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1.
Am J Cancer Res ; 13(2): 452-463, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36895970

RESUMEN

Double hit diffuse large B-cell lymphoma (DLBCL) with rearrangement and overexpression of both c-Myc and Bcl-2 responds poorly to standard R-CHOP therapy. In a recent phase I study, Venetoclax (ABT-199) targeting Bcl-2 also exhibited disappointing response rates in patients with relapsed/refractory DLBCL, suggesting that targeting only Bcl-2 is not sufficient for achieving successful efficacy due to the concurrent oncogenic function of c-Myc expression and drug resistance following an increase in Mcl-1. Therefore, co-targeting c-Myc and Mcl-1 could be a key combinatorial strategy to enhance the efficacy of Venetoclax. In this study, BR101801 a novel drug for DLBCL, effectively inhibited DLBCL cell growth/proliferation, induced cell cycle arrest, and markedly inhibited G0/G1 arrest. The apoptotic effect of BR101801 was also observed by increased Cytochrome C, cleaved PARP, and Annexin V-positive cell populations. This anti-cancer effect of BR101801 was confirmed in animal models, where it effectively inhibited tumor growth by reducing the expression of both c-Myc and Mcl-1. Furthermore, BR101801 exhibited a significant synergistic antitumor effect even in late xenograft models when combined with Venetoclax. Our data strongly suggest that c-Myc/Bcl-2/Mcl-1 triple targeting through a combination of BR101801 and Venetoclax could be a potential clinical option for double-hit DLBCL.

2.
Biomol Ther (Seoul) ; 30(3): 274-283, 2022 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-34663758

RESUMEN

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

3.
Am J Cancer Res ; 11(11): 5440-5451, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34873471

RESUMEN

DNA-dependent protein kinase (DNA-PK), an essential component of the non-homologous end-joining (NHEJ) repair pathway, plays an important role in DNA damage repair (DDR). Therefore, DNA-PK inhibition is a promising approach for overcoming radiotherapy or chemotherapy resistance in cancers. In this study, we demonstrated that BR101801, a potent DNA-PK inhibitor, acted as an effective radiosensitizer in various human solid cancer cells and an in vivo xenograft model. Overall, BR101801 strongly elevated ionizing radiation (IR)-induced genomic instability via induction of cell cycle G2/M arrest, autophagic cell death, and impairment of DDR pathway in human solid cancer cells. Interestingly, BR101801 inhibited not only phosphorylation of DNA-PK catalytic subunit in NHEJ factors but also BRCA2 protein level in homologous recombination (HR) factors. In addition, combination BR101801 and IR suppressed tumor growth compared with IR alone by reducing phosphorylation of DNA-PK in human solid cancer xenografts. Our findings suggested that BR101801 is a selective DNA-PK inhibitor with a synergistic radiosensitizing effect in human solid cancers, providing evidence for clinical applications.

4.
Cancer Lett ; 519: 185-198, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34311032

RESUMEN

Oncogenic KRASG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRASG12D-mediated ADM and early PDAC intervention remains unknown. In the current study, we investigated the role of ANGPTL4 in KRASG12D-induced ADM, PanIN formation, and PDAC maintenance. We found that ANGPTL4 was highly expressed in human and mouse ADM lesions and contributed to the promotion of KRASG12D-driven ADM in mice. Consistently, ANGPTL4 rapidly induced ADM in three-dimensional culture of acinar cells with KRAS mutation and formed ductal cysts that silenced acinar genes and activated ductal genes, which are characteristic of in vivo ADM/PanIN lesions. We also found that periostin works as a downstream regulator of ANGPTL4-mediated ADM/PDAC. Genetic ablation of periostin diminished the ADM/PanIN phenotype induced by ANGPTL4. A high correlation between ANGPTL4 and periostin was confirmed in human samples. These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC.


Asunto(s)
Proteína 4 Similar a la Angiopoyetina/metabolismo , Carcinogénesis/metabolismo , Carcinoma de Células Acinares/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Metaplasia/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Células Acinares/metabolismo , Células Acinares/patología , Animales , Carcinogénesis/patología , Carcinoma de Células Acinares/patología , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Humanos , Metaplasia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/patología , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Neoplasias Pancreáticas
5.
Cancer Lett ; 507: 97-111, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33744388

RESUMEN

KRAS mutation is associated with the progression and growth of pancreatic cancer and contributes to chemo-resistance, which poses a significant clinical challenge in pancreatic cancer. Here, we developed a RT22-ep59 antibody (Ab) that directly targets the intracellularly activated GTP-bound form of oncogenic KRAS mutants after it is internalized into cytosol by endocytosis through tumor-associated receptor of extracellular epithelial cell adhesion molecule (EpCAM) and investigated its synergistic anticancer effects in the presence of gemcitabine in pancreatic cancer. We first observed that RT22-ep59 specifically recognized tumor-associated EpCAM and reached the cytosol by endosomal escape. In addition, the anticancer effect of RT22-ep59 was observed in the high-EpCAM-expressing pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells, but it had little effect on the low-EpCAM-expressing pancreatic cancer cells. Additionally, co-treatment with RT22-ep59 and gemcitabine synergistically inhibited cell viability, migration, and invasion in 3D-cultures and exhibited synergistic anticancer activity by inhibiting the RAF/ERK or PI3K/AKT pathways in cells with high-EpCAM expression. In an orthotopic mouse model, combined administration of RT22-ep59 and gemcitabine significantly inhibited tumor growth. Furthermore, the co-treatment suppressed cancer metastasis by blocking EMT signaling in vitro and in vivo. Our results demonstrated that RT22-ep59 synergistically increased the antitumor activity of gemcitabine by inhibiting RAS signaling by specifically targeting KRAS. This indicates that co-treatment with RT22-ep59 and gemcitabine might be considered a potential therapeutic strategy for pancreatic cancer patients harboring KRAS mutation.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Antineoplásicos Inmunológicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Endosomas/metabolismo , Molécula de Adhesión Celular Epitelial/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Desoxicitidina/farmacología , Sinergismo Farmacológico , Endocitosis , Endosomas/genética , Molécula de Adhesión Celular Epitelial/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Invasividad Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina
6.
EMBO Mol Med ; 12(8): e11222, 2020 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-32638512

RESUMEN

Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin-like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis-associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS-activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis.


Asunto(s)
Pancreatitis , Células Acinares , Enfermedad Aguda , Proteína 4 Similar a la Angiopoyetina/genética , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Páncreas , Fosfatidilinositol 3-Quinasas , Regulación hacia Arriba
7.
Sci Rep ; 9(1): 1740, 2019 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-30741955

RESUMEN

Blood transfusions temporarily improve the physical state of the patient but exert widespread effects on immune and non-immune systems. Perioperative allogeneic blood transfusions (ABT) are associated with various risks, including coagulopathy, incompatibility, transmission of infectious agents, and allergic reactions. Nevertheless, little is known about the global metabolic alterations that reflect the possible reactions of blood transfusions. In this study, we investigated metabolite changes generated by ABT in a rat model using metabolomics technology. To further profile the "metabolome" after blood transfusions, we used both liquid chromatography-quadrupole time-of-flight high-definition mass spectrometry and gas chromatography-mass spectrometry. ABT promoted a stimulatory microenvironment associated with a relative increase in glucose transporter 1/4 (GLUT1/GLUT4) expression. Supporting this result, glucose metabolism-related enzyme IRS1 and interleukin-6 (IL-6) were abnormally expressed, and levels of lysophosphatidylcholine (LysoPC) and its related enzyme phospholipase A2 (PLA2) were significantly altered in allogeneic groups compared to those in autologous groups. Finally, amino acid metabolism was also altered following ABT. Taken together, our results show a difference between autologous and allogeneic blood transfusions and demonstrate correlations with cancer-associated metabolic changes. Our data provide endogenous information for a better understanding of blood transfusion reactions.


Asunto(s)
Metaboloma , Metabolómica , Reacción a la Transfusión/metabolismo , Cromatografía Líquida de Alta Presión , Ensayo de Inmunoadsorción Enzimática , Cromatografía de Gases y Espectrometría de Masas , Humanos , Redes y Vías Metabólicas , Metabolómica/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Reacción a la Transfusión/etiología
8.
Cancer Lett ; 438: 174-186, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30217561

RESUMEN

Pancreatic cancer exhibits an oncogenic KRAS mutation rate of ∼90%. Despite research and drug development efforts focused on KRAS, no targeted therapy has been clinically approved for the treatment of pancreatic cancer with KRAS mutation. Also, the efficacy of gemcitabine is poor due to rapidly acquired resistance. We developed RT11-i antibody, which directly targets the intracellularly activated GTP-bound form of oncogenic RAS mutants. Here, we investigated the combined effects of RT11-i and gemcitabine in vitro and in vivo, and the mechanism involved. RT11-i significantly sensitized pancreatic cancer cells to gemcitabine. Also, the co-treatment synergistically inhibited angiogenesis, migration, and invasion, and showed synergistic anticancer activity by inhibiting the RAF/MEK/ERK or PI3K/AKT pathways. Furthermore, co-treatment inhibited endothelial barrier disruption in tumor vessels, which is a critical step in vascular leakiness of metastasis, and improved vessel structural stability. Importantly, co-treatment significantly suppressed tumor growth in an orthotopic tumor model. Taken together, our findings show that RT11-i synergistically increased the antitumor activity of gemcitabine by inhibiting RAS downstream signaling, which suggests RT11-i and gemcitabine be viewed a potential combination treatment option for pancreatic cancer patients with KRAS mutation.


Asunto(s)
Anticuerpos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Animales , Anticuerpos/inmunología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Sinergismo Farmacológico , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Gemcitabina
9.
Cancer Lett ; 403: 339-353, 2017 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-28688971

RESUMEN

Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Vasos Sanguíneos/efectos de los fármacos , Doxorrubicina/farmacología , Melanoma Experimental/tratamiento farmacológico , Neovascularización Patológica , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Sulfonamidas/farmacología , Animales , Apoptosis/efectos de los fármacos , Vasos Sanguíneos/enzimología , Vasos Sanguíneos/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/enzimología , Humanos , Imidazoles/farmacología , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Masculino , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/enzimología , Melanoma Experimental/secundario , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/patología , Fosfatidilinositol 3-Quinasa/metabolismo , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Carga Tumoral/efectos de los fármacos , Hipoxia Tumoral , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Cancer Lett ; 396: 155-166, 2017 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-28315430

RESUMEN

Pancreatic cancer is a highly lethal disease for which limited therapeutic options are available. Pancreatic cancer exhibits a pronounced collagen-rich stromal reaction, which induces chemoresistance by inhibiting drug diffusion into the tumor. Complementary treatment with oncolytic virus such as an oncolytic adenovirus expressing relaxin (YDC002) is an innovative treatment option for combating chemoresistant pancreatic cancer. Here, we examined the ability of combined treatment with gemcitabine and YDC002, which degrades extracellular matrix (ECM), to efficiently treat chemoresistant and desmoplastic pancreatic cancer. Gemcitabine alone exhibited similarly low cytotoxicity toward pancreatic cancer cells throughout the concentration range (1-50 µM) used, whereas the combination of YDC002 and a subtherapeutic dose of gemcitabine (0.01-0.05 µM) resulted in potent anticancer effects through effective induction of apoptosis. Importantly, YDC002 combined with gemcitabine significantly attenuated the expression of major ECM components including collagens, fibronectin, and elastin in tumor spheroids and xenograft tumors compared with gemcitabine alone, resulting in potent induction of apoptosis, gemcitabine-mediated cytotoxicity, and an oncolytic effect through degradation of tumor ECM. Our results demonstrate that YDC002 can selectively degrade aberrant ECM and attenuate the ECM-induced chemoresistance observed in desmoplastic pancreatic tumor, resulting in a potent antitumor effect through effective induction of apoptosis.


Asunto(s)
Adenoviridae/metabolismo , Desoxicitidina/análogos & derivados , Viroterapia Oncolítica/métodos , Neoplasias Pancreáticas/terapia , Relaxina/biosíntesis , Adenoviridae/genética , Animales , Antimetabolitos Antineoplásicos/farmacología , Terapia Combinada , Desoxicitidina/farmacología , Células HEK293 , Humanos , Masculino , Ratones , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/virología , Distribución Aleatoria , Relaxina/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina
12.
Oncotarget ; 8(68): 112893-112906, 2017 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-29348875

RESUMEN

Activation of PI3K/AKT pathway occurs frequently in tumors and is correlated with radioresistance. The PI3K/AKT pathway can be an important target for improvement of radiotherapy. Although adding of chemotherapy to radiation therapy regimen enhances survival in patients with locally advanced pancreatic cancer, more effective therapies for increasing radiosensitivity are urgently needed. In this study, we investigated whether the novel PI3K inhibitor HS-173 could attenuate radiation-induced up-regulation of DNA damage repair processes and assessed its efficacy as a radio- and chemo-sensitizer. Radiosensitizing effects of HS-173 were tested in human pancreatic cells using clonogenic survival and growth assays. Mechanisms underlying the effects of HS-173 and radiation were determined by assessing cell cycle and DNA damage- repair pathway components, including ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The in vivo efficacy of HS-173 in cancer radiotherapy was evaluated using a human tumor xenograft model. HS-173 significantly increased the sensitivity of pancreatic cancer cells to radiation, an effect that was associated with G2/M cell cycle arrest. HS-173 also significantly attenuated DNA damage repair by potently inhibiting ATM and DNA-PKcs, the two major kinases that respond to radiation-induced DNA double-strand breaks (DSBs), resulting in sustained DNA damage. Moreover, the combination of HS-173 and radiation delayed tumor growth and impaired DNA repair in a pancreatic cancer xenograft model, reflecting enhanced radiosensitization. These results showed that HS-173 significantly improved radiotherapy by inhibiting the DNA damage-repair pathway in pancreatic cancer. We therefore suggest that HS-173 may be an effective radiosensitizer for pancreatic cancer.

13.
Oncotarget ; 7(47): 78029-78047, 2016 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-27793006

RESUMEN

Pancreatic cancer is one of the most aggressive solid malignancies prone to metastasis. Epithelial-mesenchymal transition (EMT) contributes to cancer invasiveness and drug resistance. In this study, we investigated whether HS-173, a novel PI3K inhibitor blocked the process of EMT in pancreatic cancer. HS-173 inhibited the growth of pancreatic cancer cells in a dose- and time-dependent manner. Moreover, it significantly suppressed the TGF-ß-induced migration and invasion, as well as reversed TGF-ß-induced mesenchymal cell morphology. Also, HS-173 reduced EMT by increasing epithelial markers and decreasing the mesenchymal markers by blocking the PI3K/AKT/mTOR and Smad2/3 signaling pathways in pancreatic cancer cells. In addition, HS-173 clearly suppressed tumor growth without drug toxicity in both xenograft and orthotopic mouse models. Furthermore, to explore the anti-metastatic effect of HS-173, we established pancreatic cancer metastatic mouse models and found that it significantly inhibited metastatic dissemination of the primary tumor to liver and lung. Taken together, our findings demonstrate that HS-173 can efficiently suppress EMT and metastasis by inhibiting PI3K/AKT/mTOR and Smad2/3 signaling pathways, suggesting it can be a potential candidate for the treatment of advanced stage pancreatic cancer.


Asunto(s)
Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Piridinas/farmacología , Sulfonamidas/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Distribución Aleatoria , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Int J Oncol ; 48(2): 747-55, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26692190

RESUMEN

The aminoacyl-tRNA synthetase interacting multi-functional protein 1 (AIMP1) participates in a variety of cellular processes, including translation, cell proliferation, inflammation and wound healing. Previously, we showed that the N-terminal peptide of AIMP1 (6-46 aa) induced ERK phosphorylation. Liver fibrosis is characterized by excessive deposition of extracellular matrix, which is induced by TGFß signaling, and activated ERK is known to induce the phosphorylation of SMAD, thereby inhibiting TGFß signaling. We assessed whether the AIMP1 peptide can inhibit collagen synthesis in hepatic stellate cells (HSCs) by activating ERK. The AIMP1 peptide induced phosphorylation of SMAD2 via ERK activation, and inhibited the nuclear translocation of SMAD, resulting in a reduction of the synthesis of type I collagen. The AIMP1 peptide attenuated liver fibrosis induced by CCl4, in a dose-dependent manner. Masson-Trichrome staining showed that the AIMP1 peptide reduced collagen deposition. Immunohistochemical staining showed that the levels of α-SMA, TGFß and type I collagen were all reduced by the AIMP1 peptide. Liver toxicity analysis showed that the AIMP1 peptide improved the levels of relevant biological parameters in the blood. These results suggest that AIMP1 peptide may have potential for development as a therapeutic agent to treat liver fibrosis.


Asunto(s)
Aminoacil-ARNt Sintetasas/metabolismo , Citocinas/metabolismo , Cirrosis Hepática/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Unión al ARN/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Núcleo Celular/metabolismo , Proliferación Celular/fisiología , Células Cultivadas , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Fosforilación/fisiología , Proteínas Smad/metabolismo
15.
Int J Oncol ; 47(1): 253-61, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25963192

RESUMEN

Chronic myeloid leukemia (CML) is characterized by a constitutively active Bcr-Abl tyrosine kinase. Although Imatinib has been proven to be an effective drug against CML, its resistance has been observed with disease relapse due to T315I predominant point mutation. Liriodendron tulipifera L., one of the fastest growing hardwood tree species, exerts antioxidant activity and anti-inflammatory effects. However, its anticancer effect has been minimally reported. In this study, we extracted CD-200 from Liriodendron tulipifera L. and investigated its effect on cell survival or apoptosis in CML cells with Bcr-Abl/T315I (BaF3/T315I) as well as wild-type Bcr-Abl (BaF3/WT). CD-200 inhibited cell proliferation in the BaF3/WT cells, and also in the BaF3/T315I cells with Imatinib resistance. Moreover, it strongly inhibited Bcr-Abl signaling pathways in a dose-dependent manner. Also, it significantly increased the sub-G1 phase and the expression of cleaved PARP and caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we observed that CD-200 induced apoptosis with a loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin. Furthermore, CD-200 showed a significant inhibition in tumor growth, compared to Imatinib in BaF3/T315I mouse xenograft models. Taken together, our study demonstrates that CD-200 exhibits apoptosis induction and anti-proliferative effect by blocking the Bcr-Abl signaling pathways in the Bcr-Abl/T315I with resistance to Imatinib. We suggest that CD-200 may be a natural product to target Bcr-Abl and overcome Imatinib resistance in CML patients.


Asunto(s)
Antineoplásicos/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Fusión bcr-abl/genética , Lactonas/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Liriodendron/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mesilato de Imatinib/farmacología , Lactonas/química , Lactonas/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Ratones , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/farmacología , Mutación Puntual , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Cell Res ; 25(6): 707-25, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25952668

RESUMEN

Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes "programmed" or "regulated" necrosis. Here we show that programmed necrosis is activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-dependent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/development. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with conventional chemotherapeutics.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Metilación de ADN , Necrosis/tratamiento farmacológico , Necrosis/patología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Animales , Neoplasias de la Mama/genética , Supervivencia Celular/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Necrosis/genética , Necrosis/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Relación Estructura-Actividad , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Arch Pharm Res ; 38(5): 742-51, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25142942

RESUMEN

Severe acute pancreatitis (SAP), a common necroinflammatory disease initiated by the premature activation of digestive enzymes within the pancreatic acinar cells, is associated with significant morbidity and mortality. In this study, we investigated whether human bone marrow-derived clonal mesenchymal stem cells (hcMSCs), isolated from human bone marrow aspirate according to our newly established isolation protocol, have potential therapeutic effects in SAP. SAP was induced by three intraperitoneal (i.p.) injections of cerulein (100 µg/kg) and sequential LPS (10 mg/kg) in Sprague-Dawley (SD) rats. hcMSCs (1 × 10(6)/head) were infused on 24 h after LPS injection via the tail vein. The rats were sacrificed 3 days after infusion of hcMSCs. We observed that infused hcMSCs reduced the levels of serum amylase and lipase. Infused hcMSCs ameliorated acinar cell necrosis, pancreatic edema, and inflammatory infiltration. Also, infused hcMSCs decreased the level of malondialdehyde, and increased the levels of glutathione peroxidase and superoxide dismutase. The number of TUNEL positive acinar cells was reduced after hcMSCs infusion. In addition, hcMSCs reduced the expression levels of pro-inflammation mediators and cytokines, and increased the expression of SOX9 in SAP. Taken together, hcMSCs could effectively relieve injury of pancreatitis as a promising therapeutics for SAP.


Asunto(s)
Trasplante de Células Madre Mesenquimatosas/métodos , Pancreatitis/patología , Pancreatitis/terapia , Índice de Severidad de la Enfermedad , Animales , Humanos , Mediadores de Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismo , Pancreatitis/metabolismo , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento
18.
Oncotarget ; 6(3): 1507-18, 2015 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-25483100

RESUMEN

Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT). HS-543 showed anti-proliferative effects in the BaF3/WT cells as well as the BaF3/T315I cells with resistance to Imatinib and strongly inhibited the Bcr-Abl signaling pathway in a dose-dependent manner. Furthermore, it significantly increased the sub G1 phase associated with early apoptosis, with increased levels of cleaved PARP and cleaved caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we found that HS-543 induced apoptosis with the loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin, together with increasing that of Bax. In BaF3/T315I xenograft models, HS-543 significantly delayed tumor growth, unlike Imatinib. Our results demonstrate that HS-543 exhibits the induction of apoptosis and anti-proliferative effect by blocking the Bcr-Abl signaling pathway in the T315I-mutated Bcr-Abl cells with resistance to Imatinib. We suggest that HS-543 may be a novel promising agent to target Bcr-Abl and overcome Imatinib resistance in CML patients.


Asunto(s)
Antineoplásicos/farmacología , Mesilato de Imatinib/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/farmacología , Urea/análogos & derivados , Urea/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Mutación , Distribución Aleatoria , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Oncotarget ; 5(20): 10180-97, 2014 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-25338206

RESUMEN

As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1α and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Colorantes Fluorescentes/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Xantinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microscopía Confocal , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Distribución Aleatoria , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Oncotarget ; 5(19): 9150-68, 2014 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-25193856

RESUMEN

Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action. Crizotinib strongly suppressed the growth and proliferation of pancreatic cancer cells in a dose-dependent manner. Also, it induced apoptosis by modulating its related factors. In the study, with regard to the mechanism of action, Crizotinib did not inhibit c-MET expression on pancreatic cancer cells; instead, it specifically inhibited the activity of ALK, which was identified to be highly expressed on various pancreatic cancer cells and tissues in our study. In 42 different receptor tyrosine kinase (RTKs) array, Crizotinib also strongly inhibited the expression of activated ALK in pancreatic cancer cells, modulating its downstream mediators such as STAT3, AKT, and ERK. Furthermore, Crizotinib inhibited angiogenesis in a mouse Matrigel plug assay as well as the progression of tumor growth in a mouse xenograft model. Taken together, our investigation shows that Crizotinib inhibits the ALK signaling pathway in pancreatic cancer, resulting in cell growth/angiogenesis inhibition and apoptosis induction. We suggest that Crizotinib might be used as a novel therapeutic drug for treating pancreatic cancer.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Crizotinib , Quinasas MAP Reguladas por Señal Extracelular/biosíntesis , Humanos , Potencial de la Membrana Mitocondrial , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Factor de Transcripción STAT3/biosíntesis , Trasplante Heterólogo
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