Abstract 2840: Development of a model of dihomo-gamma-linolenic acid interference with platelet promotion of ovarian cancer

Abstract

Abstract Background: Cancer is the second leading cause of deaths worldwide after cardiovascular diseases. A commonality between cancer and cardiovascular diseases is disregulation of platelets. Platelets and cancer are known to promote each other in a feedforward mechanism that is poorly understood. A long chain polyunsaturated fatty acids dihomo-gamma-linolenic acid (DGLA) was shown to reduce cardiovascular events in a platelet dependent manner while the exact mechanism of DGLA-mediated cancer cells death is yet to be explored. Objectives: The objective of our study was to develop an experimental model to study interventions that could disrupt the cancer/platelets loop. Methods: The effects of a range of DGLA concentrations on platelet aggregation and growth of high grade serous ovarian cancer cell lines (OVCAR3, MesOV, OVSAHO), normal human fallopian tube secretory epithelial cells (hFTSECs) primary culture and an immortalized hFTSEC cultures were determined with an MTT assay. Cocultures were used to evaluate effects of platelets on ovarian cancer cell line spheroid formation and size and effects of ovarian cancer cells and hFTSECs on platelet aggregation. Results: The minimal cytotoxic DGLA concentrations for cancer and normal epithelial cells were above physiologically-achievable concentrations, and the half maximal inhibitory concentrations (IC50's) were similar across epithelial cell types with the IC50's for hFTSEC primary culture (261 µM) and immortalized culture (206 µM) falling within the range of cancer cell IC50's (153-275 µM). DGLA inhibited platelet aggregation at concentrations ≥250 µM. Platelets increased cancer spheroid sizes in a concentration-dependent manner and cancer cells, but not hFTSECs, induced platelet aggregation in cocultures. Conclusions: Our model incorporates both platelet effects on cancer cells and cancer cell effects on platelets. Physiologically-achievable DGLA concentrations that affect platelet aggregation without affecting epithelial cells were identified. Minimal doses of DGLA needed to cause cytotoxicity against cancer and normal cells are above levels that are physiologically achievable. Future studies will utilize DGLA doses that can interfere with platelet aggregation without directly causing cytotoxicity to cancer or healthy cells. This experimental model will allow study of DGLA's potential for interfering with platelet promotion of ovarian cancer in the absence of direct effects of DGLA on cancer cells. Funded by NCI R01 CA196200 Citation Format: Zitha Redempta Isingizwe, Doris M. Benbrook. Development of a model of dihomo-gamma-linolenic acid interference with platelet promotion of ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2840.