Epigenetic Therapy Augments Classic Chemotherapy in Suppressing the Growth of 3D High-Grade Serous Ovarian Cancer Spheroids over an Extended Period of Time.

Michelle Bilbao,Olga Ostrovsky,James K Aikins,Stephanie L Kass,David Warshal,Chelsea Katz,Devon Smith,Krystal Hunter

doi:10.3390/biom11111711

Abstract

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients’ lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture.

Highlights

We explore the efficacy of classic chemotherapy and epigenetic therapies in both platinum-sensitive and platinum-resistant recurrent human ovarian cancer cells in a 3D culture model and compare it to the classic 2D monolayer culture
Cisplatin, paclitaxel, and cisplatin–paclitaxel are typically administered to patients every 3 weeks
Our model demonstrates that classic chemotherapy induces cell death mostly by apoptosis in our spheroid model, whereas epigenetic therapy induces cell death by both apoptosis and necrosis (Figure 5)

Summary

Introduction

Ovarian cancer comprises 3.4% of all female cancers worldwide, but is responsible for. 4.4% of all female deaths due to cancer [1]. High-grade serous ovarian, fallopian tube, and primary peritoneal cancer are thought to originate from similar fallopian tube precursors; the term “HGSC” will serve to encompass all three of these tumors [2]. 50–75% of patients enter remission after primary surgery and chemotherapy for HGSC, but 65% of these patients recur [3]. HGSC deaths are largely due to widely metastatic and chemoresistant disease and, despite recent advances, most patients who recur will succumb to their disease [4]

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