RESUMEN
BACKGROUND/AIM: Cholangiocarcinoma (CCA) is a highly aggressive disease. Most of CCA patients are diagnosed in an advanced stage of the disease, when it is unresectable and there is chemoresistance, resulting in poor prognosis. However, effective therapeutic regimens and molecular targets for CCA remain poor. Cyclin-dependent kinases (CDKs) are key regulatory enzymes in cell cycle progression. Aberrant CDK activation is a hallmark of cancer. Dinaciclib is a small molecule inhibitor of multiple CDKs, currently under clinical evaluation for treating advanced malignancies. The efficacy of anti-tumor activity of dinaciclib against chemotherapy resistant CCA cells was examined in vitro and in vivo. MATERIALS AND METHODS: In this study, the effect of dinaciclib on growth and cell cycle in CCA cell lines were determined using the MTT assay and cell cycle analysis. The anti-tumor activity of dinaciclib was investigated in CCA-inoculated mice. In addition, the chemosensitizing effect of dinaciclib was investigated in gemcitabine-treated CCA cell lines. RESULTS: Dinaciclib significantly suppressed cell proliferation, induced G1/S phase cell cycle arrest and apoptosis of CCA cell lines. It significantly suppressed the growth of CCA cells in xenograft mouse models. We also found that dinaciclib significantly inhibited the growth of gemcitabine-resistant CCA cell lines (KKU-213A-GemR and KKU-100-GemR). Furthermore, dinaciclib significantly enhanced the anti-tumor activity of gemcitabine in CCA cell lines. CONCLUSION: Dinaciclib has the potential to be an effective therapeutic agent to control tumor cell growth of both parental and gemcitabine-resistant CCA cells.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Proliferación Celular , Colangiocarcinoma , Óxidos N-Cíclicos , Indolizinas , Compuestos de Piridinio , Ensayos Antitumor por Modelo de Xenoinjerto , Indolizinas/farmacología , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Animales , Óxidos N-Cíclicos/farmacología , Humanos , Compuestos de Piridinio/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Apoptosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Gemcitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Ciclo Celular/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Skin hyperpigmentation is an aesthetic problem that leads to psychosocial issues. Thus, skin whitening agents from agro- and poultry-industrial co-products are considered high economic value ingredients of interest for sustainable application. Therefore, this study aimed to determine the cosmeceutical potential of anserine/carnosine-rich chicken extract (ACCE) from the Thai native chicken Pradu Hang Dam Mor Kor 55 (PD) meat. The chemical composition was identified and quantified using the HPLC-UV method. Then, the antioxidation potential of the extract was compared to that of L-anserine and L-carnosine, using 1,1-diphenyl-2-picrylhydrazyl assay and shikonin-induced production of reactive oxygen species in CCD-986Sk cell models, and the anti-melanogenesis effect in the MNT-1 melanoma cell line model was investigated. Furthermore, related mechanisms were identified using colorimetric tyrosinase assay and the Western blot technique. The ACCE was composed of L-anserine and L-carnosine as two major constituents. In a dose-dependent manner, ACCE, L-anserine, and L-carnosine manifested significant antioxidation potential and significant reduction of melanin production. Activation of the extracellular signal-regulated kinase (ERK) signaling pathway and inhibition of tyrosinase activity of ACCE were demonstrated as the mechanisms of the anti-melanogenesis effect. In conclusion, ACCE has been revealed as a potential cosmeceutical agent due to its antioxidation and anti-melanogenic activity in association with L-anserine and L-carnosine composition and biomolecular regulating ability. Therefore, further studies and development should be considered to support the utilization of anserine/carnosine-rich chicken extract in the cosmetic industry for economic value creation and sustainability.
Asunto(s)
Carnosina , Cosmecéuticos , Animales , Anserina/química , Carnosina/química , Pollos/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Monofenol Monooxigenasa/metabolismo , Tailandia , Antioxidantes/farmacología , Antioxidantes/metabolismo , Transducción de SeñalRESUMEN
Diabetes is a major risk factor in the development and progression of several cancers including cholangiocarcinoma (CCA). However, the molecular mechanism by which hyperglycemia potentiates progression of CCA is not clearly understood. Here, we showed that a high glucose condition significantly increased reactive oxygen species (ROS) production and promoted aggressive phenotypes of CCA cells, including proliferation and migration activities. Mannosidase alpha class 2a member 2 (MAN2A2), was upregulated at both mRNA and protein levels in a high glucose- and ROS-dependent manner. In addition, cell proliferation and migration were significantly reduced by MAN2A2 knockdown. Based on our proteome and in silico analyses, we further found that chromodomain helicase DNA-binding protein 8 (CHD8) was induced by ROS signaling and regulated MAN2A2 expression. Overexpression of CHD8 increased MAN2A2 expression, while CHD8 knockdown dramatically reduced proliferation and migration as well as MAN2A2 expression in CCA cells. Moreover, both MAN2A2 and CHD8 were highly expressed with positive correlation in CCA tumor tissues. Collectively, these data suggested that high glucose conditions promote CCA progression through ROS-mediated upregulation of MAN2A2 and CHD8. Thus, glucose metabolism is a promising therapeutic target to control tumor progression in patients with CCA and diabetes.
Asunto(s)
Neoplasias de los Conductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Proteínas de Unión al ADN/metabolismo , Glucosa/metabolismo , Manosidasas/metabolismo , Factores de Transcripción/metabolismo , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Colangiocarcinoma/patología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Hiperglucemia/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND/AIM: Pyruvate kinase M2 (PKM2) is an enzyme that is predominantly overexpressed in various types of cancer. The role of PKM2 in liver fluke-associated cholangiocarcinoma (CCA) remains unclear. This study aimed to investigate the antitumor activity of shikonin, a PKM2 inhibitor, in CCA cells. MATERIALS AND METHODS: Immunohistochemistry and immunoblotting were used to determine PKM2 expression in CCA tissues and cells. Antiproliferative effects of shikonin were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation and trypan blue exclusion assays. The anti-metastatic activity of shikonin was determined using the Boyden chamber assay. Mechanisms by which shikonin inhibited CCA progression were determined. RESULTS: PKM2 was overexpressed in CCA compared to normal bile duct epithelial cells. Shikonin significantly inhibited growth, and migration of CCA cells while inducing their death. A mechanistic study revealed that antitumor effects of shikonin in CCA cells depended on increased production of reactive oxygen species. CONCLUSION: Shikonin may be a novel therapeutic agent for patients with CCA.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de los Conductos Biliares/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Colangiocarcinoma/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Naftoquinonas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular/efectos de los fármacos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Humanos , Especies Reactivas de Oxígeno/metabolismo , Hormonas Tiroideas , Proteínas de Unión a Hormona TiroideRESUMEN
Lactate dehydrogenase A (LDHA), a key metabolic enzyme, plays a crucial role in the final step of anaerobic glycolysis. Overexpression of LDHA is observed in many human malignancies in association with tumor progression. The purpose of this study was to investigate LDHA expression pattern during carcinogenesis, its clinico-pathological association, and evaluate the prognostic value of LDHA in CCA patients. LDHA expression was investigated using immunohistochemistry technique in both hamster- (n=60) and human-CCA tissues (n=82). Plasma LDH from healthy control (n=40) and CCA patients (n=29) were determined using an enzymatic based assay. The association of LDHA expression with clinico-pathological findings and prognostic value were evaluated by statistical analysis. In the CCA hamster model, an increase of LDHA expression was associated with the progression of CCA-genesis. Higher LDHA overexpression was associated with shorter survival of CCA patients. Multivariate analysis indicated that LDHA expression including histological type and N stage of tumor were independent prognostic risk factor of patient's survival. However, there was no difference in plasma LDH level between CCA patients and healthy controls. LDHA expression is involved in cholangiocarcinogenesis. Overexpression of LDHA can be a marker of poor prognosis in CCA patients and it might be a potential target for CCA treatment.