Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy

Abstract

Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer survivors, which adversely affects their quality of life. Moreover, available treatments are vastly inadequate, warranting a better understanding of the biochemical and metabolic mechanisms that occur in response to chemotherapeutics which would be critical for the development of novel therapies for CIPN. Using extracellular flux analysis, this study demonstrated that the proteasome inhibitor, bortezomib, enhanced glycolysis while suppressing oxidative phosphorylation in the sensory neurons of mice. This metabolic phenotype is known as aerobic glycolysis. Bortezomib upregulated lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which consequently enhanced the production of lactate and repressed pyruvate oxidation, respectively. Moreover, lactate dehydrogenase A- and pyruvate dehydrogenase kinase 1-driven aerobic glycolysis was associated with increased extracellular acidification, augmented calcium responses, and pain in bortezomib-induced CIPN. Remarkably, pharmacological blockade and in vivo knockdown of lactate dehydrogenase A or pyruvate dehydrogenase kinase 1 reversed the metabolic phenotype, attenuated calcium responses, and alleviated pain induced by bortezomib. Collectively, these results elucidate the mechanisms by which bortezomib induces aerobic glycolysis. Moreover, these findings establish aerobic glycolysis as a metabolic phenotype that underpins bortezomib-induced CIPN.

Bortezomib and metformin opposingly regulate the expression of hypoxia-inducible factor alpha and the consequent development of chemotherapy-induced painful peripheral neuropathy

“…Bortezomib and paclitaxel are known to reprogram the metabolism of sensory neurons in a manner consistent with aerobic glycolysis. 9,10 Crucially, targeted inhibition of the enzymes that maintain the aerobic glycolysis phenotype alleviate existing neuropathic pain, 10 suggesting that aerobic glycolysis is critical for the maintenance of CIPN. However, the mechanisms that sustain the expression of the enzymes that maintain aerobic glycolysis remain elusive.…”

“…Aerobic glycolysis is characterized by enhanced glycolytic flux and reduced oxidative phosphorylation. Bortezomib treatment has been shown to limit mitochondrial oxidation of pyruvate, 10 which would deplete the metabolic intermediates that are essential for chromatin remodeling and altering the epigenetic landscape. 55–59 Crucially, altered metabolic states are now recognized to produce epigenetic changes.…”

Pain Management in Patients with Multiple Myeloma: An Update

“…Several studies have suggested multifactorial pathways towards nerve fiber degeneration. Bortezomib induces aerobic glycolysis in sensory neurons, which may lead to the extrusion of metabolites sensitizing primary sensory afferents, finally causing pain [73]. One study in mice demonstrated bortezomib effects resulting in oxidative stress, mitochondrial dysfunction, cell apoptosis, and endoplasmatic reticulum stress [74].…”

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…The effect of the CIPN-inducing proteasome inhibitor bortezomib on mitochondria in sensory neurons has also been investigated [56]. In a previous study bortezomib was shown to alter the metabolic phenotype of sensory neurons and increase the production of metabolites due to aerobic glycolysis, thus resulting in CIPN development.…”