Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma

Zaal, Esther A.; Grooth, Harm-Jan de; Oudaert, Inge; Langerhorst, Pieter; Levantovsky, Sophie; Slobbe, Gijs J. J. van; Jansen, Jeroen W. A.; Menu, Eline; Wu, Wei; Berkers, Celia R.

doi:10.1039/d1mo00106j

Cited by 15 publications

(13 citation statements)

References 53 publications

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Section: Multiple Myeloma Metabolism and Its Involvement In Drug Resi...mentioning

confidence: 99%

“…OXPHOS has been described as an important energy source for MM ( 21 , 62 , 63 ) ( Figure 1A ). Several studies show that high expression of mitochondrial enzymes of TCA cycle and OXPHOS are correlated with poor survival ( 21 , 26 , 58 ). MM cells mostly depend on glutamine to feed the TCA cycle ( 64 , 65 ), supported by overexpression of Glutaminase-1 (GLS1) and glutamine transporters ASCT2, LAT1 and SNAT1 ( 65 ).…”

Section: Multiple Myeloma Metabolism and Its Involvement In Drug Resi...mentioning

confidence: 99%

“…OXPHOS and ATP production are especially high in BTZ-resistant cells ( 21 , 62 , 74 ) ( Figure 1B ). In addition, the mevalonate pathway is upregulated in BTZ-resistant MM cells, which generates the electron carrier coenzyme Q10 (CoQ10) and is thereby important for electron transport chain (ETC) function ( 21 ). This dependence of resistant MM cells on OXPHOS makes them susceptible to its inhibition.…”

Section: Multiple Myeloma Metabolism and Its Involvement In Drug Resi...mentioning

confidence: 99%

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Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment

et al. 2023

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Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM remains an incurable disease, with the majority of patients experiencing multiple relapses from different drugs. The MM tumor microenvironment (TME) and in particular bone-marrow stromal cells (BMSCs) play a crucial role in the development of drug resistance. Metabolic reprogramming is emerging as a hallmark of cancer that can potentially be exploited for cancer treatment. Recent studies show that metabolism is further adjusted in MM cells during the development of drug resistance. However, little is known about the role of BMSCs in inducing metabolic changes that are associated with drug resistance. In this Perspective, we summarize current knowledge concerning the metabolic reprogramming of MM, with a focus on those changes associated with drug resistance to the proteasome inhibitor Bortezomib (BTZ). In addition, we present proof-of-concept fluxomics (glucose isotope-tracing) and Seahorse data to show that co-culture of MM cells with BMSCs skews the metabolic phenotype of MM cells towards a drug-resistant phenotype, with increased oxidative phosphorylation (OXPHOS), serine synthesis pathway (SSP), TCA cycle and glutathione (GSH) synthesis. Given the crucial role of BMSCs in conveying drug resistance, insights into the metabolic interaction between MM and BMSCs may ultimately aid in the identification of novel metabolic targets that can be exploited for therapy.

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Section: Multiple Myeloma Metabolism and Its Involvement In Drug Resi...mentioning

confidence: 99%

Section: Multiple Myeloma Metabolism and Its Involvement In Drug Resi...mentioning

confidence: 99%

Section: Multiple Myeloma Metabolism and Its Involvement In Drug Resi...mentioning

confidence: 99%

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Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment

et al. 2023

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“…Coenzyme Q10, a mitochondrial electron carrier and product of the cholesterol producing mevalonate pathway, was shown to be relevant in bortezomib resistant MM. Bortezomib resistant MM appears to have elevated vulnerability to electron transport chain inhibition and targeting the biosynthesis of coenzyme Q10 had a synergistic effect with bortezomib in treating bortezomib resistant MM [ 55 ].…”

Section: Fatty Acid/lipid Metabolismmentioning

confidence: 99%

Metabolic Alterations in Multiple Myeloma: From Oncogenesis to Proteasome Inhibitor Resistance

Weir

Donaldson

McMullin

et al. 2023

Cancers

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Despite significant improvements in treatment strategies over the past couple of decades, multiple myeloma (MM) remains an incurable disease due to the development of drug resistance. Metabolic reprogramming is a key feature of cancer cells, including MM, and acts to fuel increased proliferation, create a permissive tumour microenvironment, and promote drug resistance. This review presents an overview of the key metabolic adaptations that occur in MM pathogenesis and in the development of resistance to proteasome inhibitors, the backbone of current MM therapy, and considers the potential for therapeutic targeting of key metabolic pathways to improve outcomes.

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“…Incidentally, glutamine derived 2-HG is associated with disease progression in MM (182). BTZ resistance correlates with high levels of the mitochondrial electron carrier CoQ, and targeting the mevalonate pathway with simvastatin decreases CoQ levels, overcoming BTZ-resistance in MM cells (183). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in combination with carfilzomib and dexamethasone in relapsed and/or refractory MM, and newer inhibitors like DRP-104 (sirpiglenastat) are in solid tumor clinical trials (184)(185)(186).…”

Section: Implications Of Mitochondrial Metabolism On MM Therapymentioning

confidence: 99%

Mitochondrial metabolic determinants of multiple myeloma growth, survival, and therapy efficacy

Nair

Gupta²,

Shanmugam³

2022

Front. Oncol.

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Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the clonal proliferation of antibody producing plasma cells. Despite the use of next generation proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and immunotherapy, the development of therapy refractory disease is common, with approximately 20% of MM patients succumbing to aggressive treatmentrefractory disease within 2 years of diagnosis. A large emphasis is placed on understanding inter/intra-tumoral genetic, epigenetic and transcriptomic changes contributing to relapsed/refractory disease, however, the contribution of cellular metabolism and intrinsic/extrinsic metabolites to therapy sensitivity and resistance mechanisms is less well understood. Cancer cells depend on specific metabolites for bioenergetics, duplication of biomass and redox homeostasis for growth, proliferation, and survival. Cancer therapy, importantly, largely relies on targeting cellular growth, proliferation, and survival. Thus, understanding the metabolic changes intersecting with a drug's mechanism of action can inform us of methods to elicit deeper responses and prevent acquired resistance. Knowledge of the Warburg effect and elevated aerobic glycolysis in cancer cells, including MM, has allowed us to capitalize on this phenomenon for diagnostics and prognostics. The demonstration that mitochondria play critical roles in cancer development, progression, and therapy sensitivity despite the inherent preference of cancer cells to engage aerobic glycolysis has re-invigorated deeper inquiry into how mitochondrial metabolism regulates tumor biology and therapy efficacy. Mitochondria are the sole source for coupled respiration mediated ATP synthesis and a key source for the anabolic synthesis of amino acids and reducing equivalents. Beyond their core metabolic activities, mitochondria facilitate apoptotic cell death, impact the activation of the cytosolic integrated response to stress, and through nuclear and cytosolic retrograde crosstalk maintain cell fitness and survival. Here, we hope to shed light on key mitochondrial functions that shape MM development and therapy sensitivity.

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Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma

Abstract: This study links CoQ synthesis to bortezomib resistance in multiple myeloma and provides a novel avenue for improving BTZ response through statin-induced inhibition of mitochondrial metabolism.

Cited by 15 publications

References 53 publications

Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment

Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment

Metabolic Alterations in Multiple Myeloma: From Oncogenesis to Proteasome Inhibitor Resistance

Mitochondrial metabolic determinants of multiple myeloma growth, survival, and therapy efficacy

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