RESUMEN

Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of BCR-ABL tyrosine kinase. Imatinib was approved for CML therapy, however, BCR-ABL-dependent drug resistance, especially BCR-ABL-T315I mutation, restricts its clinical application. In this study, we reported anthraquinone lactone AS1041, a synthesized derivative of marine natural compound Aspergiolide A, showed anti-leukemia effect in vitro and in vivo by promoting cell senescence. Mechanistic study revealed the pro-senescence effect of AS1041 was dependent on oxidative stress-induced DNA damage, and the resultant activation of P53/P21 and P16INK4a/Rb. Also, AS1041 promoted ubiquitin proteasome system (UPS)-mediated BCR-ABL degradation, which also contributed to AS1041-induced senescence. In vivo, AS1041-induced senescence promoted tumor growth inhibition. In summary, the in vitro and in vivo antitumor effect of AS1041 suggests it can serve as a pro-senescence agent for alternative antileukemia therapy and imatinib-resistant cancer therapy by enhancing cellular oxidative stress and BCR-ABL degradation.

Asunto(s)

Antraquinonas , Resistencia a Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/farmacología , Apoptosis , Proliferación Celular , Proteínas de Fusión bcr-abl/metabolismo , Estrés Oxidativo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Daño del ADN , Inhibidores de Proteínas Quinasas/farmacología

RESUMEN

Src homology 2 domain-containing phosphatase (SHP2) is a non-receptor protein phosphatase that transduces signals from upstream receptor tyrosine kinases (RTKs)/non-RTKs to Ras/MAPK pathway. Accumulating studies indicated that SHP2 is a critical mediator of resistance to current targeted therapies in multiple cancers. Here, we reported a novel SHP2 allosteric inhibitor JC-010a, which was highly selective to SHP2 and bound at the "tunnel" allosteric site of SHP2. The effect of JC-010a on combating RTK/non-RTK or MAPK inhibitors-induced acquired resistance was explored. Our study demonstrated that JC-010a monotherapy significantly inhibited the proliferation of cancer cells with different oncogenic drivers via inhibiting signaling through SHP2. Importantly, JC-010a abolished acquired resistance induced by targeted therapies: in KRAS-mutant cancers, JC-010a abrogated selumetinib-induced adaptive resistance mediated by RTK/SHP2; in BCR-ABL-driven leukemia cells, we demonstrated JC-010a inhibited BCR-ABL T315I mutation-mediated imatinib resistance and proposed a novel mechanism of JC-010a involving the disrupted co-interaction of SHP2, BCR-ABL, and Hsp90; in non-small cell lung cancer (NSCLC) cells, JC-010a inhibited both EGFR T790M/C797S mutation and alternate RTK-driven resistance to gefitinib or osimertinib; importantly, we first proposed a novel potential therapeutic strategy for RET-rearranged cancer, we confirmed that JC-010a monotherapy inhibited cell resistance to BLU-667, and JC-010a/BLU-667 combination prolonged anticancer response both in vivo and in vitro cancer models by inhibiting the alternate MET activation-induced RAS/MAPK reactivation, thereby promoting cancer cell apoptosis. These findings suggested that JC-010a was a novel selective SHP2 allosteric inhibitor, and combing JC-010a with current targeted therapy agents provided a promising therapeutic approach for clinical resistant cancers.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Receptores ErbB/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Oncogenes , Resistencia a Medicamentos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Línea Celular Tumoral

RESUMEN

The clinical drugs for ulcerative colitis mainly affect the inflammatory symposiums with limited outcomes and various side effects. Repairing the damaged intestinal mucosa is a promising and alternative strategy to treat ulcerative colitis. Trefoil factor family 2 (TFF2) could repair the intestinal mucosa, however, it has a short half-life in vivo. To improve the stability of TFF2, we have prepared a new fusion protein TFF2-Fc with much stability, investigated the therapeutic effect of TFF2-Fc on ulcerative colitis, and further illustrated the related mechanisms. We found that intrarectally administered TFF2-Fc alleviated the weight loss, the colon shortening, the disease activity index, the intestinal tissue injury, and the lymphocyte infiltration in dextran sulfate sodium (DSS)-induced colitis mice. In vitro, TFF2-Fc inhibited Caco2 cells injury and apoptosis, promoted cellular migration, and increased the expression of Occludin and ZO-1 by activating P-ERK in the presence of H2O2 or inflammatory conditioned medium (LPS-RAW264.7/CM). Moreover, TFF2-Fc could reduce lipopolysaccharide (LPS)-induced production of inflammation cytokines and reactive oxygen species in RAW264.7 cells, and also inhibits the polarization of RAW264.7 cells to M1 phenotype by reducing glucose consumption and lactate production. Taken together, in this work, we have prepared a novel fusion protein TFF2-Fc, which could alleviate ulcerative colitis in vivo via promoting intestinal epithelial cells repair and inhibiting macrophage inflammation, and TFF2-Fc might serve as a promising ulcerative colitis therapeutic agent.

Asunto(s)

Colitis Ulcerosa , Factor Trefoil-2 , Animales , Humanos , Ratones , Células CACO-2 , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Peróxido de Hidrógeno/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mucosa Intestinal , Lipopolisacáridos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Factor Trefoil-2/farmacología , Células RAW 264.7

RESUMEN

Diabetic skin ulcer is one of the most severe complications in diabetes, however, current therapeutic approaches are not effective enough. Agents modulating oxidative stress, inflammation, and angiogenesis are quite promising for alleviation of diabetic skin ulcers. In this study, a novel Sargassum kjellmanianum-derived polysaccharide (SARP) was prepared. SARP was an alginate with Mw of 45.4 kDa, consisting of 76.56% mannuronic acid, 18.89% guluronic acid, and 4.55% glucuronic acid. SARP could attenuate oxidative stress-induced cell damage via activating nuclear factor erythroid 2-related factor 2 (Nrf2). SARP also promoted the migration and tube formation of HUVECs, which was related to the increased vascular endothelial growth factor (VEGF) expression. In diabetic wound model, SARP (iv, 200 mg/kg) administration increased angiogenesis, alleviated oxidative stress, ameliorated diabetes-related aberrations, and thereby accelerated diabetic wound healing. These findings identified SARP had potential to be developed as a drug candidate for diabetic skin ulcers.

Asunto(s)

Complicaciones de la Diabetes , Diabetes Mellitus Experimental , Sargassum , Algas Marinas , Úlcera Cutánea , Alginatos/farmacología , Alginatos/uso terapéutico , Animales , Diabetes Mellitus Experimental/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Estrés Oxidativo , Sargassum/metabolismo , Algas Marinas/metabolismo , Úlcera Cutánea/complicaciones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cicatrización de Heridas

RESUMEN

Diabetic skin ulcer is one of the most common complications in patients suffering diabetes mellitus. Xanthohumol (XN), a hop-derived prenylated dietary flavonoid, has multiple health beneficial bioactivities. In the present study, we reported XN alleviates oxidative damage and accelerates diabetic wound healing via Nrf2 activation. In vitro, XN attenuated hydrogen peroxide (H2O2)-induced cytotoxicity, ROS production, cell apoptosis, as well as high glucose-induced cell damage. Mechanistic studies further demonstrated that XN could stabilize nuclear factor erythroid 2-related factor 2 (Nrf2) and promote its nuclear translocation, which was associated with AMPKα activation and covalent modification of Keap1 by XN. In vivo, XN increased Nrf2 expression and accelerated diabetic wound healing. Our study revealed a novel function of XN in diabetic wound healing as well as the underlying molecular mechanisms, suggesting XN is a promising lead compound and a potential food and/or drug candidate for the treatment of diabetic skin ulcers.

Asunto(s)

Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/fisiopatología , Flavonoides/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Propiofenonas/administración & dosificación , Úlcera Cutánea/tratamiento farmacológico , Úlcera Cutánea/fisiopatología , Animales , Complicaciones de la Diabetes/genética , Complicaciones de la Diabetes/metabolismo , Flavonoides/química , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Masculino , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Prenilación , Propiofenonas/química , Ratas , Ratas Sprague-Dawley , Úlcera Cutánea/genética , Úlcera Cutánea/metabolismo , Cicatrización de Heridas/efectos de los fármacos

RESUMEN

Excessive reactive oxygen species (ROS) promotes the oxidative stress of keratinocytes, eventually causing cell damage. The natural bromophenol bis (2,3,6-tribromo-4,5-dihydroxybenzyl) ether (BTDE) from marine red algae has been reported to have a varied bioactivity; however, its antioxidant effect has yet to be investigated systemically. Our present work aimed to explore the antioxidant effect of BTDE both on the molecular and cellular models and also to illustrate the antioxidant mechanisms. Our results showed that BTDE could effectively scavenge ABTS free radicals and protect HaCaT cells from damage induced by H2O2. Mechanism studies in HaCaT cells demonstrated that BTDE attenuated hydrogen peroxide (H2O2)-induced ROS production, reduced the malondialdehyde (MDA) level, decreased the oxidized glutathione (GSSG)/glutathione (GSH) ratio, and increased the antioxidant enzyme superoxide dismutase (SOD). Moreover, BTDE could inhibit the expression of Kelch-like epichlorohydrin-associated protein 1 (Keap1) and increase the expression of both nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins TrXR1, HO-1, and NQO1. BTDE also activated the upstream signaling pathway of Nrf2 such as AKT pathway, while not activating the ERK or AMPKα pathways. In general, BTDE is a promising antioxidant to protect HaCaT cells against oxidative damage via Nrf2-mediated pathways.

RESUMEN

Hepatocellular carcinoma (HCC) is one of the major cancers with high mortality rate. Traditional drugs used in clinic are usually limited by the drug resistance and side effect and novel agents are still needed. Macrolide brefeldin A (BFA) is a well-known lead compound in cancer chemotherapy, however, with poor solubility and instability. In this study, to overcome these disadvantages, BFA was encapsulated in mixed nanomicelles based on TPGS and F127 copolymers (M-BFA). M-BFA was conferred high solubility, colloidal stability, and capability of sustained release of intact BFA. In vitro, M-BFA markedly inhibited the proliferation, induced G0/G1 phase arrest, and caspase-dependent apoptosis in human liver carcinoma HepG2 cells. Moreover, M-BFA also induced autophagic cell death via Akt/mTOR and ERK pathways. In HepG2 tumor-bearing xenograft mice, indocyanine green (ICG) as a fluorescent probe loaded in M-BFA distributed to the tumor tissue rapidly, prolonged the blood circulation, and improved the tumor accumulation capacity. More importantly, M-BFA (10 mg/kg) dramatically delayed the tumor progression and induced extensive necrosis of the tumor tissues. Taken together, the present work suggests that M-BFA has promising potential in HCC therapy.

Asunto(s)

Antineoplásicos/administración & dosificación , Brefeldino A/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Micelas , Nanoestructuras/administración & dosificación , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Brefeldino A/sangre , Brefeldino A/química , Brefeldino A/farmacocinética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Nanoestructuras/química , Polietilenos/administración & dosificación , Polietilenos/química , Polipropilenos/administración & dosificación , Polipropilenos/química , Ratas Sprague-Dawley , Distribución Tisular , Vitamina E/administración & dosificación , Vitamina E/química

RESUMEN

Brefeldin A (1), a potent cytotoxic natural macrolactone, was produced by the marine fungus Penicillium sp. (HS-N-29) from the medicinal mangrove Acanthus ilicifolius. Series of its ester derivatives 2-16 were designed and semi-synthesized, and their structures were characterized by spectroscopic methods. Their cytotoxic activities were evaluated against human chronic myelogenous leukemia K562 cell line in vitro, and the preliminary structure-activity relationships revealed that the hydroxy group played an important role. Moreover, the monoester derivatives exhibited stronger cytotoxic activity than the diester derivatives. Among them, brefeldin A 7-O-2-chloro-4,5-difluorobenzoate (7) exhibited the strongest inhibitory effect on the proliferation of K562 cells with an IC50 value of 0.84 µM. Further evaluations indicated that 7 induced cell cycle arrest, stimulated cell apoptosis, inhibited phosphorylation of BCR-ABL, and thereby inactivated its downstream AKT signaling pathway. The expression of downstream signaling molecules in the AKT pathway, including mTOR and p70S6K, was also attenuated after 7-treatment in a dose-dependent manner. Furthermore, molecular modeling of 7 docked into 1 binding site of an ARF1-GDP-GEF complex represented well-tolerance. Taken together, 7 had the potential to be served as an effective antileukemia agent or lead compound for further exploration.

Asunto(s)

Antineoplásicos/farmacología , Brefeldino A/farmacología , Penicillium , Humedales , Animales , Antineoplásicos/química , Organismos Acuáticos , Brefeldino A/química , Proliferación Celular/efectos de los fármacos , Humanos , Células K562/efectos de los fármacos , Relación Estructura-Actividad

RESUMEN

BCR-ABL oncoprotein drives the initiation, promotion, and progression of chronic myelogenous leukemia (CML). Tyrosine kinase inhibitors are the first choice for CML therapy, however, BCR-ABL mediated drug resistance limits its clinical application and prognosis. A novel promising therapeutic strategy for CML therapy is to degrade BCR-ABL using small molecules. Antioxidant xanthohumol (XN) is a hop-derived prenylated flavonoid with multiple bioactivities. In this study, we showed XN could inhibit the proliferation, induce S phase cell cycle arrest, and stimulate apoptosis in K562 cells. XN degraded BCR-ABL in a concentration- and time-dependent manner, and the involved degradation pathway was caspase activation, while not autophagy induction or ubiquitin proteasome system (UPS) activation. Moreover, we revealed for the first time that XN could inhibit the UPS and autophagy in K562 cells, and the inhibitory effect of XN on autophagy could attenuate imatinib-induced autophagy and enhance the therapeutic efficiency of imatinib in K562 cells. Our present findings identified XN act as a degrader of BCR-ABL in K562 cells, and XN had potential to be developed as an alternate agent for CML therapy.

RESUMEN

Jervine is a natural teratogenic compound isolated from Veratrum californicum. In this study, for the first time, we revealed a novel activity of jervine in sensitizing the anti-proliferation effect of doxorubicin (DOX). We demonstrated that the synergistic mechanism was related to the intracellular accumulation of DOX via modulating ABCB1 transportation. Jervine did not affect the expression of ABCB1 in mRNA nor protein levels. However, jervine increased the ATPase activity of ABCB1 and possibly served as a substrate of ABCB1. The molecular docking results indicated that jervine was bound to a closed ABCB1 conformation and blocked drug entrance to the central binding site at the transmembrane domain. The present study identifies jervine acts as a substrate of ABCB1, and has potential to be developed as a novel and potent chemotherapy sensitizer used for patients developing multidrug resistance.

Asunto(s)

Doxorrubicina/farmacología , Teratógenos/toxicidad , Alcaloides de Veratrum/toxicidad , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Células MCF-7 , Estructura Secundaria de Proteína , Especificidad por Sustrato/efectos de los fármacos , Teratógenos/química , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacología