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Carcinogenesis Advance Access published online on January 9, 2009
Carcinogenesis, doi:10.1093/carcin/bgp015
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Phosphoaspirin (MDC-43), a novel benzyl ester of aspirin, inhibits the growth of human cancer cell lines more potently than aspirin: A redox-dependent effect

Wenping Zhao, Gerardo Mackenzie, Onika Murray, Zhiquan Zhang and Basil Rigas

Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794-5200

Corresponding author Basil Rigas, Division of Cancer Prevention, Stony Brook University, Life Sciences Building, Room 06, Stony Brook, NY 11794-5200, Tel: (631) 632-9035; Fax: (631) 632-1992; e-mail: basil.rigas{at}stonybrook.edu

Aspirin is chemopreventive against colon and likely other cancers, but this effect is relatively weak and its chronic administration to humans is associated with significant side effects. Because of these limitations, extensive effort has been exerted to improve the pharmacological properties of aspirin. We have determined the anticancer activity and mechanisms of action of the novel para positional isomer of phosphoaspirin (P-ASA; MDC-43; 4-((diethoxyphosphoryloxy)methyl)phenyl 2-acetoxybenzoate). P-ASA inhibited the growth of ten human cancer cell lines originating from colon, lung, liver, pancreas and breast, at least 18-144 fold more potently than conventional aspirin. P-ASA achieved this effect by modulating cell kinetics: compared to controls, P-ASA reduced cell proliferation by up to 68%, increased apoptosis 5.5 fold, and blocked cell cycle progression in the G2/M phase. P-ASA increased intracellular levels of reactive oxygen species (ROS), depleted glutathione levels, and modulated cell signaling predominantly through the MAPK (p38 and JNK), COX, and NF-{kappa}B pathways. P-ASA targeted the mitochondria, increasing mitochondrial superoxide anion levels; this effect on ROS led to collapsed mitochondrial membrane potential and triggered the intrinsic apoptotic pathway. The antioxidant N-acetyl cysteine abrogated the cell growth inhibitory and signaling effects of P-ASA, underscoring the centrality of ROS in its mechanism of action. Our results, establishing P-ASA as a potent inhibitor of the growth of several human cancer cell lines, suggest that it may possess broad anticancer properties. We conclude that the novel P-ASA is a promising anti-cancer agent, which merits further evaluation.

Received September 22, 2008; revised December 31, 2008; accepted January 5, 2009.


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