RESUMO
Advanced stage nasopharyngeal carcinoma (NPC) has a poor prognosis. Triptonide ("TN") is a small molecule monomer extract from the ancient Chinese herb Tripterygium wilfordii Hook. We show that TN, at nanomolar concentrations, potently inhibited survival and proliferation of multiple established and primary human NPC cells. TN induced NPC cell cycle arrest and apoptosis activation. NPC cell migration and invasion were also inhibited by TN. Importantly, TN was non-cytotoxic to nasopharyngeal epithelial cells. TN treatment in NPC cells disrupted LncRNA THOR ("Lnc-THOR")-IGF2BP1 association, causing depletion of Lnc-THOR and downregulation of IGF2BP1 mRNA targets (Myc, IGF2 and Gli1). Lnc-THOR or IGF2BP1 knockout by CRISPR/Cas9 gene-editing methods mimicked and abolished TN's actions in NPC cells. Conversely, ectopic Lnc-THOR overexpression inhibited TN-induced cytotoxicity in NPC cells. Significantly, Lnc-THOR, IGF2BP1 and its mRNA targets are elevated in human NPC tissues and cells, but almost undetectable in nasopharyngeal epithelial tissues and cells. In vivo, intraperitoneal TN administration significantly inhibited subcutaneous NPC xenograft growth in mice. Similarly, Lnc-THOR-knockout HONE-1 xenografts grew significantly slower than control tumors. Thus, TN inhibits human NPC cell growth in vitro and in vivo via disrupting Lnc-THOR-IGF2BP1 signaling.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Triterpenos/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Triterpenos/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Compound Danshen Dripping Pill (CDDP) has been used for the treatment of coronary heart disease for decades. We aimed to increase the understanding of the mechanisms by evaluating the urinary metabolomics of CDDP using Gas Chromatography-Mass Spectrometer (GC-MS) in a myocardial ischaemia (MI) rat model. One hundred Sprague-Dawley rats were divided into Con (normal saline and no surgery), Con+ (107 mg/kg d CDDP solution and no surgery), Sham (normal saline and surgery without aorta ligation), Mod (normal saline and surgery with aorta ligation), and Mod+ (107 mg/kg d CDDP solution and surgery with aorta ligation) groups. Urine samples on days 0, 3, 14, and 28 were tested using GC-MS and analyzed with PCA and partial least squares-discriminant analysis models. In the Mod group, creatine kinase and malondialdehyde levels were higher, and superoxide-dismutase levels were lower; the same variables normalized in the Mod+ group. CDDP resulted in improvement in the Mod+ group, as indicated by the reduced necrosis in the myocardial tissue. A total of 36 metabolites were identified in the urine samples, and 8 metabolites (malate, succinate, creatinine, methionine, cysteine, serine, phenylalanine, and tyrosine) were increased remarkably and recovered to normal levels after treatment with CDDP. Differentially expressed metabolites implied that energy, amino acid, fatty acid, and polyol metabolism might be disrupted by MI and reversed by CDDP. Urinary metabolomics provide a dynamic monitoring approach that highlights interference by MI and the therapeutic effects of CDDP on MI in rats throughout the recovery process.
