Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a Mouse Xenograft Model

Jin, Hao; Lee, Yu Ran; Kim, Sungmin; Choi, Eunju; Lee, Ka-Young; Joo, Hee Kyoung; Lee, Eun-Ok; Kim, Cuk-Seong; Kim, Je Ryong; Lee, Sang Hun; Jeon, Byeong Hwa

doi:10.3390/biomedicines13112767

This is an early access version, the complete PDF, HTML, and XML versions will be available soon.

Open AccessArticle

Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a Mouse Xenograft Model

by

Hao Jin

^1,2,†,

Yu Ran Lee

^1,†,

Sungmin Kim

^1,3

,

Eunju Choi

^1,2

,

Ka-Young Lee

^1,2

,

Hee Kyoung Joo

^1,3,

Eun-Ok Lee

^1,3

,

Cuk-Seong Kim

^1,2,3

,

Je Ryong Kim

⁴,

Sang Hun Lee

^5,*

and

Byeong Hwa Jeon

^1,2,3,*

¹

Department of Physiology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea

²

Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea

³

Research Institute of Medical Sciences, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea

⁴

Department of Surgery, Chungnam National University Hospital, 282, Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea

⁵

Department of Chemical and Biological Engineering, Hanbat National University, Daejeon 34158, Republic of Korea

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Biomedicines 2025, 13(11), 2767; https://doi.org/10.3390/biomedicines13112767 (registering DOI)

Submission received: 10 September 2025 / Revised: 31 October 2025 / Accepted: 10 November 2025 / Published: 12 November 2025

(This article belongs to the Special Issue Molecular Research in Breast Cancer)

Download Versions Notes

Abstract

Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options due to the lack of estrogen, progesterone, and HER2 receptors. This study investigated the synergistic anticancer effects of recombinant human apurinic/apyrimidinic endonuclease 1/redox factor-1 (rhAPE1/Ref-1) and acetylsalicylic acid (ASA), a combination that has not been previously tested in vivo. Methods: We treated MDA-MB-231 TNBC cells with rhAPE1/Ref-1, ASA, or their combination to assess cell viability and apoptosis in vitro. In vivo, a murine xenograft model was established to evaluate the efficacy of the combination treatment on tumor growth, tumor-specific biomarkers, and key apoptotic proteins. The safety profile of the combination therapy was also assessed by monitoring hematological parameters. Results: While monotherapy with either rhAPE1/Ref-1 or ASA had minimal effects, their combination significantly reduced cell viability and enhanced apoptosis in vitro by increasing DNA fragmentation. These synergistic cytotoxic effects were significantly inhibited by the receptor for advanced glycation end-products (RAGE) siRNA, suggesting that RAGE acts as an important mediator. In the xenograft model, the combination treatment suppressed tumor growth by approximately 70%, an effect comparable to paclitaxel (PTX). This was confirmed by a significant reduction in the plasma levels of TNBC biomarkers (CEA, CA27-29, and CA15-3) and increased tumor apoptosis via the upregulation of p53 and Bax and downregulation of Bcl-2. Notably, ASA, alone or combined with rhAPE1/Ref-1, induced the expression of RAGE in MDA-MB-231 tumors. In contrast to PTX, the combination of rhAPE1/Ref-1 and ASA did not cause hematological toxicity, such as anemia or thrombocytopenia. Conclusions: The combination of rhAPE1/Ref-1 and ASA represents a promising new therapeutic strategy for TNBC by enhancing apoptosis and significantly inhibiting tumor progression in a mouse xenograft model.

Keywords: triple-negative breast cancer (TNBC); APE1/Ref-1; acetylsalicylic acid (ASA); apoptosis; MDA-MB-231

Share and Cite

MDPI and ACS Style

Jin, H.; Lee, Y.R.; Kim, S.; Choi, E.; Lee, K.-Y.; Joo, H.K.; Lee, E.-O.; Kim, C.-S.; Kim, J.R.; Lee, S.H.; et al. Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a Mouse Xenograft Model. Biomedicines 2025, 13, 2767. https://doi.org/10.3390/biomedicines13112767

AMA Style

Jin H, Lee YR, Kim S, Choi E, Lee K-Y, Joo HK, Lee E-O, Kim C-S, Kim JR, Lee SH, et al. Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a Mouse Xenograft Model. Biomedicines. 2025; 13(11):2767. https://doi.org/10.3390/biomedicines13112767

Chicago/Turabian Style

Jin, Hao, Yu Ran Lee, Sungmin Kim, Eunju Choi, Ka-Young Lee, Hee Kyoung Joo, Eun-Ok Lee, Cuk-Seong Kim, Je Ryong Kim, Sang Hun Lee, and et al. 2025. "Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a Mouse Xenograft Model" Biomedicines 13, no. 11: 2767. https://doi.org/10.3390/biomedicines13112767

APA Style

Jin, H., Lee, Y. R., Kim, S., Choi, E., Lee, K.-Y., Joo, H. K., Lee, E.-O., Kim, C.-S., Kim, J. R., Lee, S. H., & Jeon, B. H. (2025). Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a Mouse Xenograft Model. Biomedicines, 13(11), 2767. https://doi.org/10.3390/biomedicines13112767

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a Mouse Xenograft Model

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI