/química , Humanos , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Nanoestruturas/química , Platina/química , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Neoplasias da Bexiga Urinária/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Proc Natl Acad Sci U S A ; 115(22): 5664-5669, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29760069

RESUMO

As an effective and noninvasive treatment of various diseases, photodynamic therapy (PTD) relies on the combination of light, a photosensitizer, and oxygen to generate cytotoxic reactive oxygen species that can damage malignant tissue. Much attention has been paid to covalent modifications of the photosensitizers to improve their photophysical properties and to optimize the pathway of the photosensitizers interacting with cells within the target tissue. Herein we report the design and synthesis of a supramolecular heterometallic Ru-Pt metallacycle via coordination-driven self-assembly. While inheriting the excellent photostability and two-photon absorption characteristics of the Ru(II) polypyridyl precursor, the metallacycle also exhibits red-shifted luminescence to the near-infrared region, a larger two-photon absorption cross-section, and higher singlet oxygen generation efficiency, making it an excellent candidate as a photosensitizer for PTD. Cellular studies reveal that the metallacycle selectively accumulates in mitochondria and nuclei upon internalization. As a result, singlet oxygen generated by photoexcitation of the metallacycle can efficiently trigger cell death via the simultaneous damage to mitochondrial function and intranuclear DNA. In vivo studies on tumor-bearing mice show that the metallacycle can efficiently inhibit tumor growth under a low light dose with minimal side effects. The supramolecular approach presented in this work provides a paradigm for the development of PDT agents with high efficacy.


Assuntos
Complexos de Coordenação , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes , Platina , Rutênio , Células A549 , Animais , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Células HeLa , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fótons , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Platina/química , Platina/farmacologia , Rutênio/química , Rutênio/farmacologia , Oxigênio Singlete/metabolismo , Oxigênio Singlete/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Mol Sci ; 19(5)2018 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-29772714

RESUMO

Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting-carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively-cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. hCtr1 expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates hCtr1. Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy.


Assuntos
Antineoplásicos/farmacologia , Cobre/metabolismo , Homeostase , Platina/farmacologia , Transcrição Genética , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Oxirredução
18.
J Obstet Gynaecol Res ; 44(7): 1330-1334, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29767464

RESUMO

Platinum-resistant recurrent ovarian cancer has a poor prognosis, but combined therapy with bevacizumab and anticancer agents may be useful. We report a patient with long-term disease control by the combination of bevacizumab and gemcitabine (BEV + GEM). The patient was a 77-year-old woman with high-grade Stage IIIC serous ovarian carcinoma. In 2012, a complete response (CR) was obtained by neoadjuvant and adjuvant chemotherapy using paclitaxel plus carboplatin and tumor debulking surgery. After recurrence in 2013, CR was achieved again with gemcitabine plus carboplatin. In 2014, recurrence was detected again, but CR was achieved by third-line combination therapy with gemcitabine, carboplatin and bevacizumab. In 2015, the third recurrence was found during bevacizumab maintenance therapy. Fourth-line treatment was initiated with BEV + GEM, which has maintained stable disease for 29 months. This is the first report about marked prolongation of survival by BEV + GEM in a patient with platinum-resistant recurrent ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Platina/farmacologia , Idoso , Feminino , Humanos , Recidiva Local de Neoplasia/cirurgia , Neoplasias Ovarianas/cirurgia
19.
Int J Nanomedicine ; 13: 1505-1524, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29559779

RESUMO

Background: Tumor microenvironment plays an important role in the chemoresistance of oral squamous cell carcinoma (OSCC). Hypoxia in the microenvironment is one of the important factors that contributes to OSCC chemoresistance; therefore overcoming hypoxia-mediated chemoresistance is one of the great challenges in clinical practice. Methods: In this study, we developed a drug delivery system based on Pt-loaded, polyethylene glycol-modified graphene quantum dots via chemical oxidation and covalent reaction. Results: Our results show that synthesized polyethylene glycol-graphene quantum dots-Pt (GPt) is about 5 nm in diameter. GPt sensitizes OSCC cells to its treatment in both normoxia and hypoxia conditions. Inductively coupled plasma-mass spectrometry assay shows that GPt enhances Pt accumulation in cells, which leads to a notable increase of S phase cell cycle arrest and apoptosis of OSCC cells in both normoxia and hypoxic conditions. Finally, compared with free cisplatin, GPt exhibits a strong inhibitory effect on the tumor growth with less systemic drug toxicity in an OSCC xenograft mouse tumor model. Conclusion: Taken together, our results show that GPt demonstrates superiority in combating hypoxia-induced chemoresistance. It might serve as a novel strategy for future microenvironment-targeted cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Grafite/análise , Neoplasias Bucais/tratamento farmacológico , Nanocompostos/química , Platina/uso terapêutico , Pontos Quânticos/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Grafite/química , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos Endogâmicos BALB C , Neoplasias Bucais/patologia , Platina/farmacologia , Microambiente Tumoral/efeitos dos fármacos
20.
Inorg Chem ; 57(5): 2917-2924, 2018 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-29436828

RESUMO

Although different types of metal-based anticancer complexes have been synthesized, novel complexes to reduce the serious side effect of cisplatin and conquer cancer metastasis are still highly desired. Here, we report the synthesis, characterization, and biological activity of a novel heterodinuclear Pt(IV)-Ru(II) anticancer prodrug. The Pt(IV)-Ru(II) complex exhibits good stability in both water and PBS solution. Biological evaluation revealed that this bifunctional Pt(IV)-Ru(II) complex utilizes the advantages of two metal centers to have both cytotoxicity and antimetastatic property as designed. Although the complex has comparable cytotoxicities to cisplatin in tested cancer cell lines, this prodrug selectively kills cancer but not normal cells, and the IC50 values of the Pt(IV)-Ru(II) complex are 7-10 times higher than those of cisplatin toward normal cells. The cancer cell selectivity is further demonstrated by a cancer-normal cell coculture system. In addition, the antimetastatic properties of the heterodinuclear complex are assessed by using highly metastatic human breast cancer cells, and the results show that the migration and invasion of cancer cells are effectively restrained after the treatment. Moreover, the Pt(IV)-Ru(II) complex displays lower toxicity than cisplatin in developing zebrafish embryos. We, therefore, report an example of heterodinuclear Pt(IV)-Ru(II) complex not only to defeat both drug resistance and cancer metastasis but also having significantly improved cancer cell selectivity and reduced in vivo toxicity than cisplatin.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Platina/farmacologia , Pró-Fármacos/farmacologia , Rutênio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Platina/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Rutênio/química , Relação Estrutura-Atividade , Peixe-Zebra/embriologia
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