Use of Epigenetic Therapy Shortens Duration of Standard Chemotherapy for Ovarian Cancer with Minimal Toxicity to Normal Tissue

Author(s): Leona Chang, Krystal Hunter, James Aikins, Spencer Brown, Olga Ostrovsky

Objective: (1) Determine if sequential administration of standard chemotherapy (paclitaxel and cisplatin, P/C) with epigenetic drugs effectively targets ovarian cancer and limits toxicity to normal cells. (2) Define whether epigenetic treatment can shorten the exposure to P/C. Methods: Normal cells—adipocyte-derived stem cells (ASC), primary fibroblasts (PF), and human intestinal epithelial cells (HIEC-6)—were treated with 48 h IC50 values of P/C and epigenetic drugs, 5-azacytidine (AZA) and or suberoylanilide hydroxamic acid (SAHA), in combination and sequentially. The least toxic regimens to normal cells were administered to the ovarian cancer cell lines Caov-3, SKOV-3, OVCAR-3. Cell viability after treatments were assessed using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) and cell count assays. Secretome analysis of conditioned medium collected from the treated ovarian cancer cells was performed using ELISA.

Results: P/C with AZA and SAHA targeted all ovarian cancer cell lines (82-99% cell death), but also caused significant normal cell death (66-100%). In contrast, P/C followed by AZA or SAHA is less toxic to ASC and PF (25-96% viability) when compared to a four-drug combination therapy (1% viability, p<0.0001). P/C followed by SAHA was least toxic to HIEC-6 (100% viability, p=0.0356). P/C followed by epigenetic drugs targets ovarian cancer cells more efficiently than two rounds of P/C (p<0.001). Levels of VEGF and IL-6 were downregulated after treatment with P/C followed by SAHA in SKOV-3 and OVCAR-3.

Conclusions: Sequential treatments of P/C with epigenetic drugs, specifically SAHA, preserves the viability of normal cells, efficiently targets ovarian cancer, and minimizes exposure to P/C.

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