Cargando…

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide...

Descripción completa

Detalles Bibliográficos
Autores principales: Khanim, F L, Merrick, B A M E, Giles, H V, Jankute, M, Jackson, J B, Giles, L J, Birtwistle, J, Bunce, C M, Drayson, M T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255256/
https://www.ncbi.nlm.nih.gov/pubmed/22829072
http://dx.doi.org/10.1038/bcj.2011.38
_version_ 1782220969287352320
author Khanim, F L
Merrick, B A M E
Giles, H V
Jankute, M
Jackson, J B
Giles, L J
Birtwistle, J
Bunce, C M
Drayson, M T
author_facet Khanim, F L
Merrick, B A M E
Giles, H V
Jankute, M
Jackson, J B
Giles, L J
Birtwistle, J
Bunce, C M
Drayson, M T
author_sort Khanim, F L
collection PubMed
description Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity.
format Online
Article
Text
id pubmed-3255256
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-32552562012-01-11 Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production Khanim, F L Merrick, B A M E Giles, H V Jankute, M Jackson, J B Giles, L J Birtwistle, J Bunce, C M Drayson, M T Blood Cancer J Original Article Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity. Nature Publishing Group 2011-10 2011-10-21 /pmc/articles/PMC3255256/ /pubmed/22829072 http://dx.doi.org/10.1038/bcj.2011.38 Text en Copyright © 2011 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Khanim, F L
Merrick, B A M E
Giles, H V
Jankute, M
Jackson, J B
Giles, L J
Birtwistle, J
Bunce, C M
Drayson, M T
Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production
title Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production
title_full Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production
title_fullStr Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production
title_full_unstemmed Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production
title_short Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production
title_sort redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255256/
https://www.ncbi.nlm.nih.gov/pubmed/22829072
http://dx.doi.org/10.1038/bcj.2011.38
work_keys_str_mv AT khanimfl redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction
AT merrickbame redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction
AT gileshv redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction
AT jankutem redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction
AT jacksonjb redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction
AT gileslj redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction
AT birtwistlej redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction
AT buncecm redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction
AT draysonmt redeploymentbaseddrugscreeningidentifiestheantihelminthicniclosamideasantimyelomatherapythatalsoreducesfreelightchainproduction