TY - JOUR
T1 - Unlocking aspirin's chemopreventive activity
T2 - Role of irreversibly inhibiting platelet cyclooxygenase-1
AU - Lichtenberger, Lenard M.
AU - Fang, Dexing
AU - Bick, Roger J.
AU - Poindexter, Brian J.
AU - Phan, Tri
AU - Bergeron, Angela L.
AU - Pradhan, Subhashree
AU - Dial, Elizabeth J.
AU - Vijayan, K. Vinod
N1 - Funding Information:
This work was supported by NIH grants R41 CA171408 awarded to PLx Pharma Inc and L.M. Lichtenberger and R21 CA182798 awarded to L. Lichtenberger and K.V. Vijayan. This material is the result of work supported in part with resources and the use of facilities of the Michael E. DeBakey VA Medical Center and the membership of Dan. L. Duncan Comprehensive Cancer at Baylor College of Medicine.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/2
Y1 - 2017/2
N2 - The mechanism by which aspirin consumption is linked to significant reductions in the incidence of multiple forms of cancer and metastatic spread to distant tissues, resulting in increased cancer patient survival is not well understood. In this study, using colon cancer as an example, we provide both in vitro (cell culture) and in vivo (chemically induced mouse model of colon cancer) evidence that this profound antineoplastic action may be associated with aspirin's ability to irreversibly inhibit COX-1-mediated platelet activation, thereby blocking platelet-cancer cell interactions, which promote cancer cell number and invasive potential. This process may be driven by platelet-induced epithelial-mesenchymal transition (EMT), as assessed using confocal microscopy, based upon changes in cell morphology, growth characteristics and fibronectin expression, and biochemical/molecular analysis by measuring changes in the expression of the EMT markers; vimentin, b-catenin, and SNAIL. We also provide evidence that a novel, gastrointestinal-safe phosphatidylcholine (PC)-Associated aspirin, PL2200 Aspirin, possesses the same or more pronounced actions versus unmodified aspirin with regard to antiplatelet effects (in vitro: reducing platelet activation as determined by measuring the release of thromboxane and VEGF in culture medium; in vivo: inhibiting platelet number/activation and extravasation into tumor tissue) and chemoprevention (in vitro: inhibiting colonic cell growth and invasive activity; in vivo: inhibiting colonic dysplasia, inflammation, and tumor mass). These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic action of platelets, and the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers.
AB - The mechanism by which aspirin consumption is linked to significant reductions in the incidence of multiple forms of cancer and metastatic spread to distant tissues, resulting in increased cancer patient survival is not well understood. In this study, using colon cancer as an example, we provide both in vitro (cell culture) and in vivo (chemically induced mouse model of colon cancer) evidence that this profound antineoplastic action may be associated with aspirin's ability to irreversibly inhibit COX-1-mediated platelet activation, thereby blocking platelet-cancer cell interactions, which promote cancer cell number and invasive potential. This process may be driven by platelet-induced epithelial-mesenchymal transition (EMT), as assessed using confocal microscopy, based upon changes in cell morphology, growth characteristics and fibronectin expression, and biochemical/molecular analysis by measuring changes in the expression of the EMT markers; vimentin, b-catenin, and SNAIL. We also provide evidence that a novel, gastrointestinal-safe phosphatidylcholine (PC)-Associated aspirin, PL2200 Aspirin, possesses the same or more pronounced actions versus unmodified aspirin with regard to antiplatelet effects (in vitro: reducing platelet activation as determined by measuring the release of thromboxane and VEGF in culture medium; in vivo: inhibiting platelet number/activation and extravasation into tumor tissue) and chemoprevention (in vitro: inhibiting colonic cell growth and invasive activity; in vivo: inhibiting colonic dysplasia, inflammation, and tumor mass). These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic action of platelets, and the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers.
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U2 - 10.1158/1940-6207.CAPR-16-0241
DO - 10.1158/1940-6207.CAPR-16-0241
M3 - Article
C2 - 27998883
AN - SCOPUS:85011965806
SN - 1940-6207
VL - 10
SP - 142
EP - 152
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 2
ER -