Abstract PR05: Low dose aspirin that reduces mortality from lung adenocarcinoma inhibits both platelet COX-1 and the biosynthesis of PGE2
Authors: Oates John , Massion Pierre , Knollmann Bjorn , Smith James , Haddad Elias , Lammers Philip , Oram Denise , Amin Taneem , Harris Bradford , Hoeksema Megan , Hwang Hyun 
Published: October 2015

Background: Meta-analysis of the trials evaluating the effect of aspirin on cardiovascular outcomes demonstrated that aspirin prevented mortality from adenocarcinomas by 47% and reduced metastasis by 46%. Equivalent benefit was seen with both high and low doses of aspirin. We hypothesize that low dose aspirin blocks metastasis by inhibiting platelet COX-1 and also by inhibiting the biosynthesis of the pro-metastatic PGE2.

Methods and Results: The effect of a range of doses of aspirin on PGE2 biosynthesis in three lung adenocarcinoma cell lines was compared with that in washed platelets. PGE2 was measured by GC/MS. In the cancer cell lines, aspirin inhibits COX-2-dependent PGE2 production with IC50s equivalent to or less than that for platelet COX-1. The IC50s were: Platelet = 19.8 ± 1.5 μM; H2122 = 19.5 ± 5 μM; HCC827 = 3.9 ± 2 μM; A549 = 1.6 ± 0.4 μM.

To explore the extra-platelet effects of low dose aspirin in vivo, we examined the effect of aspirin 81 mg daily for 2 weeks on the biosynthesis of PGE2 and prostacyclin as reflected by their respective urinary metabolites in 54 healthy humans. The PGE2 metabolite was measured by LC/MS/MS and the prostacyclin metabolite by GC/MS. This dose of aspirin inhibited PGE2 production by 45% (p &lt; 0.0001) and reduced prostacyclin by 37% (p &lt; 0.0001).

Adherence of platelets to tumor cells facilitates metastasis. We determined the effect of adherence of ADP-activated washed platelets to lung adenocarcinoma cells (A549) on the PGE2 biosynthetic pathway. COX-2 expression was determined by Western blot, and cytosolic calcium by Fura-2 AM. Activated platelets increased cytosolic calcium in A549 cells by 22% (p &lt; 0.001), increased expression of COX-2 by 8.6 fold (p&lt;0.0001) and increased PGE2 biosynthesis by 8.1 fold (p &lt; 0.0001), indicating that PGE2 production by tumor cells is enhanced by activated platelets.

Conclusion: These findings form the basis for a hypothesis that the remarkable effect of low dose aspirin on adenocarcinoma prevention and reduction in metastatic behavior could result from inhibition of platelet activation in concert with inhibition of platelet-induced PGE2 biosynthesis and direct inhibition of the catalytic activity COX-2 in circulating tumor cells.

Work funded by the Thoracic Program of the Vanderbilt Ingram Cancer Center

Citation Format: John Oates, Pierre Massion, Bjorn Knollmann, James Smith, Elias Haddad, Philip Lammers, Denise Oram, Taneem Amin, Bradford Harris, Megan Hoeksema, Hyun Hwang. Low dose aspirin that reduces mortality from lung adenocarcinoma inhibits both platelet COX-1 and the biosynthesis of PGE2. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PR05.