Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect

Abstract Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting to...

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Autores principales:	A. Malacrida, S. Semperboni, A. Di Domizio, A. Palmioli, L. Broggi, C. Airoldi, C. Meregalli, G. Cavaletti, G. Nicolini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5bb52f7cbfd047d0957809e366036543
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spelling	oai:doaj.org-article:5bb52f7cbfd047d0957809e3660365432021-12-02T16:51:09ZTubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect10.1038/s41598-021-89856-32045-2322https://doaj.org/article/5bb52f7cbfd047d0957809e3660365432021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89856-3https://doaj.org/toc/2045-2322Abstract Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. We investigated possible BTZ and CFZ off-targets able to explain their different neurotoxicity profiles. In order to identify the possible PIs off-targets we used the SPILLO-PBSS software that performs a structure-based in silico screening on a proteome-wide scale. Among the top-ranked off-targets of BTZ identified by SPILLO-PBSS we focused on tubulin which, by contrast, did not turn out to be an off-target of CFZ. We tested the hypothesis that the direct interaction between BTZ and microtubules would inhibit the tubulin alfa GTPase activity, thus reducing the microtubule catastrophe and consequently furthering the microtubules polymerization. This hypothesis was validated in a cell-free model, since BTZ (but not CFZ) reduces the concentration of the free phosphate released during GTP hydrolysis. Moreover, NMR binding studies clearly demonstrated that BTZ, unlike CFZ, is able to interact with both tubulin dimers and polymerized form. Our data suggest that different BTZ and CFZ neurotoxicity profiles are independent from their proteasome inhibition, as demonstrated in adult mice dorsal root ganglia primary sensory neurons, and, first, we demonstrate, in a cell free model, that BTZ is able to directly bind and perturb microtubules.A. MalacridaS. SemperboniA. Di DomizioA. PalmioliL. BroggiC. AiroldiC. MeregalliG. CavalettiG. NicoliniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q A. Malacrida S. Semperboni A. Di Domizio A. Palmioli L. Broggi C. Airoldi C. Meregalli G. Cavaletti G. Nicolini Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect
description	Abstract Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. We investigated possible BTZ and CFZ off-targets able to explain their different neurotoxicity profiles. In order to identify the possible PIs off-targets we used the SPILLO-PBSS software that performs a structure-based in silico screening on a proteome-wide scale. Among the top-ranked off-targets of BTZ identified by SPILLO-PBSS we focused on tubulin which, by contrast, did not turn out to be an off-target of CFZ. We tested the hypothesis that the direct interaction between BTZ and microtubules would inhibit the tubulin alfa GTPase activity, thus reducing the microtubule catastrophe and consequently furthering the microtubules polymerization. This hypothesis was validated in a cell-free model, since BTZ (but not CFZ) reduces the concentration of the free phosphate released during GTP hydrolysis. Moreover, NMR binding studies clearly demonstrated that BTZ, unlike CFZ, is able to interact with both tubulin dimers and polymerized form. Our data suggest that different BTZ and CFZ neurotoxicity profiles are independent from their proteasome inhibition, as demonstrated in adult mice dorsal root ganglia primary sensory neurons, and, first, we demonstrate, in a cell free model, that BTZ is able to directly bind and perturb microtubules.
format	article
author	A. Malacrida S. Semperboni A. Di Domizio A. Palmioli L. Broggi C. Airoldi C. Meregalli G. Cavaletti G. Nicolini
author_facet	A. Malacrida S. Semperboni A. Di Domizio A. Palmioli L. Broggi C. Airoldi C. Meregalli G. Cavaletti G. Nicolini
author_sort	A. Malacrida
title	Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect
title_short	Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect
title_full	Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect
title_fullStr	Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect
title_full_unstemmed	Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect
title_sort	tubulin binding potentially clears up bortezomib and carfilzomib differential neurotoxic effect
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5bb52f7cbfd047d0957809e366036543
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Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect

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