RESUMO
Multidrug resistance (MDR) in cancer remains a major challenge for the success of chemotherapy. Natural products have been a rich source for the discovery of drugs against MDR cancers. Here, we applied high-throughput cytotoxicity screening of an in-house natural product library against MDR SGC7901/VCR cells and identified that the cyclodepsipeptide verucopeptin demonstrated notable antitumor potency. Cytological profiling combined with click chemistry-based proteomics revealed that ATP6V1G directly interacted with verucopeptin. ATP6V1G, a subunit of the vacuolar H+-ATPase (v-ATPase) that has not been previously targeted, was essential for SGC7901/VCR cell growth. Verucopeptin exhibited strong inhibition of both v-ATPase activity and mTORC1 signaling, leading to substantial pharmacological efficacy against SGC7901/VCR cell proliferation and tumor growth in vivo. Our results demonstrate that targeting v-ATPase via its V1G subunit constitutes a unique approach for modulating v-ATPase and mTORC1 signaling with great potential for the development of therapeutics against MDR cancers.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Depsipeptídeos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Depsipeptídeos/síntese química , Depsipeptídeos/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Subunidades Proteicas/efeitos dos fármacos , Proteômica , ATPases Vacuolares Próton-Translocadoras/metabolismoRESUMO
Four new 12,8-Eudesmanolides (1-4) and one known compound 5 named 13-Hydroxy-3,7(11)-eudesmadien-12,8-olide, were isolated from a mangrove rhizosphere-derived fungus Eutypella sp. 1-15. Their structures with absolute stereochemistry were determined by the comprehensive spectroscopic data, experimental and calculated ECD analysis. Compound 1 exhibited potent anticancer activity against JEKO-1 and HepG2 with IC50 values of 8.4 and 28.5 µM, respectively. Additionally, compound 1 also showed moderate antimicrobial activity.
Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Xylariales/química , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Rizosfera , Sesquiterpenos/química , Microbiologia do Solo , Análise Espectral , Xylariales/isolamento & purificaçãoRESUMO
Aspertetranones A-D (1-4), four new highly oxygenated putative rearranged triketide-sesquiterpenoid meroterpenes, were isolated from the marine algal-associated fungus Aspergillus sp. ZL0-1b14. On the basis of a comprehensive spectroscopic analysis, the planar structures of aspertetranones were determined to possess an unusual skeleton in the terpenoid part. The relative and absolute configurations of the aspertetranones were assigned on the basis of NOESY analysis, X-ray crystallography, and circular dichroism spectroscopy. Compounds 1-4 were evaluated for anti-inflammatory activity in LPS-stimulated RAW264.7 macrophages. Aspertetranone D exhibited an inhibitory effect against IL-6 production with 69% inhibition at 40 µM.
Assuntos
Aspergillus/química , Sesquiterpenos/isolamento & purificação , Algoritmos , Animais , Anti-Inflamatórios/farmacologia , China , Cristalografia por Raios X , Interleucina-6/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Biologia Marinha , Camundongos , Conformação Molecular , Estrutura Molecular , Óxido Nítrico/análise , Ressonância Magnética Nuclear Biomolecular , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Two new spirooxindole alkaloids spindomycins A (1) and B (2) were isolated from rhizosphere strain Streptomyces sp. xzqh-9. Their structures were elucidated by comprehensive spectroscopic analyses of NMR and MS data. The absolute configurations of 1 and 2 were determined by experimental and theoretical calculation of electronic circular dichroism (ECD). Antitumor, lactate dehydrogenase, and tyrosine kinase inhibitory activities of two compounds were evaluated, while only spindomycin B (2) exhibited weak inhibitory activity against tyrosine kinase Bcr-Abl.