Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer

Abstract

To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC vs. aspirin on 3 human (A2780, SKOV3ip1, HeyA8), and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following anti-angiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50–90% (depending on the ovarian cell line/density). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust anti-neoplastic action in the presence of VEGF blocking drugs.

Chemoprevention with phosphatidylcholine non-steroidal anti-inflammatory drugs in�vivo and in�vitro

“…1 for the chemical structures of aspirin, indomethacin and soy PC). In the animal experiments, we used different procedures preparing Aspirin-PC as described previously (9,22). To make Indomethacin-PC stock for both cell culture and animal study, 8 gram of indomethacin (acid form) and 16 gram of Lipoid S-100 were subsequently dissolved into 60 ml of Acetone (Thermo Fisher Scientific, Inc., Fair Lawn, NJ, USA) in a 500-ml flat bottom round flask in 40˚C water bath.…”

“…MTT assay. MTT (purchased from Sigma-Aldrich; Merck KGaA) was added to the culture media of cells at a final concentration of 0.5 mg/ml for 4 h. The purple formazan product was then extracted into a solvent (90% isopropanol, 0.2% sodium dodecyl sulfate, and 0.01 mol/l HCl) which was then collected from the wells and read at an absorbance of 570 nm, as previously described (22).…”

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

“…An apparent discrepancy is that the concentrations required to exert these effects in cancer cells were significantly higher than that required to inhibit the activity of COX-1 or COX-2, suggesting the implications of other potential targets (12,13). Indeed, cell-based studies have demonstrated that aspirin inhibits cell proliferation, induces cell-cycle arrest and apoptosis in multiple cancer cell lines irrespective of COX-2 expression level (14)(15)(16)(17)(18). Aspirin can also sensitize cancer cell to TRAIL-induced apoptosis through a COX-2-independent mechanism (19).…”

Stress, inflammation, and eicosanoids: an emerging perspective

“…In line with this, the positive feedback between COX-2 and PGE2 is essential for expression of CXCR4 in cancer-associated MDSCs and the production of its ligand of CXCL2 in ovarian cancer [99]. Similarly, aspirin-PC inhibits cell proliferation, angiogenesis, and increased apoptosis in ovarian cancer cells and mouse models [100]. PGE 2 also functions as an immunosuppressive factor and contributed to the microenvironment of ovarian cancer by compromising the Toll-like receptor-mediated dendritic cell activation [101].…”