Abstract
BackgroundOvarian 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.MethodsSKOV3 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.ResultsPNCs 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.ConclusionsPNC’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.
Highlights
Ovarian cancer remains a major health problem for women as it is often diagnosed at a late stage with metastatic disease
Given the growth and metastatic characteristics of ovarian cancer and the urgent need to better treat this deadly disease, we investigated the effects of the novel drug, ML246 on perinucleolar compartment (PNC) prevalence and invasive activity of ovarian cancer cells in vitro and tested its efficacy on tumor growth and spread in xenograft models
Effect of ML246 on PNCs in ovarian cancer cell lines PNCs were detected in the ovarian cancer cell lines, SKOV3 and OVCAR3, using immunolabeling with SH54 antibody that recognizes Polypyrimidine tract-binding protein (PTB), a key marker protein of PNCs
Summary
Ovarian cancer remains a major health problem for women as it is often diagnosed at a late stage with metastatic disease. Targeted therapy is changing the therapeutic landscape in oncology and agents including angiogenesis inhibitors and PARP inhibitors, alone or in combination with chemotherapies, have been shown to be promising advancements for the treatment of ovarian cancer [2]. The perinucleolar compartment (PNC) is a nuclear body, containing RNA polymerase III transcripts and polypyrimidine tract-binding protein (PTB), that is adherent to but distinct from the nucleolus [3,4,5] They are observed in various metastatic solid tumors and transformed cell lines including breast, prostate, pancreatic and colorectal cancers, but absent in normal cells including embryonic stem cells [6,7,8,9]. Given the growth and metastatic characteristics of ovarian cancer and the urgent need to better treat this deadly disease, we investigated the effects of the novel drug, ML246 on PNC prevalence and invasive activity of ovarian cancer cells in vitro and tested its efficacy on tumor growth and spread in xenograft models
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