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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

Department of Medicine, Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794-5200, USA.
Carcinogenesis (Impact Factor: 5.27). 02/2009; 30(3):512-9. DOI: 10.1093/carcin/bgp015
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ABSTRACT 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.

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    • "Considering the limited efficacy of NSAIDs and the prevalence of their side effects, it is questionable whether their clinical benefits outweigh their toxic effects (Cuzick et al., 2009). This prompted us to synthesize novel phospho-derivatives of NSAIDs (Sun and Rigas, 2008; Hua et al., 2009; Zhao et al., 2009; Mackenzie et al., 2010; Huang et al., 2010, 2011; Xie et al., 2011b). Traditionally, modified NSAIDs are considered pharmacologically inactive prodrugs that temporarily mask the acidic moiety as a means to reduce gastrointestinal toxicity (Halen et al., 2009). "
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    ABSTRACT: Phospho-nonsteroidal anti-inflammatory drugs (phospho-NSAIDs) are novel NSAID derivatives with improved anticancer activity and reduced side effects in preclinical models. Here, we studied the metabolism of phospho-NSAIDs by carboxylesterases and assessed the impact of carboxylesterases on the anticancer activity of phospho-NSAIDs in vitro and in vivo. The expression of human liver carboxylesterase (CES1) and intestinal carboxylesterase (CES2) in human embryonic kidney 293 cells resulted in the rapid intracellular hydrolysis of phospho-NSAIDs. Kinetic analysis revealed that CES1 is more active in the hydrolysis of phospho-sulindac, phospho-ibuprofen, phospho-naproxen, phospho-indomethacin, and phospho-tyrosol-indomethacin that possessed a bulky acyl moiety, whereas the phospho-aspirins are preferentially hydrolyzed by CES2. Carboxylesterase expression leads to a significant attenuation of the in vitro cytotoxicity of phospho-NSAIDs, suggesting that the integrity of the drug is critical for anticancer activity. Benzil and bis-p-nitrophenyl phosphate (BNPP), two carboxylesterase inhibitors, abrogated the effect of carboxylesterases and resensitized carboxylesterase-expressing cells to the potent cytotoxic effects of phospho-NSAIDs. In mice, coadministration of phospho-sulindac and BNPP partially protected the former from esterase-mediated hydrolysis, and this combination more effectively inhibited the growth of AGS human gastric xenografts in nude mice (57%) compared with phospho-sulindac alone (28%) (p = 0.037). Our results show that carboxylesterase mediates that metabolic inactivation of phospho-NSAIDs, and the inhibition of carboxylesterases improves the efficacy of phospho-NSAIDs in vitro and in vivo.
    Journal of Pharmacology and Experimental Therapeutics 11/2011; 340(2):422-32. DOI:10.1124/jpet.111.188508 · 3.86 Impact Factor
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    • "We determined the ability of phospho-NSAIDs and conventional chemotherapeutic agents to induce oxidative stress in SW480 human colon cancer and MCF-7 human breast cancer cells. We studied four phospho-NSAIDs: P-S, P-A, P-F, and P-I (Sun and Rigas, 2008; Zhao et al., 2009; Mackenzie et al., 2010, 2011; Xie et al., 2011); their structures are shown in Supplemental Fig. 1. We also studied six conventional chemotherapeutic agents: 5-FU, irinotecan, oxaliplatin, chlorambucil, paclitaxel, and vincristine. "
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    ABSTRACT: We assessed the relationship between oxidative stress, cytokinetic parameters, and tumor growth in response to novel phospho-nonsteroidal anti-inflammatory drugs (NSAIDs), agents with significant anticancer effects in preclinical models. Compared with controls, in SW480 colon and MCF-7 breast cancer cells, phospho-sulindac, phospho-aspirin, phospho-flurbiprofen, and phospho-ibuprofen (P-I) increased the levels of reactive oxygen and nitrogen species (RONS) and decreased GSH levels and thioredoxin reductase activity, whereas the conventional chemotherapeutic drugs (CCDs), 5-fluorouracil (5-FU), irinotecan, oxaliplatin, chlorambucil, paclitaxel, and vincristine, did not. In both cell lines, phospho-NSAIDs induced apoptosis and inhibited cell proliferation much more potently than CCDs. We then treated nude mice bearing SW480 xenografts with P-I or 5-FU that had an opposite effect on RONS in vitro. Compared with controls, P-I markedly suppressed xenograft growth, induced apoptosis in the xenografts (8.9 ± 2.7 versus 19.5 ± 3.0), inhibited cell proliferation (52.6 ± 5.58 versus 25.8 ± 7.71), and increased urinary F2-isoprostane levels (10.7 ± 3.3 versus 17.9 ± 2.2 ng/mg creatinine, a marker of oxidative stress); all differences were statistically significant. 5-FU's effects on tumor growth, apoptosis, proliferation, and F2-isoprostane were not statistically significant. F2-isoprostane levels correlated with the induction of apoptosis and the inhibition of cell growth. P-I induced oxidative stress only in the tumors, and its apoptotic effect was restricted to xenografts. Our data show that phospho-NSAIDs act against cancer through a mechanism distinct from that of various CCDs, underscore the critical role of oxidative stress in their effect, and indicate that pathways leading to oxidative stress may be useful targets for anticancer strategies.
    Journal of Pharmacology and Experimental Therapeutics 06/2011; 338(3):775-83. DOI:10.1124/jpet.111.183533 · 3.86 Impact Factor
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    • "We determined the ability of phospho-NSAIDs and conventional chemotherapeutic agents to induce oxidative stress in SW480 human colon cancer and MCF-7 human breast cancer cells. We studied four phospho-NSAIDs: P-S, P-A, P-F, and P-I (Sun and Rigas, 2008; Zhao et al., 2009; Mackenzie et al., 2010, 2011; Xie et al., 2011); their structures are shown in Supplemental Fig. 1. We also studied six conventional chemotherapeutic agents: 5-FU, irinotecan, oxaliplatin, chlorambucil, paclitaxel, and vincristine. "
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    ABSTRACT: We assessed the relationship between oxidative stress, cytoki-netic parameters, and tumor growth in response to novel phos-pho-nonsteroidal anti-inflammatory drugs (NSAIDs), agents with significant anticancer effects in preclinical models. Compared with controls, in SW480 colon and MCF-7 breast cancer cells, phos-pho-sulindac, phospho-aspirin, phospho-flurbiprofen, and phos-pho-ibuprofen (P-I) increased the levels of reactive oxygen and nitrogen species (RONS) and decreased GSH levels and thiore-doxin reductase activity, whereas the conventional chemothera-peutic drugs (CCDs), 5-fluorouracil (5-FU), irinotecan, oxaliplatin, chlorambucil, paclitaxel, and vincristine, did not. In both cell lines, phospho-NSAIDs induced apoptosis and inhibited cell prolifera-tion much more potently than CCDs. We then treated nude mice bearing SW480 xenografts with P-I or 5-FU that had an opposite effect on RONS in vitro. Compared with controls, P-I markedly suppressed xenograft growth, induced apoptosis in the xeno-grafts (8.9 2.7 versus 19.5 3.0), inhibited cell proliferation (52.6 5.58 versus 25.8 7.71), and increased urinary F2-isoprostane levels (10.7 3.3 versus 17.9 2.2 ng/mg creatinine, a marker of oxidative stress); all differences were statistically sig-nificant. 5-FU's effects on tumor growth, apoptosis, proliferation, and F2-isoprostane were not statistically significant. F2-isopros-tane levels correlated with the induction of apoptosis and the inhibition of cell growth. P-I induced oxidative stress only in the tumors, and its apoptotic effect was restricted to xenografts. Our data show that phospho-NSAIDs act against cancer through a mechanism distinct from that of various CCDs, underscore the critical role of oxidative stress in their effect, and indicate that pathways leading to oxidative stress may be useful targets for anticancer strategies.
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