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Phospho-aspirin-2 (MDC-22) inhibits estrogen receptor positive breast cancer growth both in vitro and in vivo by a redox-dependent effect.

Huang L, Wong CC, Cheng KW, Rigas B - PLoS ONE (2014)

Bottom Line: An upstream mediator of the signaling effects of PA-2 is RONS.PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific.Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America.

ABSTRACT
Phospho-aspirin (PA-2) is a novel aspirin derivative that exhibits promising anticancer properties and is considerably safer than conventional aspirin. In this study, we investigated the chemotherapeutic efficacy of PA-2 in preclinical models of estrogen receptor positive (ER+) breast cancer and elucidated its mechanism of action. PA-2 inhibited the growth of ER+ cells more potently than aspirin in vitro, and exerted a triple cytokinetic effect that includes induction of apoptosis and cell cycle arrest as well as the inhibition of cell proliferation. PA-2 is highly efficacious in vivo, as treatment of established MCF7 xenografts with PA-2 induced tumor stasis (98.2% inhibition, p<0.01). PA-2 triggered the activation of p53-dependent apoptosis via two distinct mechanisms: 1) acetylation of p53 (at K373), which disrupts its interaction with its transcription repressor MDM2, and 2) translocation of p53 to the mitochondria leading to the dissipation of mitochondrial transmembrane potential (ΔΨ(m)). Consistent with these observations, both the RNAi-mediated knockdown of p53 and forced deactylation via HDAC1 over-expression attenuated the anticancer effect of PA-2 in MCF7 cells. An upstream mediator of the signaling effects of PA-2 is RONS. PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific. Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2. In summary, our findings demonstrate that PA-2 is a promising antineoplastic compound against ER+ breast cancer, warranting further evaluation as an anticancer agent.

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Phospho-aspirin-2 inhibits the growth of ER+ breast cancer cells.A: Chemical structure of phospho-aspirin-2 (PA-2, MDC-22). B: 24 h-IC50 values of PA-2 and aspirin in ER+ breast cancer cell lines. C: Chemotherapeutic effect of PA-2 on subcutaneous MCF7 xenografts in nude mice. Nude mice bearing established MCF7 xenografts were treated with vehicle or PA-2 (500 mg/kg in corn oil) for five times a week. *, p<0.01, compared to control; n = 16 tumors/group.
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pone-0111720-g001: Phospho-aspirin-2 inhibits the growth of ER+ breast cancer cells.A: Chemical structure of phospho-aspirin-2 (PA-2, MDC-22). B: 24 h-IC50 values of PA-2 and aspirin in ER+ breast cancer cell lines. C: Chemotherapeutic effect of PA-2 on subcutaneous MCF7 xenografts in nude mice. Nude mice bearing established MCF7 xenografts were treated with vehicle or PA-2 (500 mg/kg in corn oil) for five times a week. *, p<0.01, compared to control; n = 16 tumors/group.

Mentions: Despite having shown promising anticancer activity, the gastrointestinal toxicity caused by aspirin use remains a significant health concern. In an effort to reduce the gastrointestinal toxicity and to improve the efficacy of aspirin, we have developed phospho-aspirin (Fig. 1A, PA-2; MDC-22) in which the -COOH group has been covalently modified by a glycerol linker containing two diethyl-phosphate moieties. Phospho-aspirin has demonstrated a much improved gastrointestinal safety profile compared to aspirin and is more efficacious in the treatment of cancer and experimental arthritis [13], [14]. In light of these previous findings, in this study we assessed the efficacy of phospho-aspirin in the treatment of ER+ breast cancer.


Phospho-aspirin-2 (MDC-22) inhibits estrogen receptor positive breast cancer growth both in vitro and in vivo by a redox-dependent effect.

Huang L, Wong CC, Cheng KW, Rigas B - PLoS ONE (2014)

Phospho-aspirin-2 inhibits the growth of ER+ breast cancer cells.A: Chemical structure of phospho-aspirin-2 (PA-2, MDC-22). B: 24 h-IC50 values of PA-2 and aspirin in ER+ breast cancer cell lines. C: Chemotherapeutic effect of PA-2 on subcutaneous MCF7 xenografts in nude mice. Nude mice bearing established MCF7 xenografts were treated with vehicle or PA-2 (500 mg/kg in corn oil) for five times a week. *, p<0.01, compared to control; n = 16 tumors/group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219766&req=5

pone-0111720-g001: Phospho-aspirin-2 inhibits the growth of ER+ breast cancer cells.A: Chemical structure of phospho-aspirin-2 (PA-2, MDC-22). B: 24 h-IC50 values of PA-2 and aspirin in ER+ breast cancer cell lines. C: Chemotherapeutic effect of PA-2 on subcutaneous MCF7 xenografts in nude mice. Nude mice bearing established MCF7 xenografts were treated with vehicle or PA-2 (500 mg/kg in corn oil) for five times a week. *, p<0.01, compared to control; n = 16 tumors/group.
Mentions: Despite having shown promising anticancer activity, the gastrointestinal toxicity caused by aspirin use remains a significant health concern. In an effort to reduce the gastrointestinal toxicity and to improve the efficacy of aspirin, we have developed phospho-aspirin (Fig. 1A, PA-2; MDC-22) in which the -COOH group has been covalently modified by a glycerol linker containing two diethyl-phosphate moieties. Phospho-aspirin has demonstrated a much improved gastrointestinal safety profile compared to aspirin and is more efficacious in the treatment of cancer and experimental arthritis [13], [14]. In light of these previous findings, in this study we assessed the efficacy of phospho-aspirin in the treatment of ER+ breast cancer.

Bottom Line: An upstream mediator of the signaling effects of PA-2 is RONS.PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific.Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America.

ABSTRACT
Phospho-aspirin (PA-2) is a novel aspirin derivative that exhibits promising anticancer properties and is considerably safer than conventional aspirin. In this study, we investigated the chemotherapeutic efficacy of PA-2 in preclinical models of estrogen receptor positive (ER+) breast cancer and elucidated its mechanism of action. PA-2 inhibited the growth of ER+ cells more potently than aspirin in vitro, and exerted a triple cytokinetic effect that includes induction of apoptosis and cell cycle arrest as well as the inhibition of cell proliferation. PA-2 is highly efficacious in vivo, as treatment of established MCF7 xenografts with PA-2 induced tumor stasis (98.2% inhibition, p<0.01). PA-2 triggered the activation of p53-dependent apoptosis via two distinct mechanisms: 1) acetylation of p53 (at K373), which disrupts its interaction with its transcription repressor MDM2, and 2) translocation of p53 to the mitochondria leading to the dissipation of mitochondrial transmembrane potential (ΔΨ(m)). Consistent with these observations, both the RNAi-mediated knockdown of p53 and forced deactylation via HDAC1 over-expression attenuated the anticancer effect of PA-2 in MCF7 cells. An upstream mediator of the signaling effects of PA-2 is RONS. PA-2 induced oxidative stress in vitro and in mice bearing MCF7 xenografts; its induction effect appears to be tumor-specific. Crucially, administration of N-acetylcysteine, a ROS scavenger, abrogated the effect of PA-2 on p53 acetylation and mitochondria translocation, thus identifying RONS as proximal molecules mediating the anticancer effect of PA-2. In summary, our findings demonstrate that PA-2 is a promising antineoplastic compound against ER+ breast cancer, warranting further evaluation as an anticancer agent.

Show MeSH
Related in: MedlinePlus