Objective To explore the effects and mechanisms of ursolic acid on drug-resistant SKOV3/DDP ovarian carcinoma xenografts in nude mice. Methods The models of drug-resistant SKOV3/DDP ovarian carcinoma on athymic mouse were established and randomly divided into four groups with intraperitoneal injection of different drugs: blank control (0.9% sodium chloride solution), cisplatin (4 mg·kg-1·d-1), ursolic acid low dose (30 mg·kg-1·d-1), and high dose (60 mg·kg-1·d-1).All drugs were injected at volumes of 10 mL·kg-1 perday for 15 days. The tumor volumes were measured during the process of drug treatment every three days. After 14 days, The tumorigenic rate and tumor inhibition rate were calculated. RT-PCR and Western blotting were performed to detect the expression of Bcl-2 and Bax.Results Anti-tumor rates of cisplatin group , low dose ursolic acid group, and high dose ursolic acid group was 33.3%, 43.3%, and 71.0%, respectively. Bcl-2 expressions were down-regulated, while Bax expressions were up-regulated in all three groups. Conclusion Ursolic acid has some anti-tumor activity on cisplatin-resistant human ovarian cancer SKOV3 /DDP cell in nude mice.It can inhibit tumor growth with dose-effect relationship. The mechanism may be to suppress the expression of anti-apoptotic factor Bcl-2 and to increase the expression of apoptosis-promoting factors Bax.
Fig.2
The mRNA expression of Bcl-2 and Bax in transplantation tumor of four groups of nude mice A. blank control group; B. cisplatin group; C. low-dose ursolic acid group; D.high-dose ursolic acid group; Compared with blank control group, * 1P< 0.01; compared with cisplatin group and low-dose ursolic acid group, * 2P<0.05
Fig.3
Protein expression of Bax and Bcl-2 in transplantation tumor of four groups of nude mice A.blank control group; B.cisplatin group; C.low-dose ursolic acid group; D.high-dose ursolic acid group
LANDEN C NJR,BIRRER MJ,SOOD AK.Early events in the pathogenesis of epithelial ovarian cancer[J].,2008,26(6):995-1005.
Ovarian carcinogenesis, as in most cancers, involves multiple genetic alterations. A great deal has been learned about proteins and pathways important in the early stages of malignant transformation and metastasis, as derived from studies of individual tumors, microarray data, animal models, and inherited disorders that confer susceptibility. However, a full understanding of the earliest recognizable events in epithelial ovarian carcinogenesis is limited by the lack of a well-defined premalignant state common to all ovarian subtypes and by the paucity of data from early-stage cancers. Evidence suggests that ovarian cancers can progress both through a stepwise mutation process (low-grade pathway) and through greater genetic instability that leads to rapid metastasis without an identifiable precursor lesion (high-grade pathway). In this review, we discuss many of the genetic and molecular disorders in each key process that is altered in cancer cells, and we present a model of ovarian pathogenesis that incorporates the role of tumor cell mutations and factors in the host microenvironment important to tumor initiation and progression.
OZOLS RF.Systemic therapy for ovarian cancer: current status and new treatments[J].,2006,33(Suppl):3-11.
Current systemic therapy for ovarian cancer consists of a combination of carboplatin and paclitaxel. While the majority of patients achieve clinical complete remission after six cycles of chemotherapy, the relapse rate stands at over 50%. Median survival time for patients after recurrence is approximately 2 years. New treatment approaches for patients with advanced ovarian cancer include consolidation and maintenance therapy, intraperitoneal administration of cytotoxic agents, new combination chemotherapy regimens, the development of new cytotoxic agents, and molecular-targeted therapies. These agents will be evaluated either singularly or with chemotherapy. Currently, the Gynecologic Oncology Group is evaluating a combination of bevacizumab together with paclitaxel and carboplatin in previously untreated patients with advanced ovarian cancer. This trial is based on phase II data that suggest that bevacizumab as a single agent has significant activity in patients with recurrent ovarian cancer. In addition, the Gynecologic Oncology Group will be conducting phase II trials of different combinations of intraperitoneal chemotherapy in an effort to decrease toxicity associated with current intraperitoneal regimens that have shown an improvement in survival in patients with small-volume stage III disease. The Gynecologic Oncology Group will also be conducting a trial of maintenance therapy in patients who enter clinical complete remission with paclitaxel plus carboplatin, comparing observation with monthly paclitaxel or monthly paclitaxel poliglumex. Novel new cytotoxic and biologic agents are also being evaluated as single agents in phase II trials in patients with recurrent ovarian cancer.
KIM SH, HONG JH, LEE YC.Ursolic acid, a potential PPARγ agonist, suppresses ovalbumin induced airway inflammationand Penh by down-regulating IL-5, IL-13, and IL-17 in a mouse model of allergic asthma[J]. , 2013, 701(1/3):131-143.
Our data suggest the therapeutic mechanism of ursolic acid in asthma is based on reductions of Th2 cytokines (IL-5 and IL-13), ovalbumin-specific IgE production, and eosinophil infiltration via the Th2-GATA-3, STAT6, and IL-17-NF-κB pathways.
MARXD,MEDENH.Differential expression of apoptosis-associated genes bax and bcl-2 in ovarian cancer[J].,2001,39(5):687-691.
The deregulation of the balance between proliferation and programmed cell death is considered one of the most important features of malignant tumors. The search for new markers, which may reflect the tumor progress and response to various therapy regimens, has recently focused on alterations of genes involved in regulation of programmed cell death and apoptosis. The bcl -2-family is a still growing family of genes, which play a major role in regulation of cell suicide, acting either as inhibitors (e.g., bcl-2, bcl-xl, mcl- 1) or promoters (e.g., bcl-xs, bax, bak, bad) of apoptosis ( 1 - 3 ). The chromosomal translocation t(14;18), leading to overexpression of the Bcl-2 protein was first described in human B-cell lymphoma ( 4 ). Later on, Bcl-2-overexpression without chromosomal translocations was also detected in various epithelial tumors ( 5 - 12 ). It has been suggested that Bcl-2 as the major inhibitor of apoptosis plays a role in tumor development and progress by prolonging the survival of malignant cells. Unexpectedly, expression of Bcl-2 has been shown to be connected with parameters of favorable prognosis and prolonged survival in nonsmall-cell lung cancer ( 6 ), breast ( 7 - 9 ), and, recently, in ovarian cancer ( 10 - 12 ). Bax-expression, in contrast, was associated with an unfavorable outcome, as well as negative histopathological features in breast ( 13 ) and ovarian cancer ( 12 ). Moreover, the association of Bax -expression with predictors of poor clinical outcome was strongly connected with concomitant downregulation of Bcl -2-expression ( 12 , 13 ). The unexpected effect of Bcl- 2- and Bax-expression on prognosis of ovarian cancer patients is underlined by the survival curves of patients. Especially, patients with exclusively Bax -positive tumors had a statistically significantly reduced survival as compared to patients with exclusively Bcl -2-positive tumors ( 12 ). This difference could be observed for patients with tumors of different stage and grade, as well as for patients with no evidence of disease or residual tumor after primary surgery ( 12 ). One explanation for these observations is that the apoptosis inhibiting or promoting effect of these homologous proteins depends partly on protein-protein interactions. Bax, for example, the main antagonist of Bcl-2, heterodimerizes with Bcl-2 or Bcl-Xl and homodimerizes with itself ( 1 - 3 ). The ratio of Bax-heterodimers to Bax-homodimers seems to be the critical determinant for regulating cell death ( 2 , 3 ). In cells in which 80% of Bax is found in homodimers, an apoptotic signal results in cell death ( 2 , 3 ), suggesting a crucial role of the Bax/Bcl-2 balance for the regulation of proliferation or cell suicide.
WANGH,ZHANGZ,WEIX,et al.Small-molecule inhibitor of Bcl-2 (TW-37) suppresses growth and enhances cisplatin-induced apoptosis in ovarian cancer cells[J].,2015,8(1):3-8.
Bcl-2 plays a major role in the pathobiology and drug resistance of ovarian cancer, and inhibition of bcl-2 was useful for OC therapy. It has previously reported that TW-37, a small-molecule inhibitor of Bcl-2 family proteins, inhibited cell growth and induced apoptosis in many cancer cells. In the present study,we investigate the effect of TW-37 or / and in combination with cisplain on several ovarian cancer (OC) cell lines with high bcl-2 expression.The bcl-2 mRNA and protein expression, and the cisplain (DDP) sensitivity of OC cell lines SKOV3, OVCAR3, OV-90 and 3AO and SKOV3DDP were determined by Quantitative real-time RT-PCR,Western blot, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and fluorescence-activated cell sorting (MTT) assays. The effects of TW-37 alone or combined with cisplain on growth and apoptosis in bcl-2 overexpressed OVCAR3, OV-90 and SKOV3DDP cells was detected by MTT,clonogenic assay, ELISA and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay.The cell lines SKOV3 and 3AO were sensitive, whereas OVCAR3, OV-90 and SKOV3DDP were resistant to cisplain. Significant positive correlation was observed between basal bcl-2 mRNA and protein and cisplain sensitivity. Cisplain treatment did not activate bcl-2 in vitro. Treatment with TW-37 inhibited bcl-2 expression in bcl-2 overexpressed OVCAR3, OV-90 and SKOV3DDP cells , and inhibited growth and induced apoptosis ,and increased cisplain killing of the bcl-2 overexpressed cells in a does and time-dependant manner in vitro.Bcl-2 level positively correlated with sensitivity to cisplain. Treatment with TW-37 was effective alone and in combination with cisplain in bcl-2 overexpressed OC cell lines in vitro. Thus, TW-37 may be a useful therapeutic agent for OCs.
KIM ES,MOONA.Ursolic acid inhibits the invasive phenotype of SNU-484 human gastric cancer cells[J].,2015, 9(2):897-902.
Metastasis is a major cause of cancerrelated mortality in patients with gastric cancer. Ursolic acid, a pentacyclic triterpenoid compound derived from medicinal herbs, has been demonstrated to exert anticancer effects in various cancer cell systems. However, to the best of our knowledge, the inhibitory effect of ursolic acid on the invasive phenotype of gastric cancer cells has yet to be reported. Therefore, the aim of the present study was to investigate the effect of ursolic acid on the invasiveness of SNU484 human gastric cancer cells. Ursolic acid efficiently induced apoptosis, possibly via the downregulation of Bcell lymphoma聽2 (Bcl2), the upregulation of Bcl2associated X聽protein and the proteolytic activation of caspase3. Furthermore, the activation of p38聽mitogenactivated protein kinase and cJun Nterminal kinase was increased by the administration of ursolic acid. In addition, ursolic acid significantly suppressed the invasive phenotype of the SNU484聽cells and significantly decreased the expression of matrix metalloproteinase (MMP)2, indicating that MMP2 may be responsible for the antiinvasive activity of ursolic acid. Taken together, the results of the present study demonstrate that ursolic acid induces apoptosis and inhibits the invasive phenotype of gastric cancer cells; therefore, ursolic acid may have a potential application as a chemopreventive agent to prevent the metastasis of gastric cancer or to alleviate the process of metastasis.
Ursolic acid, a potential PPARγ agonist, suppresses ovalbumin induced airway inflammationand Penh by down-regulating IL-5, IL-13, and IL-17 in a mouse model of allergic asthma