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

Liqun Huang, Chi C. Wong, Gerardo Mackenzie, Yu Sun, Ka W. Cheng, Kvetoslava Vrankova, Ninche Alston, Nengtai Ouyang, Basil Rigas

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article number141
JournalBMC Cancer
Volume14
Issue number1
DOIs
StatePublished - Feb 28 2014
Externally publishedYes

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Triple Negative Breast Neoplasms
Acetylation
Epidermal Growth Factor Receptor
Aspirin
Oxidative Stress
Animal Models
Breast Neoplasms
Heterografts
Thioredoxins
Chemoprevention
Growth
Cell Cycle Checkpoints
Phosphatidylinositol 3-Kinases
Nude Mice
Antineoplastic Agents
Lysine
Oxidation-Reduction
Transcription Factors
DNA
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models : An effect mediated by EGFR inhibition, p53 acetylation and oxidative stress. / Huang, Liqun; Wong, Chi C.; Mackenzie, Gerardo; Sun, Yu; Cheng, Ka W.; Vrankova, Kvetoslava; Alston, Ninche; Ouyang, Nengtai; Rigas, Basil.

In: BMC Cancer, Vol. 14, No. 1, 141, 28.02.2014.

Research output: Contribution to journalArticle

Huang, Liqun ; Wong, Chi C. ; Mackenzie, Gerardo ; Sun, Yu ; Cheng, Ka W. ; Vrankova, Kvetoslava ; Alston, Ninche ; Ouyang, Nengtai ; Rigas, Basil. / Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models : An effect mediated by EGFR inhibition, p53 acetylation and oxidative stress. In: BMC Cancer. 2014 ; Vol. 14, No. 1.
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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.",
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T2 - An effect mediated by EGFR inhibition, p53 acetylation and oxidative stress

AU - Huang, Liqun

AU - Wong, Chi C.

AU - Mackenzie, Gerardo

AU - Sun, Yu

AU - Cheng, Ka W.

AU - Vrankova, Kvetoslava

AU - Alston, Ninche

AU - Ouyang, Nengtai

AU - Rigas, Basil

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Y1 - 2014/2/28

N2 - 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.

AB - 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.

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KW - Epidermal growth factor receptor (EGFR)

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KW - Triple-negative breast cancer

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