Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence.
- 作者列表："Guo B","Rodriguez-Gabin A","Prota AE","Mühlethaler T","Zhang N","Ye K","Steinmetz MO","Horwitz SB","Smith AB 3rd","McDaid HM
:The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers, malignancies that typically succumb to taxane resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anticancer activity, thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anticancer efficacy relative to taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated 1) improved pharmacologic properties, specifically increased maximum response achievable and area under the curve, and decreased EC50; 2) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to taxol or DDM; 3) reduced propensity for senescence induction relative to DDM; 4) superior long-term activity in cancer cells versus taxol or DDM; and 5) attenuation of metastatic characteristics in treated cancer cells. To contrast the binding of B2 versus DDM in tubulin, X-ray crystallography studies revealed a shift in the position of the lactone ring associated with removal of the C2-methyl and C3-hydroxyl. Thus, B2 may be more adaptable to changes in the taxane site relative to DDM that could account for its favorable properties. In conclusion, we have identified a DDM congener with broad range anticancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence. SIGNIFICANCE STATEMENT: Here, we describe the anticancer activity of novel congeners of the tubulin-polymerizing molecule (+)-discodermolide. A lead molecule is identified that exhibits an improved dose-response profile in taxane-sensitive and taxane-resistant cancer cell models, diminished risk of chemotherapy-mediated senescence, and suppression of tumor cell invasion endpoints. X-ray crystallography studies identify subtle changes in the pose of binding to β-tubulin that could account for the improved anticancer activity. These findings support continued preclinical development of discodermolide, particularly in the chemorefractory setting.
: 天然产物 (+)-discodermolide (DDM) 是一种微管稳定剂和有效的衰老诱导剂。我们改进了DDM的结构，并评估了新型同源物在三阴性乳腺癌和卵巢癌 (通常死于紫杉烷耐药性的恶性肿瘤) 中的活性。先前的结构-活性分析鉴定了内酯和二烯作为赋予抗癌活性的部分，从而鉴定了本文所述的结构细化研究的优先级。具有单二烯与简化内酯的同源物相对于紫杉醇具有优异的抗癌功效，特别是在抗性模型中。具体而言，这些同源物之一，B2，证明了1) 改善的药理学性质，具体增加了可实现的最大响应和曲线下面积，并降低了EC50; 2) 相对于taxol或DDM，遗传异质性癌细胞系的均匀剂量-反应曲线; 3) 相对于DDM，衰老诱导倾向降低;4) 与紫杉醇或DDM相比，在癌细胞中具有优异的长期活性; 以及5) 在经处理的癌细胞中转移特征的减弱。为了对比微管蛋白中B2与DDM的结合，X-射线晶体学研究揭示了与C2-methyl和C3-hydroxyl的去除相关的内酯环位置的改变。因此，相对于DDM，B2可以更适合于紫杉烷位点的变化，这可以解释其有利的性质。总之，我们已经鉴定了具有广泛抗癌功效的DDM同系物，其还具有降低的诱导化疗介导的衰老的风险。显著性声明: 在这里，我们描述了微管蛋白聚合分子 (+)-discodermolide的新型同源物的抗癌活性。鉴定出一种先导分子，其在紫杉烷敏感和紫杉烷耐药的癌细胞模型中表现出改善的剂量-反应谱，降低了化疗介导的衰老的风险，并抑制了肿瘤细胞侵袭终点。X-射线晶体学研究鉴定了与 β-微管蛋白结合的姿势的细微变化，这可以解释改善的抗癌活性。这些发现支持discodermolide的持续临床前开发，特别是在化学工业环境中。
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.