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1.
Free Radic Biol Med ; 146: 306-323, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536771

RESUMO

Seaweeds are an important component of human diets, especially in Asia and the Pacific islands, and have shown chemopreventive as well as anti-inflammatory properties. However, structural characterization and mechanistic insight of seaweed components responsible for their biological activities are lacking. We isolated cymopol and related natural products from the marine green alga Cymopolia barbata and demonstrated their function as activators of transcription factor Nrf2-mediated antioxidant response to increase the cellular antioxidant status. We probed the reactivity of the bioactivation product of cymopol, cymopol quinone, which was able to modify various cysteine residues of Nrf2's cytoplasmic repressor protein Keap1. The observed adducts are reflective of the polypharmacology at the level of natural product, due to multiple electrophilic centers, and at the amino acid level of the cysteine-rich target protein Keap1. The non-polar C. barbata extract and its major active component cymopol, reduced inflammatory gene transcription in vitro in macrophages and mouse embryonic fibroblasts in an Nrf2-dependent manner. Cymopol-containing extracts attenuated neutrophil migration in a zebrafish tail wound model. RNA-seq analysis of colonic tissues of mice exposed to non-polar extract or cymopol showed an antioxidant and anti-inflammatory response, with more pronounced effects exhibited by the extract. Cymopolia extract reduced DSS-induced colitis as measured by fecal lipocalin concentration. RNA-seq showed that mucosal-associated bacterial composition and transcriptional profile in large intestines were beneficially altered to varying degrees in mice treated with either the extract or cymopol. We conclude that seaweed-derived compounds, especially cymopol, alter Nrf2-mediated host and microbial gene expression, thereby providing polypharmacological effects.


Assuntos
Produtos Biológicos , Microbiota , Alga Marinha , Animais , Produtos Biológicos/farmacologia , Colo/metabolismo , Fibroblastos/metabolismo , Expressão Gênica , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Alga Marinha/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
2.
ACS Chem Biol ; 11(5): 1322-31, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-26938486

RESUMO

Colorectal cancer (CRC) is a genetic disease, due to progressive accumulation of mutations in oncogenes and tumor suppressor genes. Large scale genomic sequencing projects revealed >100 mutations in any individual CRC. Many of these mutations are likely passenger mutations, and fewer are driver mutations. Of these, activating mutations in RAS proteins are essential for cancer initiation, progression, and/or resistance to therapy. There has been significant interest in developing drugs targeting mutated cancer gene products or downstream signaling pathways. Due to the number of mutations involved and inherent redundancy in intracellular signaling, drugs targeting one mutation or pathway have been either ineffective or led to rapid resistance. We have devised a strategy whereby multiple cancer pathways may be simultaneously targeted for drug discovery. For proof-of-concept, we targeted the oncogenic KRAS and HIF pathways, since oncogenic KRAS has been shown to be required for cancer initiation and progression, and HIF-1α and HIF-2α are induced by the majority of mutated oncogenes and tumor suppressor genes in CRC. We have generated isogenic cell lines defective in either oncogenic KRAS or both HIF-1α and HIF-2α and subjected them to multiplex genomic, siRNA, and high-throughput small molecule screening. We have identified potential drug targets and compounds for preclinical and clinical development. Screening of our marine natural product library led to the rediscovery of the microtubule agent dolastatin 10 and the class I histone deacetylase (HDAC) inhibitor largazole to inhibit oncogenic KRAS and HIF pathways. Largazole was further validated as an antiangiogenic agent in a HIF-dependent manner in human cells and in vivo in zebrafish using a genetic model with activated HIF. Our general strategy, coupling functional genomics with drug susceptibility or chemical-genetic interaction screens, enables the identification of potential drug targets and candidates with requisite selectivity. Molecules prioritized in this manner can easily be validated in suitable zebrafish models due to the genetic tractability of the system. Our multidimensional platform with cellular and organismal components can be extended to larger scale multiplex screens that include other mutations and pathways.


Assuntos
Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Técnicas de Inativação de Genes , Células HCT116 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , Reto/efeitos dos fármacos , Reto/metabolismo , Reto/patologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Transcriptoma/efeitos dos fármacos , Peixe-Zebra
3.
ACS Chem Biol ; 10(8): 1871-9, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25946346

RESUMO

Nematodes parasitize ∼1/3 of humans worldwide, and effective treatment via administration of anthelmintics is threatened by growing resistance to current therapies. The nematode transcription factor SKN-1 is essential for development of embryos and upregulates the expression of genes that result in modification, conjugation, and export of xenobiotics, which can promote resistance. Distinct differences in regulation and DNA binding relative to mammalian Nrf2 make SKN-1 a promising and selective target for the development of anthelmintics with a novel mode of action that targets stress resistance and drug detoxification. We report 17 (ML358), a first in class small molecule inhibitor of the SKN-1 pathway. Compound 17 resulted from a vanillamine-derived hit identified by high throughput screening that was advanced through analog synthesis and structure-activity studies. Compound 17 is a potent (IC50 = 0.24 µM, Emax = 100%) and selective inhibitor of the SKN-1 pathway and sensitizes the model nematode C. elegans to oxidants and anthelmintics. Compound 17 is inactive against Nrf2, the homologous mammalian detoxification pathway, and is not toxic to C. elegans (LC50 > 64 µM) and Fa2N-4 immortalized human hepatocytes (LC50 > 5.0 µM). In addition, 17 exhibits good solubility, permeability, and chemical and metabolic stability in human and mouse liver microsomes. Therefore, 17 is a valuable probe to study regulation and function of SKN-1 in vivo. By selective targeting of the SKN-1 pathway, 17 could potentially lead to drug candidates that may be used as adjuvants to increase the efficacy and useful life of current anthelmintics.


Assuntos
Anti-Helmínticos/química , Anti-Helmínticos/farmacologia , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Caenorhabditis elegans/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Helmintíase/tratamento farmacológico , Helmintíase/parasitologia , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos
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