Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Proteasome inhibitors represent a significant advancement in multiple myeloma (MM) therapy.
• Understanding the precise mechanisms of action, particularly downstream cellular events, is crucial for optimizing MM treatment and developing novel combination therapies.

Purpose of the Study:

• To investigate the intricate relationship between redox homeostasis and the efficacy of bortezomib treatment in multiple myeloma cells.
• To elucidate how modulating cellular redox balance influences sensitivity to proteasome inhibition.

Main Methods:

• Assessed the impact of glutathione depletion (using buthionine sulfoximine) and antioxidant treatment on bortezomib toxicity in MM cell lines.
• Quantified intracellular glutathione levels in MM cell lines and patient-derived malignant plasma cells following bortezomib treatment.
• Analyzed the expression of genes involved in the Nrf-2 antioxidant response (GCLM, HMOX1) and eIF2α-mediated stress response (ATF4, CHOP) in bortezomib-treated MM cells.

Main Results:

• Decreasing intracellular glutathione levels significantly potentiated bortezomib-induced toxicity.
• Antioxidant administration protected MM cells from bortezomib-mediated cell death.
• Bortezomib treatment led to a reduction in intracellular glutathione levels in both MM cell lines and patient samples.
• Upregulation of GCLM, HMOX1, ATF4, and CHOP indicated the activation of adaptive redox-related responses in bortezomib-treated MM cells.

Conclusions:

• Demonstrated a strong correlation between cellular redox homeostasis and sensitivity to proteasome inhibition in multiple myeloma.
• Findings suggest that targeting redox balance could be a promising strategy to enhance bortezomib efficacy and overcome resistance in MM and potentially other cancers.