ArticleMolecular pain
Bortezomib and metformin opposingly regulate the expression of hypoxia-inducible factor alpha and the consequent development of chemotherapy-induced painful peripheral neuropathy.
Article in Molecular pain. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- The Effect of Metformin on Chemotherapy-Induced Toxicities in Non-diabetic Breast Cancer Patients: A Randomised Controlled Study.Drug safety · 2023Trial
- Transcript architecture predetermines m6A remodeling and sensory neuron vulnerability in chemotherapy-induced peripheral neuropathy.bioRxiv : the preprint server for biology · 2026Article
- Vascular dysfunction is at the onset of oxaliplatin-induced peripheral neuropathy symptoms in mice.Life science alliance · 2025Article
- Bortezomib-induced peripheral neuropathy: from molecular mechanisms to clinical management.Frontiers in pharmacology · 2025Review
- Glutamine Oxidation in Mouse Dorsal Root Ganglia Regulates Pain Resolution and Chronification.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Article
- Targeting therapy-induced senescence as a novel strategy to combat chemotherapy-induced peripheral neuropathy.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2024Review
- Targeting metabolic pathways alleviates bortezomib-induced neuropathic pain without compromising anticancer efficacy in a sex-specific manner.Frontiers in pain research (Lausanne, Switzerland) · 2024Article
- Review
- Hypoxia-Inducible Factor-1: A Novel Therapeutic Target for the Management of Cancer, Drug Resistance, and Cancer-Related Pain.Cancers · 2022Review
- Vincristine- and bortezomib-induced neuropathies - from bedside to bench and back.Experimental neurology · 2021Review
- Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy.International journal of molecular sciences · 2021Review
- Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system.Expert review of neurotherapeutics · 2021Article
- An Investigation of the Molecular Mechanisms Underlying the Analgesic Effect of Jakyak-Gamcho Decoction: A Network Pharmacology Study.Evidence-based complementary and alternative medicine : eCAM · 2020Article
- The Actions and Mechanisms of P2X7R and p38 MAPK Activation in Mediating Bortezomib-Induced Neuropathic Pain.BioMed research international · 2020Article
- Metformin: A Prospective Alternative for the Treatment of Chronic Pain.Frontiers in pharmacology · 2020Review
- Recent advances in understanding chemotherapy-induced peripheral neuropathy.F1000Research · 2020Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chemotherapy-induced painful peripheral neuropathy is a significant clinical problem that is associated with widely used chemotherapeutics. Unfortunately, the molecular mechanisms by which chemotherapy-induced painful peripheral neuropathy develops have remained elusive. The proteasome inhibitor, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons. This altered metabolic phenotype leads to the extrusion of metabolites which sensitize primary afferents and cause pain. Hypoxia-inducible factor alpha is a transcription factor that is known to reprogram cellular metabolism. Furthermore, hypoxia-inducible factor 1 alpha protein is constantly synthesized and undergoes proteasomal degradation in normal conditions. However, metabolic stress or hypoxia stabilizes the expression of hypoxia-inducible factor 1 alpha leading to the transcription of genes that reprogram cellular metabolism. This study demonstrates that treatment of mice with bortezomib stabilizes the expression of hypoxia-inducible factor 1 alpha. Moreover, knockdown of hypoxia-inducible factor 1 alpha, inhibition of hypoxia-inducible factor 1 alpha binding to its response element, or limiting its translation by using metformin prevent the development of bortezomib-induced neuropathic pain. Strikingly, the blockade of hypoxia-inducible factor 1 alpha expression does not attenuate mechanical allodynia in mice with existing bortezomib-induced neuropathic pain. These results establish the stabilization of hypoxia-inducible factor 1 alpha expression as the molecular mechanism by which bortezomib initiates chemotherapy-induced painful peripheral neuropathy. Crucially, these findings reveal that the initiation and maintenance of bortezomib-induced neuropathic pain are regulated by distinct mechanisms.
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