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1.
J Med Chem ; 59(10): 5121-7, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27077228

RESUMO

Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-µM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Isatina/farmacologia , Compostos de Espiro/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isatina/química , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
2.
BMC Cancer ; 16: 220, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26979107

RESUMO

BACKGROUND: Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. METHODS: Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. RESULTS: We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. CONCLUSION: Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.


Assuntos
Cério/administração & dosagem , Cisplatino/administração & dosagem , Nanopartículas/administração & dosagem , Neovascularização Patológica/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cério/química , Cisplatino/química , Feminino , Receptor 1 de Folato/biossíntese , Ácido Fólico/administração & dosagem , Ácido Fólico/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/química , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Oncotarget ; 6(13): 10908-23, 2015 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-25895126

RESUMO

Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR's tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent.


Assuntos
Anticarcinógenos/farmacologia , Restrição Calórica , Metabolismo Energético/efeitos dos fármacos , Metformina/farmacologia , Neoplasias Ovarianas/prevenção & controle , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ativação Enzimática , Feminino , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Carga Tumoral
4.
J Ovarian Res ; 8: 13, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25880539

RESUMO

BACKGROUND: Acquisition of metabolic alterations has been shown to be essential for the unremitting growth of cancer, yet the relation of such alterations to chemosensitivity has not been investigated. In the present study our aim was to identify the metabolic alterations that are specifically associated with platinum resistance in ovarian cancer. A global metabolic analysis of the A2780 platinum-sensitive and its platinum-resistant derivative C200 ovarian cancer cell line was performed utilizing ultra-high performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy. Per-metabolite comparisons were made between cell lines and an interpretive analysis was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic library and the Ingenuity exogenous molecule library. RESULTS: We observed 288 identified metabolites, of which 179 were found to be significantly different (t-test p < 0.05) between A2780 and C200 cells. Of these, 70 had increased and 109 had decreased levels in platinum resistant C200 cells. The top altered KEGG pathways based on number or impact of alterations involved the cysteine and methionine metabolism. An Ingenuity Pathway Analysis also revealed that the methionine degradation super-pathway and cysteine biosynthesis are the top two canonical pathways affected. The highest scoring network of altered metabolites was related to carbohydrate metabolism, energy production, and small molecule biochemistry. Compilation of KEGG analysis and the common network molecules revealed methionine and associated pathways of glutathione synthesis and polyamine biosynthesis to be most significantly altered. CONCLUSION: Our findings disclose that the chemoresistant C200 ovarian cancer cells have distinct metabolic alterations that may contribute to its platinum resistance. This distinct metabolic profile of platinum resistance is a first step towards biomarker development for the detection of chemoresistant disease and metabolism-based drug targets specific for chemoresistant tumors.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Metabolômica/métodos , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Cisplatino/metabolismo , Feminino , Humanos
5.
Oncotarget ; 5(15): 6063-75, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25026276

RESUMO

A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.


Assuntos
Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Animais , Carcinoma Epitelial do Ovário , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Neoplasias Epiteliais e Glandulares/dietoterapia , Neoplasias Ovarianas/dietoterapia , Fosforilação , Transdução de Sinais
6.
Oncotarget ; 5(13): 4746-64, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24970804

RESUMO

Omental adipocytes promote ovarian cancer by secretion of adipokines, cytokines and growth factors, and acting as fuel depots. We investigated if metformin modulates the ovarian cancer promoting effects of adipocytes. Effect of conditioned media obtained from differentiated mouse 3T3L1 preadipoctes on the proliferation and migration of a mouse ovarian surface epithelium cancer cell line (ID8) was estimated. Conditioned media from differentiated adipocytes increased the proliferation and migration of ID8 cells, which was attenuated by metformin. Metformin inhibited adipogenesis by inhibition of key adipogenesis regulating transcription factors (CEBPα, CEBPß, and SREBP1), and induced AMPK. A targeted Cancer Pathway Finder RT-PCR (real-time polymerase chain reaction) based gene array revealed 20 up-regulated and 2 down-regulated genes in ID8 cells exposed to adipocyte conditioned media, which were altered by metformin. Adipocyte conditioned media also induced bio-energetic changes in the ID8 cells by pushing them into a highly metabolically active state; these effects were reversed by metformin. Collectively, metformin treatment inhibited the adipocyte mediated ovarian cancer cell proliferation, migration, expression of cancer associated genes and bio-energetic changes. Suggesting, that metformin could be a therapeutic option for ovarian cancer at an early stage, as it not only targets ovarian cancer, but also modulates the environmental milieu.


Assuntos
Adipócitos/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Metformina/farmacologia , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Meios de Cultivo Condicionados/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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