JQ1 inhibits tumour growth in combination with cisplatin and suppresses JAK/STAT signalling pathway in ovarian cancer.
- 作者列表："Bagratuni T","Mavrianou N","Gavalas NG","Tzannis K","Arapinis C","Liontos M","Christodoulou MI","Thomakos N","Haidopoulos D","Rodolakis A","Kastritis E","Scorilas A","Dimopoulos MA","Bamias A
BACKGROUND:Overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET (Bromodomain and extraterminal domain family) bromodomain (BRDs) inhibitor, has been found to suppress tumour progression in several cancer cell types. RESULTS:Using a panel of ovarian cancer cell lines and primary cell cultures from human ovarian cancer ascites, we demonstrated that JQ1 significantly suppressed cell proliferation and induced apoptosis in an ovarian cancer cell by targeting BRD4 and c-Μyc. In addition, JQ1 sensitized ovarian cancer cells to cisplatin, the most commonly used chemotherapeutic agent in ovarian cancer. Importantly, this effect was observed in ovarian cells, which exhibited resistance to cisplatin alone. Finally, we show that JQ1 interacts with the JAK-STAT signalling pathway, a pathway important in supporting ovarian cancer cell survival by suppressing or inducing genes involved in cell survival and apoptosis, respectively. CONCLUSION:Our data, taken together, suggest that JQ1 is an attractive antitumour candidate for further investigation in the treatment of ovarian cancer, as it associates with cell proliferation, apoptosis, and alterations in the JAK-STAT signalling pathway, especially in patients with a platinum-resistant profile or in patients with relapsed disease.
背景: c-Myc的过度表达在人卵巢癌中很常见，这可能是该疾病潜在的新的治疗靶点。已经发现JQ1，一种选择性小分子BET (溴结构域和外星人结构域家族) 溴结构域 (BRDs) 抑制剂，在几种癌细胞类型中抑制肿瘤进展。 结果: 使用一组卵巢癌细胞系和来自人卵巢癌腹水的原代细胞培养物，我们证明JQ1通过靶向BRD4和c-Μ yc显著抑制卵巢癌细胞的细胞增殖和诱导凋亡。另外，JQ1使卵巢癌细胞对顺铂致敏，顺铂是卵巢癌最常用的化疗药物。重要的是，在卵巢细胞中观察到这种作用，其表现出对单独的顺铂的抗性。最后，我们表明JQ1与jak-stat信号通路相互作用，jak-stat信号通路是通过分别抑制或诱导参与细胞存活和凋亡的基因来支持卵巢癌细胞存活的重要通路。 结论: 我们的数据综合表明，JQ1是一种有吸引力的抗肿瘤候选药物，用于卵巢癌治疗的进一步研究，因为它与细胞增殖、凋亡和jak-stat信号通路的改变有关，特别是在具有铂耐药谱的患者或复发性疾病的患者中。
METHODS:INTRODUCTION:Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is an effective treatment option for selected patients with peritoneal metastases (PM), but national utilization patterns are poorly understood. The objectives of this study were to (1) describe population-based trends in national utilization of CRS/IPC; (2) define the most common indications for the procedure; and (3) characterize the types of hospitals performing the procedure. METHODS:The National Inpatient Sample (NIS) was used to identify patients from 2006 to 2015 who underwent CRS/IPC, and to calculate national estimates of procedural frequency and oncologic indication. Hospitals performing CRS/IPC were classified based on size and teaching status. RESULTS:The estimated annual number of CRS/IPC cases increased significantly from 189 to 1540 (p < 0.001). Overall, appendiceal cancer was the most common indication (25.7%), followed by ovarian cancer (23.3%), colorectal cancer (22.5%), and unspecified PM (15.0%). Remaining cases (13.5%) were performed for other indications. Most cases were performed in large teaching hospitals (65.9%), compared with smaller teaching hospitals (25.1%), large non-teaching hospitals (5.3%), or small non-teaching hospitals (3.2%). Patients were more likely to undergo CRS/IPC without a diagnosis based on level I evidence (appendiceal, ovarian, or colorectal) at large non-academic hospitals (odds ratio 2.00, 95% confidence interval 1.18-3.38, p = 0.010) compared with large academic hospitals. CONCLUSIONS:Utilization of CRS/IPC is increasing steadily in the US, is performed at many types of facilities, and often for a variety of indications that are not supported by high-level evidence. Given associated morbidity of CRS/IPC, a national registry dedicated to cases of IPC is necessary to further evaluate use and outcomes.
METHODS::Results of epidemiologic studies of physical activity and ovarian cancer risk are inconsistent. Few have attempted to measure physical activity over the lifetime or in specific age windows, which may better capture etiologically relevant exposures. We examined participation in moderate-to-vigorous recreational physical activity (MVPA) in relation to ovarian cancer risk. In a population-based case-control study conducted in Montreal, Canada from 2011 to 2016 (485 cases and 887 controls), information was collected on lifetime participation in various recreational physical activities, which was used to estimate MVPA for each participant. MVPA was represented as average energy expenditure over the lifetime and in specific age-periods in units of metabolic equivalents (METs)-hours per week. Odds ratios (OR) and 95% confidence intervals (CI) for the relation between average MVPA and ovarian cancer risk were estimated using multivariable logistic regression models. Confounding was assessed using directed acyclic graphs combined with a change-in-estimate approach. The adjusted OR (95% CI) for each 28.5 MET-hr/week increment of lifetime recreational MVPA was 1.11 (0.99-1.24) for ovarian cancer overall. ORs for individual age-periods were weaker. When examined by menopausal status, the OR (95% CI) for lifetime MVPA was 1.21 (1.00-1.45) for those diagnosed before menopause and 1.04 (0.89-1.21) for those diagnosed postmenopausally. The suggestive positive associations were stronger for invasive ovarian cancers and more specifically for high-grade serous carcinomas. These results do not support a reduced ovarian cancer risk associated with MVPA.
METHODS::The aim of our study was to evaluate whether cardiovascular disease risks seen in adults with polycystic ovary syndrome (PCOS) develop in adolescents with PCOS using conventional Doppler echocardiography (CDE) and tissue Doppler echocardiography (TDE) or not. The other aim was to investigate the association of paraoxonase-1 (PON-1) level with cardiovascular parameters. 30 PCOS patients and 30 control patients were included in the study. All patients were evaluated with TDE and CDE. Paraoxonase-1 levels of both groups were studied. In CDE study, myocardial performance index (MPI) was higher in the PCOS group than in the control group (0.54 ± 0.11, 0.50 ± 0.12, p = .049, respectively). In the TDE study, early diastolic myocardial velocity (E)'/late diastolic myocardial velocity (A') was lower in PCOS group than in the control group (2.07 ± 0.08, 2.44 ± 0.10, p = .008, respectively). PON-1 was higher in PCOS group than in the control group (26.81 ± 3.05, 18.68 ± 1.18, p = .011, respectively). Cardiovascular disease risks, which are among the long-term complications of PCOS, seem to begin from the early stage of PCOS. The high PON-1 level was thought to increase in response to increased oxidative stress in PCOS.Impact statementWhat is already known on this subject? Polycystic ovary syndrome (PCOS) is one of the most commonly seen endocrinopathy in the adolescent age group. PCOS has detrimental effects on the cardiovascular system in the adult population which is reported in many studies.What the results of this study add? The result of this study showed that cardiovascular effects, which are among the long-term complications of PCOS, seem to begin from the early stage of PCOS. And also, serum paraoxonase-1 level increases in response to the oxidative stress in the adolescent with PCOS.What are the implications of these findings for clinical practice and/or further research? The cardiovascular system evaluation should be started in early phases of PCOS development in the adolescent age group. The potential role of oxidative effect of Paraoxonase-1 on the PCOS needs to be elucidated in further studies.