Implication of integrins in eptifibatide interference with platelet stimulation of ovarian cancer

SIGNIFICANCE: A third of ovarian cancer patients have high platelet counts at diagnosis resulting in reduced survival compared to patients with low/normal platelet counts. Current studies suggest that platelets and ovarian cancer induce each other in a feed-forward loop. OBJECTIVE AND HYPOTHESIS: The objectives were to: 1) evaluate differences in platelet counts and aggregation between healthy and newly-diagnosed ovarian cancer patients; 2) develop an experimental model of the pathological interactions between platelets and ovarian cancer spheroids; and 3) identify pathways affected by these interactions and ways to intervene. Our hypothesis is that high platelet counts of ovarian cancer patients are associated with hypercoagulability, and inhibiting platelet aggregation reduces platelet-mediated effects on ovarian cancer spheroids. MATERIALS AND METHODS: Complete blood count was evaluated between healthy controls and newly-diagnosed ovarian cancer patients before treatment. A platelet aggregation assay was performed to assess platelet physiology between the two groups. The molecular mechanism of platelet effects on ovarian cancer spheroid properties was evaluated using mass spectrometry and bioinformatics analysis of a magnetic 3D cancer spheroid assay, in the presence and absence of eptifibatide, a potent platelet inhibitor. RESULTS: While ovarian cancer patients had significantly higher platelet counts than healthy controls, platelet aggregation profiles and parameters were similar between the two groups. Incubation of platelets with cancer spheroids altered spheroid size and density in an eptifibatide-sensitive manner. Co-incubation of platelets with ovarian cancer spheroids activated the LXR/RXR pathway, a known down-stream effector of the integrin receptor that eptifibatide targets. CONCLUSION: Platelet count does not predict platelet hypercoagulability in ovarian cancer patients. Pathological interaction between platelets and cancer cells can be mimicked in co-culture, and eptifibatide inhibits these pathological interactions, suggesting that eptifibatide is a candidate drug for prevention of ovarian cancer and thrombosis in ovarian cancer patients. The LXR/RXR pathway is a likely mediator of the eptifibatide interference in platelet-cancer interaction, and represents a candidate target for reducing platelet-mediated adverse events in ovarian cancer patients. © FASEB.