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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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Proposed mechanism for the anticancer effect of phospho-aspirin-2 in ER+ breast cancer.PA-2 inhibits ER+ breast cancer through (i) induction of oxidative stress; (ii) acetylation of p53, which disrupts p53-MDM2 interaction and increases the expression of p21; and (iii) translocation of p53 to the mitochondria; which ultimately results in mitochondrial-dependent apoptosis and cell growth arrest.
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pone-0111720-g008: Proposed mechanism for the anticancer effect of phospho-aspirin-2 in ER+ breast cancer.PA-2 inhibits ER+ breast cancer through (i) induction of oxidative stress; (ii) acetylation of p53, which disrupts p53-MDM2 interaction and increases the expression of p21; and (iii) translocation of p53 to the mitochondria; which ultimately results in mitochondrial-dependent apoptosis and cell growth arrest.

Mentions: Our findings indicate that the novel aspirin derivative PA-2 is an efficacious agent against ER+ breast cancer in preclinical models. PA-2 induced a potent cytokinetic effect on ER+ breast cancer cells in vitro and in vivo, mediated via a cascade of events involving a) profound induction of oxidative stress; b) p53 acetylation; and c) translocation of p53 to the mitochondria, culminating in p53-dependent apoptosis and cell cycle arrest, the net result of which is the potent inhibition of tumor growth (Fig. 8).


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)

Proposed mechanism for the anticancer effect of phospho-aspirin-2 in ER+ breast cancer.PA-2 inhibits ER+ breast cancer through (i) induction of oxidative stress; (ii) acetylation of p53, which disrupts p53-MDM2 interaction and increases the expression of p21; and (iii) translocation of p53 to the mitochondria; which ultimately results in mitochondrial-dependent apoptosis and cell growth arrest.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111720-g008: Proposed mechanism for the anticancer effect of phospho-aspirin-2 in ER+ breast cancer.PA-2 inhibits ER+ breast cancer through (i) induction of oxidative stress; (ii) acetylation of p53, which disrupts p53-MDM2 interaction and increases the expression of p21; and (iii) translocation of p53 to the mitochondria; which ultimately results in mitochondrial-dependent apoptosis and cell growth arrest.
Mentions: Our findings indicate that the novel aspirin derivative PA-2 is an efficacious agent against ER+ breast cancer in preclinical models. PA-2 induced a potent cytokinetic effect on ER+ breast cancer cells in vitro and in vivo, mediated via a cascade of events involving a) profound induction of oxidative stress; b) p53 acetylation; and c) translocation of p53 to the mitochondria, culminating in p53-dependent apoptosis and cell cycle arrest, the net result of which is the potent inhibition of tumor growth (Fig. 8).

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