一种核仁周围区室的小分子抑制剂ML246可减弱卵巢癌的生长和扩散。

A small molecule inhibitor of the perinucleolar compartment, ML246, attenuates growth and spread of ovarian cancer.

作者信息

Kanis Margaux J, Qiang Wenan, Pineda Mario, Maniar Kruti P, Kim J Julie

机构信息

1Division of Gynecology Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL USA.

2Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL USA.

出版信息

Gynecol Oncol Res Pract. 2018 Oct 2;5:7. doi: 10.1186/s40661-018-0064-2. eCollection 2018.

DOI:10.1186/s40661-018-0064-2

PMID:30305911

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6167785/

Abstract

BACKGROUND

Ovarian cancer remains a major health problem for women as it is often diagnosed at a late stage with metastatic disease. There are limited therapeutic agents and survival rates remain poor. The perinucleolar compartment (PNC) has been shown to be associated with malignancy and is considered a surrogate phenotypic marker for metastatic cancer cells. A small molecule, ML246, was derived from a screen against PNCs. In this study, the effect of ML246 on ovarian cancer growth and spread was investigated.

METHODS

SKOV3 or OVCAR3 cells were treated with ML246 in vitro and PNC was visualized with immunofluorescent staining. Cell invasion was assessed using Matrigel-coated transwell systems. SKOV3 cells were xenografted orthotopically under the ovarian bursa of immunocompromised mice. Additionally, a patient derived ovarian cancer cell line was grafted subcutaneously. Mice were treated with ML246 and tumor growth and spread was assessed.

RESULTS

PNCs were prevalent in the ovarian cancer cell lines OVCAR3 and SKOV3 with higher prevalence in OVCAR3 cells. Treatment with ML246 significantly reduced PNC prevalence in OVCAR3 and SKOV3 cells. Moreover, the invasive activity of both cell lines was significantly inhibited in vitro. Orthotopic implantation of SKOV3 cells resulted in growth of the tumor on the ovary as well as spread of tumor tissues outside of the primary site on organs into the abdominal cavity. Treatment with ML246 decreased the incidence of tumors outside of the ovary. In addition, a patient-derived xenograft (PDX) line was grafted subcutaneously to monitor tumor growth. ML246 significantly attenuated growth of tumors over a 5-week treatment period.

CONCLUSIONS

PNC's are present in ovarian cancer cells and treatment with ML246 decreases invasion in vitro and tumor growth and spread in vivo. Additional studies are warranted to determine the efficacy of ML246 as an inhibitor of metastatic disease in ovarian cancer and to determine its precise mechanism of action.

摘要

背景

卵巢癌仍然是女性面临的一个主要健康问题，因为它常常在晚期伴转移性疾病时才被诊断出来。治疗药物有限，生存率仍然很低。核仁周区（PNC）已被证明与恶性肿瘤有关，被认为是转移性癌细胞的替代表型标志物。一种小分子化合物ML246是通过针对PNC的筛选获得的。在本研究中，研究了ML246对卵巢癌生长和扩散的影响。

方法

体外使用ML246处理SKOV3或OVCAR3细胞，并用免疫荧光染色观察PNC。使用基质胶包被的Transwell系统评估细胞侵袭能力。将SKOV3细胞原位移植到免疫缺陷小鼠的卵巢囊下。此外，将一株来源于患者的卵巢癌细胞系皮下接种。给小鼠注射ML246，评估肿瘤的生长和扩散情况。

结果

PNC在卵巢癌细胞系OVCAR3和SKOV3中普遍存在，在OVCAR3细胞中的发生率更高。用ML246处理可显著降低OVCAR3和SKOV3细胞中PNC的发生率。此外，两种细胞系的体外侵袭活性均受到显著抑制。SKOV3细胞的原位植入导致卵巢上肿瘤生长，以及肿瘤组织从原发部位扩散到器官外并进入腹腔。用ML246治疗可降低卵巢外肿瘤的发生率。此外，皮下接种一株来源于患者的异种移植（PDX）细胞系以监测肿瘤生长。在为期5周的治疗期内，ML246显著抑制了肿瘤生长。