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Evaluating Therapeutic Efficacy of SCL7A11 and GLUT1 Inhibition in Triple-Negative Breast Cancer via a GSH/ATP
Jiao Lu1, Fabiao Yu2, Zhirong Geng3
1State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210023, P. R. China.
Abstract:
Triple-negative breast cancer (TNBC) lacks receptor expression and exhibits metabolic heterogeneity, leading to ineffective targeted therapy and chemotherapy resistance. There is an urgent need to investigate its metabolic reprogramming mechanisms and develop targeted intervention strategies. In TNBC, the overexpression of a solute carrier family member (SLC7A11) and glucose transporter 1 (GLUT1) drives tumor cell proliferation and survival through excessive glutathione (GSH)/adenosine triphosphate (ATP) production. Whether combined inhibition of SLC7A11 and GLUT1 produces synergistic antitumor effects via oxidative stress and energy imbalance and how GSH/ATP levels change remain unclear. We constructed the first near-infrared dual-activation probe M1219, which successfully visualized the regulatory relationship between oxidative stress and energy imbalance under the stimulation of sulfasalazine (SAS, SLC7A11 inhibitor) and rapamycin A (RgA, GLUT1 inhibitor) by real-time monitoring of the dynamic changes of GSH/ATP in cells. For the first time, we elucidated the NADPH/G6PD/GPX4/ACSL4 axis-mediated metabolic regulatory network under dual-target inhibition. Leveraging the tumor microenvironment's GSH/ATP-specific activation mechanism, M1219 achieved the in vivo visualization of therapeutic efficacy in TNBC mice, validated the enhanced antitumor effect of the combined inhibition strategy, enabled precise resection of TNBC infiltration boundaries (negative margin of <0.1 mm), and successfully distinguished tumor tissue from marginal tissue in clinically resected breast cancer specimens.
Insights
Triple-negative breast cancer (TNBC) treatment is challenging due to metabolic issues. A new probe, M1219, visualizes how inhibiting SLC7A11 and GLUT1 synergistically targets TNBC metabolism and improves therapeutic outcomes.
Area of Science:
- Biochemistry
- Oncology
- Medical Imaging
Background:
- Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its metabolic heterogeneity and resistance to conventional treatments.
- Overexpression of solute carrier family 7 member 11 (SLC7A11) and glucose transporter 1 (GLUT1) in TNBC fuels tumor growth via enhanced glutathione (GSH) and adenosine triphosphate (ATP) production.
- The precise mechanisms of metabolic reprogramming and the synergistic effects of combined SLC7A11 and GLUT1 inhibition on oxidative stress and energy balance in TNBC remain incompletely understood.
Purpose of the Study:
- To investigate the synergistic antitumor effects of combined SLC7A11 and GLUT1 inhibition in TNBC.
- To elucidate the underlying metabolic regulatory network, including the NADPH/G6PD/GPX4/ACSL4 axis, affected by dual-target inhibition.
- To develop and validate a novel near-infrared dual-activation probe (M1219) for real-time monitoring of GSH/ATP dynamics and therapeutic efficacy in TNBC.
Main Methods:
- Construction and application of the near-infrared dual-activation probe M1219 for real-time monitoring of intracellular GSH and ATP levels.
- Utilizing sulfasalazine (SAS) as an SLC7A11 inhibitor and rapamycin A (RgA) as a GLUT1 inhibitor to assess combined therapeutic strategies.
- In vivo studies in TNBC mouse models to evaluate the probe's ability to visualize therapeutic efficacy and guide precise tumor resection.
Main Results:
- The M1219 probe successfully visualized the dynamic interplay between oxidative stress and energy imbalance under SAS and RgA treatment, correlating with GSH/ATP level changes.
- The study elucidated the NADPH/G6PD/GPX4/ACSL4 axis as a key metabolic regulator in TNBC under dual-target inhibition.
- Combined inhibition demonstrated enhanced antitumor effects, enabling precise identification of TNBC infiltration boundaries (<0.1 mm) and differentiation from healthy tissue in resected specimens.
Conclusions:
- Combined inhibition of SLC7A11 and GLUT1 exhibits synergistic antitumor effects in TNBC by inducing oxidative stress and energy imbalance.
- The M1219 probe serves as a valuable tool for real-time monitoring of metabolic changes and therapeutic response in TNBC.
- This dual-targeting strategy and imaging approach hold promise for improving TNBC treatment and surgical precision.
