Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate.

Phospho-sulindac (P-S), a promising anticancer agent, is efficacious in pre-clinical models of human cancer and is apparently safe. Here, we studied the effect of P-S on pancreatic cancer growth. We found that P-S strongly inhibits the growth of human pancreatic cancer cells in vitro, is efficacious in inhibiting the growth of pancreatic xenografts in nude mice, and has an excellent safety profile. Microarray analysis revealed that P-S induced the expression of nuclear factor of activated T-cells, isoform c1 (NFATc1) gene. NFATc1, a calcineurin-responsive transcription factor associated with aggressive pancreatic cancer. The role of increased NFATc1 expression on the growth inhibitory effect of P-S on cancer growth was evaluated by silencing or by overexpressing it both in vitro and in vivo. We found that when the expression of NFATc1 was abrogated by RNAi, pancreatic cancer cells were more responsive to treatment with P-S. Conversely, overexpressing the NFATc1 gene made the pancreatic cancer cells less responsive to treatment with P-S. NFATc1 likely mediates drug resistance to P-S and is an unfavorable prognostic factor that predicts poor tumor response. We also demonstrated that NFATc1-mediated resistance can be overcome by cyclosporin A (CsA), an NFAT inhibitor, and that the combination of P-S and CsA synergistically inhibited pancreatic cancer cell growth. In conclusion, our preclinical data establish P-S as an efficacious drug for pancreatic cancer in preclinical models, which merits further evaluation.

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.

Aspirin is chemopreventive against colon and probably 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 10 human cancer cell lines originating from colon, lung, liver, pancreas and breast, at least 18- to 144-fold more potently than conventional aspirin. P-ASA achieved this effect by modulating cell kinetics; compared with controls, P-ASA reduced cell proliferation by up to 68%, increased apoptosis 5.5-fold and blocked cell cycle progression in the G(2)/M phase. P-ASA increased intracellular levels of reactive oxygen species (ROS), depleted glutathione levels and modulated cell signaling predominantly through the mitogen-activated protein kinase (p38 and c-jun N-terminal kinase), cyclooxygenase (COX) and nuclear factor-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 anticancer agent, which merits further evaluation.