Oxaliplatin is a cornerstone chemotherapeutic used in the treatment of colorectal cancer, the third leading cause of death in Western countries. Most side effects of this platinum-containing drug are adequately managed in the clinic, although acute and long-term neurotoxicity still severely compromises the quality of life of patients treated with oxaliplatin. We have previously demonstrated that therapeutically relevant concentrations/doses of oxaliplatin lead to a reduction in intracellular pH in mouse dorsal root ganglion (DRG) neurons in vitro and in vivo and that this alteration sensitizes TRPA1 and TRPV1 channels, which most likely mediate the allodynia associated with treatment. In this study, we show that oxaliplatin leads to a reduction of intracellular pH by forming adducts with neuronal haemoglobin, which acts in this setting as a proton buffer. Furthermore, we show that FDA-approved drugs that inhibit carbonic anhydrase (an enzyme that is linked to haemoglobin in intracellular pH homeostasis), ie, topiramate and acetazolamide, revert (1) oxaliplatin-induced cytosolic acidification and TRPA1 and TRPV1 modulation in DRG neurons in culture, (2) oxaliplatin-induced cytosolic acidification of DRG of treated animals, and (3) oxaliplatin-induced acute cold allodynia in mice while not affecting OHP-induced cytotoxicity on cancer cells. Our data would therefore suggest that reversal of oxaliplatin-induced cytosolic acidification is a viable strategy to minimize acute oxaliplatin-induced symptoms

Potenzieri, A., Riva, B., Rigolio, R., Chiorazzi, A., Pozzi, E., Ballarini, E., et al. (2020). Oxaliplatin-induced neuropathy occurs through impairment of haemoglobin proton buffering and is reversed by carbonic anhydrase inhibitors. PAIN, 161(2), 405-415 [10.1097/j.pain.0000000000001722].

Oxaliplatin-induced neuropathy occurs through impairment of haemoglobin proton buffering and is reversed by carbonic anhydrase inhibitors

Rigolio R.;Chiorazzi A.;Pozzi E.;Ballarini E.;Cavaletti G.;
2020

Abstract

Oxaliplatin is a cornerstone chemotherapeutic used in the treatment of colorectal cancer, the third leading cause of death in Western countries. Most side effects of this platinum-containing drug are adequately managed in the clinic, although acute and long-term neurotoxicity still severely compromises the quality of life of patients treated with oxaliplatin. We have previously demonstrated that therapeutically relevant concentrations/doses of oxaliplatin lead to a reduction in intracellular pH in mouse dorsal root ganglion (DRG) neurons in vitro and in vivo and that this alteration sensitizes TRPA1 and TRPV1 channels, which most likely mediate the allodynia associated with treatment. In this study, we show that oxaliplatin leads to a reduction of intracellular pH by forming adducts with neuronal haemoglobin, which acts in this setting as a proton buffer. Furthermore, we show that FDA-approved drugs that inhibit carbonic anhydrase (an enzyme that is linked to haemoglobin in intracellular pH homeostasis), ie, topiramate and acetazolamide, revert (1) oxaliplatin-induced cytosolic acidification and TRPA1 and TRPV1 modulation in DRG neurons in culture, (2) oxaliplatin-induced cytosolic acidification of DRG of treated animals, and (3) oxaliplatin-induced acute cold allodynia in mice while not affecting OHP-induced cytotoxicity on cancer cells. Our data would therefore suggest that reversal of oxaliplatin-induced cytosolic acidification is a viable strategy to minimize acute oxaliplatin-induced symptoms
Articolo in rivista - Articolo scientifico
oxaliplatin, carbonic anhydrase, neurotoxicity, peripheral nerve, DRG
English
2020
161
2
405
415
none
Potenzieri, A., Riva, B., Rigolio, R., Chiorazzi, A., Pozzi, E., Ballarini, E., et al. (2020). Oxaliplatin-induced neuropathy occurs through impairment of haemoglobin proton buffering and is reversed by carbonic anhydrase inhibitors. PAIN, 161(2), 405-415 [10.1097/j.pain.0000000000001722].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/261613
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