Epigenetic therapy can inhibit growth of ovarian cancer cells and reverse chemoresistant properties acquired from metastatic omentum

Abstract

Objective To examine the cytotoxicity of epigenetic drugs independently and in combination with chemotherapy on ovarian cancer cells Caov‐3, and to investigate their ability to acquire chemoresistance in omental microenvironments and whether epigenetic drugs can counteract this chemoresistance. Methods A pilot study was conducted in Cooper University Hospital, NJ, USA from August 1 to October 31, 2017, among women undergoing surgeries for uterine and ovarian cancer. Cytotoxicity assays using IC50 values of epigenetic drugs and paclitaxel and cisplatin were performed on Caov‐3. Omental adipose‐derived stem cells (OASCs) were isolated from omentum with/without metastases. Caov‐3 was cultured with OASCs’ conditioned medium and subjected to different drugs. Cell viability and secretome was measured using MTT and Elisa, respectively. Results Three women met the eligibility criteria and were included in the study. Epigenetic drugs alone or in combination with chemotherapy showed 85%–94% increased cytotoxicity against Caov‐3 (P≤0.005). Metastatic OASCs conditioned medium showed up to 27‐fold increase in tumorigenic factors and promoted chemoresistance (28%–35%; P < 0.050) against chemotherapy. Epigenetic therapy resulted in up to a 40‐fold reversal in this chemoresistance. Conclusion Epigenetic therapies could have an important role in treating a subgroup of ovarian cancer patients that demonstrate resistance to first‐line chemotherapy.

Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis

“…Emerging evidence has indicated that cancer cells can adapt to environmental conditions through epigenetic mechanisms in response to their niche during tumor progression [ 38 ]. Epigenetic changes, including DNA methylation and miRNA-mediated silencing, primarily drive tumorigenesis and metastasis in multiple cancer types, including ovarian cancer [ 39 , 40 , 41 ]. In ovarian cancer, tumor suppressor genes or miRNAs are often silenced by epigenetic events, consequently promoting cancer proliferation, metastasis, and chemoresistance [ 24 , 42 ].…”

“…In ovarian cancer, tumor suppressor genes or miRNAs are often silenced by epigenetic events, consequently promoting cancer proliferation, metastasis, and chemoresistance [ 24 , 42 ]. The omental microenvironment is a major metastatic site and plays a key role in ovarian cancer peritoneal metastases [ 39 , 43 ]. Recent studies have reported aberrant epigenetic crosstalk between ovarian cancer cells and adipocytes in the omental metastatic TME, which contributes to the metastatic progression of ovarian cancer [ 5 , 22 ].…”

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

“…As Modesitt et al have suggested, the timing of epigenetic therapy with chemotherapy may be critical [44]. Sequential use of conventional chemotherapy and epigenetic drugs has been shown to decrease toxicity to normal cells while maintaining cytotoxicity in ovarian cancer cells in vitro [29]. This method has not been utilized in clinical trials involving epigenetic therapy.…”

Ovarian cancer: epigenetics, drug resistance, and progression

“…The key prognostic factor for OC is the resistance of the patient’s tumor to chemotherapy, especially platinum-based drugs. Epigenetic drugs combined with paclitaxel and platinum are more effective than chemotherapy alone [ 13 ].…”