ABSTRACT
SCOPE: Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with higher interleukin-6 (IL-6) levels, and suppression of the Janus kinase 2/Signal transducer and activator of transription 3 (JAK2/STAT3) pathway may contribute to the suppression of this cancer. This study aims to compare the anti-cancer effect of pterostilbene (PSB) and 2'- and 3'-hydroxypterostilbene (2HPSB and 3HPSB, respectively) on the JAK2/STAT3 pathway. METHODS AND RESULTS: In vitro experiments with the OCCC cell line TOV21G and a xenograft nude mouse model are used to achieve the study aims. The results showed that 3HPSB has the greatest anti-proliferative and pro-apoptotic effects of the three compounds studied. Activation of the JAK2/STAT3 pathway and the nuclear translocation of STAT3 are effectively inhibited by 3HPSB and PSB. Both 3HPSB and PSB can effectively suppress tumor growth, which is mediated by the inhibition of JAK2/STAT3 phosphorylation. CONCLUSION: This is the first study to compare the efficacy of PSB, 3HPSB, and the newly identified compound 2HPSB regarding ovarian cancer. Moreover, targeting JAK2/STAT3 is shown to be a potentially effective strategy for OCCC treatment. This study is expected to provide new insights into the potential of the abovementioned phytochemicals for development as adjuvants for cancer treatment in the future.
Subject(s)
Carcinoma , Ovarian Neoplasms , Female , Animals , Mice , Humans , Janus Kinase 2/metabolism , Janus Kinase 2/pharmacology , Cell Line, Tumor , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , STAT3 Transcription Factor/metabolism , Cell ProliferationABSTRACT
In this study we investigated the effects of curcumin, derived from plant Curcuma longa, on oxidative toxicity, and the possible molecular mechanism of antitumour of curcumin in liver cancer rats. Results showed that blood levels of Gamma-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, glutathione S-transferase, and liver level of MD were significantly decreased after curcumin feeding. Levels of the liver malondialdehyde MDA, nitric oxide and antioxidant enzymes were significantly increased. Moreover, RT-PCR and Western blot analysis results showed that curcumin treatment significantly decreased liver vascular endothelial growth factor (VEGF), CyclinD1 and CDK4 mRNA expression levels and CyclinD1 and CDK4 proteins levels in liver cancer rats. These findings were confirmed by histopathology. It is concluded that curcumin can protect the liver from the damage caused by N-nitrosodiethylamine. Moreover, curcumin has the potential to be used in a therapy for liver cancer. The present data provide evidence to support the presence of free radicals and VEGF, CyclinD1 and CDK4 mRNA in rat tumour cells. Studies are in progress in order to further characterize the role of VEGF, CyclinD1 and CDK4 mRNA in liver cancer cells and in hepatic therapeutics.
Subject(s)
Curcumin/pharmacology , Cyclin D1/genetics , Cyclin-Dependent Kinase 4/genetics , Diethylnitrosamine/administration & dosage , Gene Expression Profiling , Liver/metabolism , Vascular Endothelial Growth Factor A/genetics , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Catalase/metabolism , Cyclin D1/metabolism , Cyclin-Dependent Kinase 4/metabolism , Gene Expression Regulation/drug effects , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Glutathione Reductase/metabolism , Glutathione Transferase/blood , Injections , Liver/drug effects , Liver/enzymology , Liver/pathology , Malondialdehyde/metabolism , Nitric Oxide/metabolism , Rats , Rats, Wistar , Superoxide Dismutase/metabolism , Vascular Endothelial Growth Factor A/metabolism , gamma-Glutamyltransferase/bloodABSTRACT
BACKGROUND AND OBJECTIVES: microRNAs (miRNAs), small non-coding RNAs, are always aberrantly expressed in many diseases including human cancers. The aim of this study was to examine and determine the clinical significance of hsa-miR-31, hsa-miR-142-3p, hsa-miR-338-3p, and hsa-miR-1261 expression in esophageal squamous cell carcinoma (ESCC). METHODS: Expression levels of four selected miRNAs, initially evaluated by microarray, were validated by qRT-PCR. Various statistical methods were used to analyze the relationship between miRNA expression and clinicopathologic features and prognosis in 91 patients with ESCC. RESULTS: MiR-31 and miR-142-3p expression were correlated to histological differentiation in ESCC (P < 0.05, Student's t-test); high miR-142-3p expression was associated with a poor prognosis in all 91 ESCC patients (P = 0.014, log-rank) and identified as an independent prognostic factor in ESCC (P = 0.017, univariate Cox; P = 0.022, multivariate Cox). More importantly, stratified analysis indicated that high miR-142-3p expression was correlated to a poor prognosis within good-prognosis groups comprised of ESCC patients with small tumor size, negative lymph node metastasis, or early stage (all P < 0.05). CONCLUSION: The main findings suggest that miR-142-3p is involved in the progression of ESCC and is a potential prognostic biomarker for ESCC.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , MicroRNAs/genetics , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Case-Control Studies , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophagus/metabolism , Esophagus/pathology , Female , Follow-Up Studies , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Oligonucleotide Array Sequence Analysis , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Survival RateABSTRACT
BACKGROUND: Doxorubicin (DOX) is an important antineoplastic agent. However, the associated cardiotoxicity, possibly mediated by the production of reactive oxygen species, has remained a significant and dose-limiting clinical problem. Our hypothesis is that the hematopoietic/megakaryocytopoietic growth factor thrombopoietin (TPO) protects against DOX-induced cardiotoxicity and might involve antiapoptotic mechanism exerted on cardiomyocytes. METHODS AND RESULTS: In vitro investigations on H9C2 cell line and spontaneously beating cells of primary, neonatal rat ventricle, as well as an in vivo study in a mouse model of DOX-induced acute cardiomyopathy, were performed. Our results showed that pretreatment with TPO significantly increased viability of DOX-injured H9C2 cells and beating rates of neonatal myocytes, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. TPO ameliorated DOX-induced apoptosis of H9C2 cells as demonstrated by assays of annexin V, active caspase-3, and mitochondrial membrane potential. In the mouse model, administration of TPO (12.5 microg/kg IP for 3 alternate days) significantly reduced DOX-induced (20 mg/kg) cardiotoxicity, including low blood cell count, cardiomyocyte lesions (apoptosis, vacuolization, and myofibrillar loss), and animal mortality. Using Doppler echocardiography, we observed increased heart rate, fractional shortening, and cardiac output in animals pretreated with TPO compared with those receiving DOX alone. CONCLUSIONS: These data have provided the first evidence that TPO is a protective agent against DOX-induced cardiac injury. We propose to further explore an integrated program, incorporating TPO with other protocols, for treatment of DOX-induced cardiotoxicity and other forms of cardiomyopathy.
