Development of hydrolytically activated, oxygen‐generating biomaterials to enhance drug efficacy on cultured ovarian cancer cells

Abstract

Ovarian cancer remains the most prevalent type in gynecological cancer, with drug resistance still being a challenge. Our previous studies have demonstrated that ovarian cancer cells are resilient due to their active EGFR and AKT/mTOR pathways. Also, abundant data suggests that similar to other cancer types, ovarian cancer cells grow and proliferate remarkably well under hypoxia situation. We hypothesize that the application of oxygen to ovarian cancer cells may render unfavorable conditions, thus leading to the enhanced cell death, when combined with chemotherapy drugs. Recent studies have shown that polydimethylsiloxane (PDMS)‐encapsulated calcium peroxide, or PDMS‐CaO2, potently deliver oxygen and eliminate hypoxia‐induced cell dysfunction and cell death in normal pancreatic cells and other types of normal cells. In this study, we followed the published protocol, produced PDMS‐CaO2 disks and tested in vitro the effects of released oxygen on cultured ovarian cancer cells (CaOV3 cells). The results showed that our manufactured disks sustainably release O2 in a time dependent manner. MTT assay results indicated that PDMS‐CaO2 disks induce cell death in an oxygen dependent manner, compared to PDMS disks only. Combination of inhibitors of EGFR, MEK/ERK and AKT/mTOR with PDMS‐CaO2 disks increases cell death. Interestingly, PDMS disks significantly enhance the effects of cisplatin, oxaliplatin and doxorubicin, but not that of paclitaxel or taxol. PDMS‐CaO2 disks inhibit exosome inhibitor GW4869 induced cellular proliferation. Also, those disks significantly augment ionophore monensin A (for Na+/H+ antiporter), and calcium ionophore A23187‐induced cell death. Confocal microscope data showed that PDMS‐CaO2 disks alter mitochondria activities. Collectively, our data suggests that PDMS‐CaO2 disks releasing O2 and inducing cell death may affect cell membrane ion channels and mitochondria activities. The combination of cancer drugs or ionophores or EGFR/MEK/AKT/mTOR inhibitors with PDMS‐O2 disks may provide novel approaches for ovarian cancer clinical management.Support or Funding InformationNIHThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.