ABSTRACT
Ovarian cancer is a serious threat to female health, although the incidence of it is relatively low, its mortality rate remains high due to its intense invasion and metastasis. Therefore, it is urgent to explore new treatment strategies for ovarian cancer. In this study, paclitaxel and emodin were encapsulated in different micelles, and loaded on the surface of the micelles with epidermal growth factor (EGF) as the targeting molecule, made compound formulations in proportion. In this study, EGF-modified paclitaxel micelles and EGF-modified emodin micelles were characterized, their inhibitory effects on SKOV3 cell proliferation and invasion were studied in vivo and in vitro, and its targeting ability was confirmed. The results showed that the shape, particle size, zeta potential, release rate, encapsulation rate, polydispersity index, and other physical and chemical properties of EGF-modified paclitaxel micelles plus EGF-modified emodin micelles meet the requirements, and the modification of EGF on the micelle surface could obviously improve the uptake of SKOV3 cells and inhibit the proliferation of SKOV3 cells. The compound formulation can inhibit the invasion and metastasis of ovarian cancer by inhibiting the expression of hypoxia inducible factor-α, MMP-2, MMP-9, and VE-cadherin. The in vivo studies have also showed significant pharmacodynamics results. These results indicated that EGF-modified paclitaxel micelles plus EGF-modified emodin micelles provide a new strategy for the treatment of ovarian cancer.
Subject(s)
Emodin , Ovarian Neoplasms , Female , Humans , Paclitaxel/chemistry , Micelles , Epidermal Growth Factor/therapeutic use , Emodin/pharmacology , Emodin/therapeutic use , Cell Line, Tumor , Liposomes , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathologyABSTRACT
BACKGROUND/AIMS: Ovarian cancer is often diagnosed at later stages with poor prognosis. Recent studies have associated the expression of deubiquitylase USP7 with the survival of ovarian cancers. Being a cysteine protease, USP7 could become a target for pharmacological intervention. Therefore, in this study, we assessed the influence of its inhibitor P5091 on ovarian cancer cells. METHODS: Ovarian cancer cells were treated with P5091, and cell proliferation was measured with MTT assay; cell morphology was inspected under a phase-contrast microscope; cell cycle and cell death were examined by flow cytometry. To gain mechanistic insights into its effects, immunoblotting was performed to detect USP7, HDM2, p53, p21, apoptosis and autophagy related proteins. RESULTS: P5091 effectively suppressed the growth of ovarian cancer cells, caused cell cycle blockage, and induced necrosis and apoptosis with more severe phenotypes observed in HeyA8 cells with wild-type p53 than in OVCAR-8 cells with mutant p53. P5091 also prompted autophagy, with more efficient p62 degradation in HeyA8. CONCLUSION: P5091 shows efficacy in suppressing ovarian cancers harbouring wild-type and mutant p53. Its effects seemed to be enhanced by wild-type p53. The potency of this USP7 inhibitor also correlated with autophagy to some extent. Therefore, the pharmacological targeting of USP7 may serve as a potential therapeutic strategy and warrants further investigation.
Subject(s)
Cell Death/drug effects , Ovarian Neoplasms/metabolism , Thiophenes/pharmacology , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Specific Peptidase 7/antagonists & inhibitors , Apoptosis/drug effects , Apoptosis/genetics , Autophagy/drug effects , Autophagy/genetics , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Flow Cytometry , Humans , Microscopy, Phase-Contrast , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Ubiquitin-Specific Peptidase 7/metabolism , p21-Activated Kinases/genetics , p21-Activated Kinases/metabolismABSTRACT
BACKGROUND: To evaluate the safety and effectiveness of argatroban for the prevention of venous thromboembolism (VTE) after posterior lumbar decompressive surgery. METHODS: Included in this retrospective study were 556 patients who underwent posterior lumbar decompressive surgery for trauma and degenerative diseases. They were divided into two groups: argatroban group (n = 274), and low molecular weight heparin (LMWH) group (n = 282). The occurrence of postoperative venous thrombosis and complications including hemorrhage and allergic reaction was compared between the two groups. Neurological and clinical outcomes in terms of Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI) were assessed before operation and at 6 and 12 months after operation. RESULTS: Postoperative venous thromboembolism (VTE) occurred in seven patient. No pulmonary embolism (PE) occurred in any patient. Thrombosis occurred in 3 cases (1.0%) and bleeding in 1 case (0.04%) in argatroban group vs. 4 (1.4%) and 4 (1.4%) in LMWH group, showing no significant between the two groups (P > 0.05). There was significant reduction in the severity of back and leg pain (VAS P < 0.05) and significant improvement in the patient quality of life (ODI, P < 0.05) 6 months and 1 year after operation, showing no significant difference between the two groups (P > 0.05). CONCLUSIONS: Argatroban proved to be equally effective as LWMH for anticoagulation therapy. Both drugs exhibited a similar preventive effect against postoperative VTE after posterior lumbar spine surgery, without increasing the risk of postoperative bleeding. The neurological and clinical outcomes are satisfactory and similar between the two pharmacological methods.
