2. Academic Validation
  3. Novel bis-pocket binding aldose reductase inhibitors sensitize MCF-7/ADR cells to doxorubicin in a dual-role manner

Novel bis-pocket binding aldose reductase inhibitors sensitize MCF-7/ADR cells to doxorubicin in a dual-role manner

  • Bioorg Chem. 2025 Apr:157:108286. doi: 10.1016/j.bioorg.2025.108286.
Chao Zhang 1,  Shuling Peng 1,  Ziyou Zheng 1,  Zhenqiang Chen 1,  Mingyue Li 1,  Nengneng Huang 1,  Zhijun Liu 1,  Mao-Xun Yang 2,  Heru Chen 3
Affiliations

Affiliations

  • 1 Institute of Traditional Chinese Medicine and Natural Products; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, PR China.
  • 2 Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan 523808, PR China; Marine Chinese Medicine Branch, National Engineering Research Center for Modernization of Traditional Chinese Medicine, Zhanjiang 524023, PR China.
  • 3 Institute of Traditional Chinese Medicine and Natural Products; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, PR China. Electronic address: thrchen@jnu.edu.cn.
PMID: 39983406 DOI: 10.1016/j.bioorg.2025.108286
Abstract

Multidrug resistance (MDR) represents a bottleneck in the treatment of breast Cancer. Although the potential of Aldose Reductase inhibitors (ARIs) as sensitizers against MDR has been explored in recent decades, the intrinsic mechanism still needs to be elucidated, and promising agents in the clinic need to be developed. In this study, three novel ARIs (5a-c), characterized by bis-pocket binding, were designed and synthesized. Inhibitory activity is positively correlated with antioxidation and benefits from rigid spacers. Only 5a with less activities in inhibition and antioxidation was demonstrated as a stronger sensitizer against doxorubicin (DOX)-resistant MCF-7 cells (MCF-7/ADR) than epalrestat (EPA). Either 5a or EPA may decrease GSH abundance and increase ROS, Fe2+, and lipid peroxidation levels. The restorative effects of both ARIs may be blocked by N-acetyl cysteine (NAC). These data suggest that both 5a and EPA may restore the sensitivity of MCF-7/ADR cells to DOX by increasing Ferroptosis activity. Furthermore, the inhibition of AKR1B1 by 5a, as well as by EPA, dramatically decreased both p-STAT3 and SLC7A11 expression. Gene knockdown of AKR1B1 has the same effects as AKR1B1 inhibition. This evidence indicates that both ARIs can suppress MCF-7/ADR cell growth via the upregulation of Ferroptosis activity via the AKR1B1/STAT3/SLC7A11 axis. Additionally, 5a was found to increase the accumulation of intramolecular DOX by inhibiting ABCB1, but EPA did not. These results support that 5a is a promising sensitizing agent against multidrug resistance in breast Cancer.

Keywords

ABCB1; AKR1B1/STAT3/SLC7A11; Aldose reductase inhibitor; Ferroptosis; Multidrug resistance.

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