ArticleBlood advances2020
Amino acid depletion triggered by ʟ-asparaginase sensitizes MM cells to carfilzomib by inducing mitochondria ROS-mediated cell death.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by suppressing the protein folding response.Haematologica · 2026Article
- A metabolic trade-off between malignant plasma cells and mesenchymal stromal cells sustains multiple myeloma growth.Blood neoplasia · 2026Article
- Metabolomic Investigation of Myelodysplastic Syndromes, Multiple Myeloma, and Homozygous β-Thalassemia.Cells · 2025Review
- Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.Nature metabolism · 2025Article
- Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.EMBO molecular medicine · 2024Article
- Mitochondrial dysfunction and drug targets in multiple myeloma.Journal of cancer research and clinical oncology · 2023Review
- Ubiquitin-proteasome system as a target for anticancer treatment-an update.Archives of pharmacal research · 2023Review
- The Interaction between Gut Microbiota and Host Amino Acids Metabolism in Multiple Myeloma.Cancers · 2023Review
- CD38-Induced Metabolic Dysfunction Primes Multiple Myeloma Cells for NADAntioxidants (Basel, Switzerland) · 2023Article
- Metabolic cross-talk within the bone marrow milieu: focus on multiple myeloma.Experimental hematology & oncology · 2022Review
- Molecular cloning, characterization, and in-silico analysis of l-asparaginase from Himalayan3 Biotech · 2022Article
- Icaritin inhibits PLK1 to activate DNA damage response in NK/T cell lymphoma and increases sensitivity to GELOX regime.Molecular therapy oncolytics · 2022Article
- Apoptosis reprogramming triggered by splicing inhibitors sensitizes multiple myeloma cells to Venetoclax treatment.Haematologica · 2022Article
- Mitochondrial metabolic determinants of multiple myeloma growth, survival, and therapy efficacy.Frontiers in oncology · 2022Review
- Multiple myeloma metabolism - a treasure trove of therapeutic targets?Frontiers in immunology · 2022Review
- ALL blasts drive primary mesenchymal stromal cells to increase asparagine availability during asparaginase treatment.Blood advances · 2021Article
- Review
- Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma.Cells · 2021Review
- Glutamine Synthetase as a Therapeutic Target for Cancer Treatment.International journal of molecular sciences · 2021Review
- The Role of Amino Acids in the Crosstalk Between Mesenchymal Stromal Cells and Neoplastic Cells in the Hematopoietic Niche.Frontiers in cell and developmental biology · 2021Review
Corrections and comments
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Authors and funding
22 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Metabolic reprogramming is emerging as a cancer vulnerability that could be therapeutically exploitable using different approaches, including amino acid depletion for those tumors that rely on exogenous amino acids for their maintenance. ʟ-Asparaginase (ASNase) has contributed to a significant improvement in acute lymphoblastic leukemia outcomes; however, toxicity and resistance limit its clinical use in other tumors. Here, we report that, in multiple myeloma (MM) cells, the DNA methylation status is significantly associated with reduced expression of ASNase-related gene signatures, thus suggesting ASNase sensitivity for this tumor. Therefore, we tested the effects of ASNase purified from Erwinia chrysanthemi (Erw-ASNase), combined with the next-generation proteasome inhibitor (PI) carfilzomib. We observed an impressive synergistic effect on MM cells, whereas normal peripheral blood mononuclear cells were not affected. Importantly, this effect was associated with increased reactive oxygen species (ROS) generation, compounded mitochondrial damage, and Nrf2 upregulation, regardless of the c-Myc oncogenic-specific program. Furthermore, the cotreatment resulted in genomic instability and DNA repair mechanism impairment via increased mitochondrial oxidative stress, which further enhanced its antitumor activity. Interestingly, carfilzomib-resistant cells were found to be highly dependent on amino acid starvation, as reflected by their higher sensitivity to Erw-ASNase treatment compared with isogenic cells. Overall, by affecting several cellular programs, Erw-ASNase makes MM cells more vulnerable to carfilzomib, providing proof of concept for clinical use of this combination as a novel strategy to enhance PI sensitivity in MM patients.
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