Can epigenetic treatments efficiently revoke the ability of 3D ovarian cancer cells to proliferate, migrate, and invade?

Abstract

e17562 Background: 3D ovarian cancer propagation and metastasis arise not only from genetic mutations, but from aberrant epigenetic modifications known to involve mechanisms of DNA methylation and histone deacetylation. Clinically, cancer induces epigenetic aberrations in adipose-derived stem cells from omentum (O-ASCs), creating a tumorigenic microenvironment that supports chemoresistance and dissemination of disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we investigate whether these diet-derived compounds can suppress proliferation, migration and invasion of ovarian cancer in 3D-spheroids or 3D-organoids with O-ASCs when compared to synthetic Panobinostat (Pano) and cisplatin/paclitaxol (C/T). Methods: 3D ovarian cancer spheroids and organoids (30% O-ASCs) were treated with EGCG (10, 50 µm), I3C (50, 200 µm), Pano (5, 15 µm) and C/T. Percent growth was followed for 17 days and compared to an untreated control group. Post-treated cancer was then derived from 3D structures and tested for its ability to regrow (MTT assay), to form colonies (CFU), and to migrate and invade (CytoSelect Cell Migration and Invasion assay). Results: Our results show that higher doses of epigenetic regimens more efficiently suppress growth of 3D ovarian cancer when compared to the control and C/T groups (p<.05). Additionally, the synthetic epigenetic drug Pano also efficiently suppressed cancer as compared to control and C/T treated cells (p<.05). Given that experimental treatments efficiently down-regulated 3D cancer growth, follow up of post-treatment cancer recovery was analyzed through multiple biochemical and biological assays. 3D derived cells pre-treated with EGCG, I3C and Pano had significant lower proliferation capacity as compared to control or C/T as demonstrated by an MTT assay (p<.05). While all epigenetic treatments inhibited CFU in the spheroid derived group, EGCG was not able to fully inhibit CFU in the organoid group. Further, inhibition of CFU was not noted in the C/T pre-treated cells. Finally, the ability of cells to migrate and invade following treatment was more efficiently suppressed in cells derived from organoids. I3C and Pano significantly suppressed cancer migration, while EGCG and Pano suppressed invasion (p<.05). Conclusions: Diet-derived epigenetic treatments can reprogram epigenetic aberrations involved in mechanisms of proliferation, migration and invasion of 3D ovarian cancer. Our results suggest that these treatments not only suppress 3D cancer growth and post-treatment regrowth, but could be considered as adjuncts to standard chemotherapy, improving efficiency and patient outcomes.