Metformin and other metabolic inhibitors attenuate neuropathic pain and tumor growth in mice with paraneoplastic syndrome and CIPN

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) and paraneoplastic neurological syndrome are two conditions that can cause significant pain and discomfort in cancer patients. CIPN is a common side effect of certain chemotherapeutics and can result in numbness, tingling, and pain. Paraneoplastic neurological syndrome, on the other hand, is a rare disorder that occurs when cancer-fighting antibodies attack parts of the nervous system. Both neuropathies can persist which can adversely affect the quality of life and the rehabilitation of cancer patients. Unfortunately, therapies that can alleviate tumor or chemotherapy-induced neuropathic pain that do not interfere with tumor growth do not currently exist. The main goal of this study was to identify a therapeutic strategy that can achieve both anti-tumor and analgesic effects. The chemotherapeutic, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons which lead to bortezomib-induce neuropathic pain. Aerobic glycolysis is also a hallmark of cancer cells, suggesting a common metabolic vulnerability. Paraneoplastic neuropathies are commonly associated with lung cancers. Hence, we used Lewis Lung Carcinoma cells (LLC1) to develop a mouse model of paraneoplastic neuropathy. We hypothesized that blocking metabolic pathways could alleviate CIPN and paraneoplastic neuropathic pain without compromising on tumor control. To test our hypothesis, we demonstrated that mice implanted with LLC1 developed significant allodynia. Treatment with bortezomib attenuated tumor growth but exacerbated the neuropathic pain. However, co-treatment with metformin, which blocks bortezomib- induced aerobic glycolysis in sensory neurons and prevents CIPN, attenuated both tumor growth and neuropathic pain. Similarly, inhibition of lactate dehydrogenase and pyruvate dehydrogenase kinase with oxamate and dichloroacetate respectively, also reduced tumor growth and pain. These results suggest that targeting metabolic pathways is a promising strategy to improve oncologic outcomes and alleviate neuropathic pain in cancer patients.