Open Access Highly Accessed Research article

Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress

Liqun Huang1, Chi C Wong1, Gerardo G Mackenzie1, Yu Sun1, Ka Wing Cheng1, Kvetoslava Vrankova1, Ninche Alston1, Nengtai Ouyang12 and Basil Rigas1*

Author Affiliations

1 Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8173, USA

2 Medicon Pharmaceuticals, Inc, Setauket, NY 11733, USA

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BMC Cancer 2014, 14:141  doi:10.1186/1471-2407-14-141

Published: 28 February 2014

Abstract

Background

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).

Methods

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.

Results

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-κB. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2.

Conclusions

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.

Keywords:
Breast cancer; Triple-negative breast cancer; Phospho-aspirin; Non-steroidal anti-inflammatory drugs; Epidermal growth factor receptor (EGFR); p53; Oxidative stress