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: 5.33). 02/2009; 30(3):512-9. DOI: 10.1093/carcin/bgp015
Source: PubMed


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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Available from: Zhiquan Zhang, Oct 04, 2015
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    • "To determine cell proliferation, we measured the incorporation of 5-bromo-2′-deoxyuridine (BrdU) into newly synthesized cellular DNA followed by the manufacture’s protocol (BD Biosciences), and cells were subjected to flow cytometric analysis. Cell cycle phase distribution was analyzed by flow cytometry as described [15]. "
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    ABSTRACT: The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC). Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of PA-2. PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established subcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect, resulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented the development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the activation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades, including PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced its DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the thioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-kappaB. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2. Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC, and is also effective in its chemoprevention, warranting further evaluation as an anticancer agent.
    BMC Cancer 02/2014; 14(1):141. DOI:10.1186/1471-2407-14-141 · 3.36 Impact Factor
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    • "Oxidative stress, marked by RONS accumulation and redox imbalance associated with the suppression of GSH and increased oxidation of Trx-1, also plays a central role in apoptosis induced by phospho-NSAIDs [19–21, 56, 110, 111]. Like NO-NSAIDs, the strong prooxidant effect exerted by phospho-NSAIDs is reported to set in motion a pleiotropic cascade of redox-sensitive signalling events including activation of MAP kinases and inhibition of NF-κB signalling [19, 21, 56] along with the depletion of cellular polyamines, at least in the case of phosphosulindac [20, 110, 111]. The collective initiation of all these antiproliferative, proapoptotic pathways accounts for the very potent growth-inhibitory effects of phospho-NSAIDs, with respect to their traditional NSAID precursors [111]. "
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    ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used to treat pain, fever, and inflammation. However, mounting evidence shows that NSAIDs, such as aspirin, have very promising antineoplastic properties. The chemopreventive, antiproliferative behaviour of NSAIDs has been associated with both their inactivation of cyclooxygenases (COX) and their ability to induce apoptosis via pathways that are largely COX-independent. In this review, the various proapoptotic pathways induced by traditional and novel NSAIDs such as phospho-NSAIDs, hydrogen sulfide-releasing NSAIDs and nitric oxide-releasing NSAIDs in mammalian cell lines are discussed, as well as the proapoptotic effects of NSAIDs on budding yeast which retains the hallmarks of mammalian apoptosis. The significance of these mechanisms in terms of the role of NSAIDs in effective cancer prevention is considered.
    Oxidative Medicine and Cellular Longevity 08/2013; 2013(1):504230. DOI:10.1155/2013/504230 · 3.36 Impact Factor
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    • "Interestingly, VPA had no effect on mitochondrial STAT3 levels. In contrast, phospho-aspirin, which shares with P-V the same aromatic linker [13], reduced mitochondrial STAT3 levels (Fig. 3B), suggesting that the linker moiety may participate in this effect. None of these three compounds affected the mitochondrial levels of Hsp90 and Hsp60 proteins, both imported into the mitochondria, indicating that the changes in STAT3 levels were not due to a generalized suppression of protein transport into the mitochondria. "
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    ABSTRACT: New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.
    PLoS ONE 05/2013; 8(5):e61532. DOI:10.1371/journal.pone.0061532 · 3.23 Impact Factor
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