Cargando…
Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments
Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-appr...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wolters Kluwer
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442742/ https://www.ncbi.nlm.nih.gov/pubmed/33872235 http://dx.doi.org/10.1097/j.pain.0000000000002256 |
_version_ | 1783753063084851200 |
---|---|
author | Ma, Jiacheng Goodwani, Sunil Acton, Paul J. Buggia-Prevot, Virginie Kesler, Shelli R. Jamal, Imran Mahant, Iteeben D. Liu, Zhen Mseeh, Faika Roth, Bruce L. Chakraborty, Chaitali Peng, Bo Wu, Qi Jiang, Yongying Le, Kang Soth, Michael J. Jones, Philip Kavelaars, Annemieke Ray, William J. Heijnen, Cobi J. |
author_facet | Ma, Jiacheng Goodwani, Sunil Acton, Paul J. Buggia-Prevot, Virginie Kesler, Shelli R. Jamal, Imran Mahant, Iteeben D. Liu, Zhen Mseeh, Faika Roth, Bruce L. Chakraborty, Chaitali Peng, Bo Wu, Qi Jiang, Yongying Le, Kang Soth, Michael J. Jones, Philip Kavelaars, Annemieke Ray, William J. Heijnen, Cobi J. |
author_sort | Ma, Jiacheng |
collection | PubMed |
description | Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-approved agents for the prevention or curative treatment of CIPN or CICI. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration that is localized to axons and coordinates the neuronal response to injury. We developed a novel brain-penetrant DLK inhibitor, IACS′8287, which demonstrates potent and highly selective inhibition of DLK in vitro and in vivo. Coadministration of IACS′8287 with the platinum derivative cisplatin prevents mechanical allodynia, loss of intraepidermal nerve fibers in the hind paws, cognitive deficits, and impairments in brain connectivity in mice, all without interfering with the antitumor activity of cisplatin. The protective effects of IACS′8287 are associated with preservation of mitochondrial function in dorsal root ganglion neurons and in brain synaptosomes. In addition, RNA sequencing analysis of dorsal root ganglia reveals modulation of genes involved in neuronal activity and markers for immune cell infiltration by DLK inhibition. These data indicate that CIPN and CICI require DLK signaling in mice, and DLK inhibitors could become an attractive treatment in the clinic when coadministered with cisplatin, and potentially other chemotherapeutic agents, to prevent neurotoxicities as a result of cancer treatment. |
format | Online Article Text |
id | pubmed-8442742 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Wolters Kluwer |
record_format | MEDLINE/PubMed |
spelling | pubmed-84427422021-09-20 Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments Ma, Jiacheng Goodwani, Sunil Acton, Paul J. Buggia-Prevot, Virginie Kesler, Shelli R. Jamal, Imran Mahant, Iteeben D. Liu, Zhen Mseeh, Faika Roth, Bruce L. Chakraborty, Chaitali Peng, Bo Wu, Qi Jiang, Yongying Le, Kang Soth, Michael J. Jones, Philip Kavelaars, Annemieke Ray, William J. Heijnen, Cobi J. Pain Research Paper Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-approved agents for the prevention or curative treatment of CIPN or CICI. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration that is localized to axons and coordinates the neuronal response to injury. We developed a novel brain-penetrant DLK inhibitor, IACS′8287, which demonstrates potent and highly selective inhibition of DLK in vitro and in vivo. Coadministration of IACS′8287 with the platinum derivative cisplatin prevents mechanical allodynia, loss of intraepidermal nerve fibers in the hind paws, cognitive deficits, and impairments in brain connectivity in mice, all without interfering with the antitumor activity of cisplatin. The protective effects of IACS′8287 are associated with preservation of mitochondrial function in dorsal root ganglion neurons and in brain synaptosomes. In addition, RNA sequencing analysis of dorsal root ganglia reveals modulation of genes involved in neuronal activity and markers for immune cell infiltration by DLK inhibition. These data indicate that CIPN and CICI require DLK signaling in mice, and DLK inhibitors could become an attractive treatment in the clinic when coadministered with cisplatin, and potentially other chemotherapeutic agents, to prevent neurotoxicities as a result of cancer treatment. Wolters Kluwer 2021-10 2021-04-15 /pmc/articles/PMC8442742/ /pubmed/33872235 http://dx.doi.org/10.1097/j.pain.0000000000002256 Text en Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Research Paper Ma, Jiacheng Goodwani, Sunil Acton, Paul J. Buggia-Prevot, Virginie Kesler, Shelli R. Jamal, Imran Mahant, Iteeben D. Liu, Zhen Mseeh, Faika Roth, Bruce L. Chakraborty, Chaitali Peng, Bo Wu, Qi Jiang, Yongying Le, Kang Soth, Michael J. Jones, Philip Kavelaars, Annemieke Ray, William J. Heijnen, Cobi J. Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments |
title | Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments |
title_full | Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments |
title_fullStr | Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments |
title_full_unstemmed | Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments |
title_short | Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments |
title_sort | inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442742/ https://www.ncbi.nlm.nih.gov/pubmed/33872235 http://dx.doi.org/10.1097/j.pain.0000000000002256 |
work_keys_str_mv | AT majiacheng inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT goodwanisunil inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT actonpaulj inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT buggiaprevotvirginie inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT keslershellir inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT jamalimran inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT mahantiteebend inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT liuzhen inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT mseehfaika inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT rothbrucel inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT chakrabortychaitali inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT pengbo inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT wuqi inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT jiangyongying inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT lekang inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT sothmichaelj inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT jonesphilip inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT kavelaarsannemieke inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT raywilliamj inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments AT heijnencobij inhibitionofdualleucinezipperkinasepreventschemotherapyinducedperipheralneuropathyandcognitiveimpairments |