Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation

Abstract

Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells. In the current study, both transcriptome and metabolome analysis were performed to comprehensively evaluate the underlying mechanism. It was demonstrated that pretreating MM cells with DHA/EPA before bortezomib potently decreased the cellular glutathione (GSH) level and altered the expression of the related metabolites and key enzymes in GSH metabolism, whereas simultaneous treatment only showed minor effects on these factors, thereby suggesting the critical role of GSH degradation in overcoming bortezomib resistance in MM cells. Moreover, RNA-seq results revealed that the nuclear factor erythroid 2-related factor 2 (NRF2)-activating transcription factor 3/4 (ATF3/4)-ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway may be implicated as the central player in the GSH degradation. Pathways of necroptosis, ferroptosis, p53, NRF2, ATF4, WNT, MAPK, NF-κB, EGFR, and ERK may be connected to the tumor suppressive effect caused by pretreatment of DHA/EPA prior to bortezomib. Collectively, this work implicates GSH degradation as a potential therapeutic target in MM and provides novel mechanistic insights into its significant role in combating bortezomib resistance.

Network Pharmacology Identifies Therapeutic Targets and the Mechanisms of Glutathione Action in Ferroptosis Occurring in Oral Cancer

“…Besides the MAPK signaling, our results highlighted the involvement of ERK signaling in ferroptosis targeted by GSH. ERK signaling is associated with ferroptosis in many cancers, including multiple myeloma ( Chen J. et al, 2021 ), endometrial carcinoma ( Qin et al, 2021 ), hepatocellular carcinoma ( Fei et al, 2021 ), and pancreatic cancer ( Ye et al, 2020 ). Specifically, the ERK signaling pathway has been linked with ferroptosis and associated with the prognosis of OC ( Chen R. et al, 2021 ).…”

Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors

“…Another study has shown that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplementation of MM cells, prior the treatment with BTZ, potently decreased cellular GSH levels and altered the expression of related metabolites and key enzymes involved in GSH metabolism, suggesting a critical role of GSH degradation in overcoming BTZ resistance in MM. In addition, the NRF2–ATF3/AFT4–ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway was shown to be potentially implicated in DHA/EPA pretreatment-mediated GSH degradation ( 282 ).…”

Ferroptosis: Redox Imbalance and Hematological Tumorigenesis

“…Studies have shown that iron exposure can reduce the activity of the proteasome, hence increasing the efficacy of Bortezomib and Carfilzomib (the second generation of proteasome inhibitors used for MM therapy) in MM cells and leading to severe MM cell death by promoting ferroptosis ( 113 ). In order to overcome the drug resistance of Bortezomib, docosahexaenoic acid or eicosapentaenoic acid in combination with Bortezomib were used to enhance the sensitivity of MM cells to Bortezomib ( Table 1 ) ( 114 ). Specifically, docosahexaenoic acid and eicosapentaenoic acid can modulate the redox balance in MM cells by reducing the content of GSH in MM cells, thus improving the therapeutic effect of Bortezomib.…”