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Novel bis-pocket binding aldose reductase inhibitors sensitize MCF-7/ADR cells to doxorubicin in a dual-role manner
Chao Zhang1, Shuling Peng1, Ziyou Zheng1
1Institute 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.
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.
Insights
Novel aldose reductase inhibitors (ARIs) show promise in overcoming breast cancer multidrug resistance. Compound 5a sensitizes cells to doxorubicin by promoting ferroptosis and inhibiting the AKR1B1/STAT3/SLC7A11 pathway.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Multidrug resistance (MDR) is a major challenge in breast cancer treatment.
- Aldose reductase inhibitors (ARIs) have shown potential in sensitizing cancer cells, but their mechanisms require further elucidation.
- Development of novel, clinically relevant ARIs is needed to combat MDR.
Purpose of the Study:
- To design and synthesize novel bis-pocket binding aldose reductase inhibitors (ARIs).
- To investigate the mechanism by which these ARIs overcome doxorubicin resistance in breast cancer cells.
- To evaluate the efficacy of the novel ARIs as sensitizers against multidrug resistance.
Main Methods:
- Synthesis and characterization of three novel ARIs (5a-c).
- Assessment of inhibitory activity, antioxidation, and sensitizing effects against doxorubicin-resistant MCF-7 cells (MCF-7/ADR).
- Measurement of reactive oxygen species (ROS), glutathione (GSH) levels, lipid peroxidation, and ferroptosis activity.
- Analysis of AKR1B1, p-STAT3, and SLC7A11 expression, including gene knockdown studies.
- Investigation of doxorubicin (DOX) accumulation and ABCB1 inhibition.
Main Results:
- Compound 5a demonstrated superior sensitization of MCF-7/ADR cells to doxorubicin compared to epalrestat (EPA).
- Both 5a and EPA increased ferroptosis activity by decreasing GSH and increasing ROS, Fe2+, and lipid peroxidation.
- Inhibition of AKR1B1 by 5a and EPA suppressed p-STAT3 and SLC7A11 expression, indicating pathway involvement.
- Compound 5a, unlike EPA, enhanced intracellular doxorubicin accumulation by inhibiting ABCB1.
Conclusions:
- Novel ARIs, particularly compound 5a, can overcome doxorubicin resistance in breast cancer.
- The mechanism involves the upregulation of ferroptosis activity via the AKR1B1/STAT3/SLC7A11 axis.
- Compound 5a is a promising sensitizing agent for breast cancer MDR treatment due to its multifaceted mechanism, including ABCB1 inhibition.
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