Synergistic Inhibition of Triple-Negative Breast Cancer by Acetylsalicylic Acid and Recombinant Human APE1/Ref-1 in a
Hao Jin1,2, Yu Ran Lee1, Sungmin Kim1,3
1Department of Physiology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea.
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.
Insights
Combining recombinant human apurinic/apyrimidinic endonuclease 1/redox factor-1 (rhAPE1/Ref-1) with acetylsalicylic acid (ASA) shows significant promise for treating triple-negative breast cancer (TNBC) by enhancing apoptosis and reducing tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
- Estrogen, progesterone, and HER2 receptor negativity defines TNBC, necessitating novel therapeutic strategies.
- Recombinant human apurinic/apyrimidinic endonuclease 1/redox factor-1 (rhAPE1/Ref-1) and acetylsalicylic acid (ASA) are investigated for combined efficacy.
Purpose of the Study:
- To investigate the synergistic anticancer effects of rhAPE1/Ref-1 and ASA in TNBC.
- To evaluate the in vitro and in vivo efficacy of the rhAPE1/Ref-1 and ASA combination.
- To assess the safety profile and underlying mechanisms of the combination therapy.
Main Methods:
- In vitro studies using MDA-MB-231 TNBC cells to assess viability and apoptosis.
- In vivo murine xenograft model to evaluate tumor growth, biomarkers, and apoptosis.
- Hematological parameters monitored for safety assessment of combination therapy.
Main Results:
- Combination therapy significantly reduced cell viability and enhanced apoptosis in vitro, mediated by RAGE.
- In vivo, the combination suppressed tumor growth by ~70%, comparable to paclitaxel (PTX).
- Combination therapy showed no hematological toxicity, unlike PTX, and induced RAGE expression.
Conclusions:
- rhAPE1/Ref-1 and ASA combination is a promising therapeutic strategy for TNBC.
- The combination enhances apoptosis and inhibits tumor progression effectively in a preclinical model.
- This novel combination offers a potentially safer alternative to existing treatments.
