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The potential of enzastaurin to enhance platelet aggregation and growth factor secretion: implications for cancer
G Lesyk1,2, T Fong3, P P Ruvolo4
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Background:
Enzastaurin is a protein kinase C (PKC)β inhibitor with antiproliferative and proapoptotic effects that was in clinical development for the treatment of a variety of cancers. However, the primary endpoints in several clinical trials of enzastaurin were not met, and thrombosis was reported as an adverse effect in some trials. While investigating the role of PKC in regulating growth factor release from platelets, we found that, unlike other PKC inhibitors, enzastaurin may potentiate platelet aggregation.
Objective:
To investigate the effects of enzastaurin on platelet aggregation, growth factor secretion from α-granules and cancer cell apoptosis in the presence of platelets.
Methods:
Prostacyclin-washed platelets and platelet-rich plasma were isolated from the blood of healthy human volunteers. Platelet light-aggregometry was performed in the presence and absence of enzastaurin and acetylsalicylic acid (ASA). P-selectin was measured by flow cytometry, and vascular endothelial growth factor (VEGF) release was measured by ELISA. A549 lung carcinoma cells were treated with releasates from enzastaurin-titrated platelets. A cell death ELISA was performed to measure A549 apoptosis.
Results And Conclusions:
Enzastaurin (10(-8) -10(-6) m) potentiated aggregation of prostacyclin-washed platelets and caused an increase in VEGF release from α-granules that, in turn, promoted cancer cell survival. In platelet-rich plasma, 10(-6) m enzastaurin inhibited platelet aggregation, but not 10(-7) m enzastaurin, which also failed to suppress VEGF secretion. ASA abrogated enzastaurin-potentiated washed-platelet aggregation and VEGF release. These findings indicate that, at high plasma protein-free drug concentrations, enzastaurin potentiates platelet aggregation and growth factor secretion, an effect that may counteract its anticancer activity. ASA nullifies this effect.
Insights
Enzastaurin, a cancer drug, unexpectedly increased platelet aggregation and vascular endothelial growth factor (VEGF) release, potentially hindering its anticancer effects. Acetylsalicylic acid (ASA) reversed this platelet-promoting action.
Area of Science:
- Oncology
- Pharmacology
- Hematology
Background:
- Enzastaurin, a protein kinase C (PKC)β inhibitor, was investigated for cancer treatment but showed mixed results and adverse effects like thrombosis.
- Previous research on PKC's role in growth factor release from platelets suggested enzastaurin might uniquely potentiate platelet aggregation, unlike other PKC inhibitors.
Purpose of the Study:
- To investigate enzastaurin's effects on platelet aggregation, growth factor secretion from α-granules, and cancer cell apoptosis in the presence of platelets.
- To determine if acetylsalicylic acid (ASA) could mitigate any observed pro-platelet effects of enzastaurin.
Main Methods:
- Platelet aggregation was measured using light-aggregometry in prostacyclin-washed platelets and platelet-rich plasma.
- Vascular endothelial growth factor (VEGF) release was quantified via ELISA, and P-selectin expression was assessed by flow cytometry.
- Cancer cell apoptosis was evaluated using a cell death ELISA after treatment with releasates from enzastaurin-exposed platelets.
Main Results:
- Enzastaurin (10⁻⁸–10⁻⁶ M) potentiated aggregation of washed platelets and increased VEGF release, promoting cancer cell survival.
- In platelet-rich plasma, higher enzastaurin concentrations (10⁻⁶ M) inhibited aggregation, but lower concentrations (10⁻⁷ M) did not suppress VEGF secretion.
- Acetylsalicylic acid (ASA) abrogated enzastaurin-induced washed-platelet aggregation and VEGF release.
Conclusions:
- Enzastaurin can potentiate platelet aggregation and growth factor secretion at high plasma protein-free concentrations, potentially counteracting its anticancer efficacy.
- The pro-platelet and pro-angiogenic effects of enzastaurin were nullified by ASA.
- These findings highlight a complex interaction between enzastaurin, platelets, and cancer cells that warrants consideration in clinical applications.
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