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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.
- Source :
-
PloS one [PLoS One] 2014 Nov 04; Vol. 9 (11), pp. e111720. Date of Electronic Publication: 2014 Nov 04 (Print Publication: 2014). - Publication Year :
- 2014
-
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.
- Subjects :
- Acetylation drug effects
Animals
Apoptosis drug effects
Breast metabolism
Breast pathology
Breast Neoplasms metabolism
Breast Neoplasms pathology
Cell Proliferation drug effects
Female
Humans
MCF-7 Cells
Mice
Oxidation-Reduction drug effects
Oxidative Stress drug effects
Receptors, Estrogen analysis
Tumor Suppressor Protein p53 metabolism
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Aspirin analogs & derivatives
Aspirin therapeutic use
Breast drug effects
Breast Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25369051
- Full Text :
- https://doi.org/10.1371/journal.pone.0111720