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 (ΔΨm). 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.
Highlights
Breast cancer is the one of the most common cancers with more than a million cases worldwide each year and is the second leading cause of cancer deaths in females [1]
PA-2 inhibits the growth of human ER+ breast cancer via a strong cytokinetic effect
We evaluated the cytokinetic effect of PA-2 in vivo
Summary
Breast cancer is the one of the most common cancers with more than a million cases worldwide each year and is the second leading cause of cancer deaths in females [1]. While the mechanisms leading to drug resistance remain poorly understood, the development of alternative therapeutic agents against ER+ breast cancer is urgently needed. Our recent studies have attempted to decipher the molecular targets of modified NSAIDs [16,17,18]; and we have identified induction of oxidative stress as a key mechanism mediating the therapeutic effect of this class of novel anticancer drugs. We demonstrate that PA-2 is efficacious against breast cancer growth in vitro and in vivo, an effect that is superior to that of aspirin. We show that PA-2 induces a state of oxidative stress in breast cancer cells, leading to the acetylation and reactivation of p53 tumor suppressor which is accompanied by reduced growth of ER+ breast cancer cells in vitro and in vivo
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