Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib

Abstract

The proteasomal system is responsible for the turnover of damaged proteins. Because of its important functions in oncogenesis, inhibiting the proteasomal system is a promising therapeutic approach for cancer treatment. Bortezomib (BTZ) is the first proteasome inhibitor approved by FDA for clinical applications. However neuropathic side effects are dose limiting for BTZ as many other chemotherapeutic agents. Therefore second-generation proteasome inhibitors have been developed including carfilzomib (CFZ). Aim of the present work was investigating the mechanisms of peripheral neuropathy triggered by the proteasome inhibitor BTZ and comparing the pathways affected by BTZ and CFZ, respectively. Neural stem cells, isolated from the cortex of E14 mouse embryos, were treated with BTZ and CFZ and mass spectrometry was used to compare the global protein pool of treated cells. BTZ was shown to cause more severe cytoskeletal damage, which is crucial in neural cell integrity. Excessive protein carbonylation and actin filament destabilization were also detected following BTZ treatment that was lower following CFZ treatment. Our data on cytoskeletal proteins, chaperone system, and protein oxidation may explain the milder neurotoxic effects of CFZ in clinical applications.

Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect

“…Moreover, the impairment of axonal transport, which strongly depends on the MT system, is a common molecular target of the neurotoxicity of other classes of chemotherapy drugs, including BTZ 28 , cisplatin 29 and oxaliplatin 30 . Our findings are consistent with reports of a relevant role of tubulin damage in the alteration of axonal integrity and development of CIPN 2 , 7 , 9 . Furthermore, a recent article shows that blocking the motor protein kinesin-5 by co-treatment with monastrol could resolve the neurotoxicity, by alleviating morphological measures of axonal injury in C57BL/6 mice treated with BTZ 31 .…”

“…These results suggested for the first time several proteasome-independent mechanisms involved in BTZ-neurotoxicity 1 . More recently, a proteomics approach to explain the different neurotoxic effects induced by BTZ and CFZ was performed in mouse neural stem cells, evidencing higher impairment of cytoskeletal proteins, related stress response systems and protein oxidation after BTZ-treatment than CFZ 2 . In addition, the same working group extended previous results on identification of affected proteins following BTZ and CFZ treatment using LC–MS based proteomics studies in human neuronal cells.…”

Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect

“…Moreover, the impairment of axonal transport, which strongly depends on the MT system, is a common molecular target of the neurotoxicity of other classes of chemotherapy drugs, including BTZ 28 , cisplatin 29 and oxaliplatin 30 . Our findings are consistent with reports of a relevant role of tubulin damage in the alteration of axonal integrity and development of CIPN 2 , 7 , 9 . Furthermore, a recent article shows that blocking the motor protein kinesin-5 by co-treatment with monastrol could resolve the neurotoxicity, by alleviating morphological measures of axonal injury in C57BL/6 mice treated with BTZ 31 .…”

“…These results suggested for the first time several proteasome-independent mechanisms involved in BTZ-neurotoxicity 1 . More recently, a proteomics approach to explain the different neurotoxic effects induced by BTZ and CFZ was performed in mouse neural stem cells, evidencing higher impairment of cytoskeletal proteins, related stress response systems and protein oxidation after BTZ-treatment than CFZ 2 . In addition, the same working group extended previous results on identification of affected proteins following BTZ and CFZ treatment using LC–MS based proteomics studies in human neuronal cells.…”

Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells

“…Recent studies have shown that bortezomib causes acute cytoskeletal damage, which is relevant in neural cell integrity. In addition, it has been demonstrated that bortezomib causes excessive protein carbonylation and destabilization of actin filaments [17]. Our current study provided interesting results that indicate a significant dysregulation of genes in neuronal cells, which may be characteristic for bortezomib activity (Figures 2, 3 and 8).…”

Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies

“…Likewise, Karademir et al showed that bortezomib causes high protein carbonylation and ubiquitinated-protein accumulation in neural stem cells, which could explain its associated neurotoxicity. Additionally, cardiomyoblastic cells exposed 24 h to carfilzomib showed also high protein carbonylation and ubiquitinated-protein accumulation, supporting the reported cardiotoxic side effects of carfilzomib in the clinic [107]. In a rat study, carfilzomib treatment resulted in a significant increase in heart MDA content, accompanied by a decrease in cardiac glutathione (GSH) levels and CAT enzyme activity.…”

Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect

“…Moreover, the impairment of axonal transport, which strongly depends on the MT system, is a common molecular target of the neurotoxicity of other classes of chemotherapy drugs, including BTZ 28 , cisplatin 29 and oxaliplatin 30 . Our findings are consistent with reports of a relevant role of tubulin damage in the alteration of axonal integrity and development of CIPN 2 , 7 , 9 . Furthermore, a recent article shows that blocking the motor protein kinesin-5 by co-treatment with monastrol could resolve the neurotoxicity, by alleviating morphological measures of axonal injury in C57BL/6 mice treated with BTZ 31 .…”

“…These results suggested for the first time several proteasome-independent mechanisms involved in BTZ-neurotoxicity 1 . More recently, a proteomics approach to explain the different neurotoxic effects induced by BTZ and CFZ was performed in mouse neural stem cells, evidencing higher impairment of cytoskeletal proteins, related stress response systems and protein oxidation after BTZ-treatment than CFZ 2 . In addition, the same working group extended previous results on identification of affected proteins following BTZ and CFZ treatment using LC–MS based proteomics studies in human neuronal cells.…”

Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells

“…Recent studies have shown that bortezomib causes acute cytoskeletal damage, which is relevant in neural cell integrity. In addition, it has been demonstrated that bortezomib causes excessive protein carbonylation and destabilization of actin filaments [17]. Our current study provided interesting results that indicate a significant dysregulation of genes in neuronal cells, which may be characteristic for bortezomib activity (Figures 2, 3 and 8).…”

Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies

“…Likewise, Karademir et al showed that bortezomib causes high protein carbonylation and ubiquitinated-protein accumulation in neural stem cells, which could explain its associated neurotoxicity. Additionally, cardiomyoblastic cells exposed 24 h to carfilzomib showed also high protein carbonylation and ubiquitinated-protein accumulation, supporting the reported cardiotoxic side effects of carfilzomib in the clinic [107]. In a rat study, carfilzomib treatment resulted in a significant increase in heart MDA content, accompanied by a decrease in cardiac glutathione (GSH) levels and CAT enzyme activity.…”

Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect

“…Moreover, the impairment of axonal transport, which strongly depends on the MT system, is a common molecular target of the neurotoxicity of other classes of chemotherapy drugs, including BTZ 28 , cisplatin 29 and oxaliplatin 30 . Our findings are consistent with reports of a relevant role of tubulin damage in the alteration of axonal integrity and development of CIPN 2 , 7 , 9 . Furthermore, a recent article shows that blocking the motor protein kinesin-5 by co-treatment with monastrol could resolve the neurotoxicity, by alleviating morphological measures of axonal injury in C57BL/6 mice treated with BTZ 31 .…”

“…These results suggested for the first time several proteasome-independent mechanisms involved in BTZ-neurotoxicity 1 . More recently, a proteomics approach to explain the different neurotoxic effects induced by BTZ and CFZ was performed in mouse neural stem cells, evidencing higher impairment of cytoskeletal proteins, related stress response systems and protein oxidation after BTZ-treatment than CFZ 2 . In addition, the same working group extended previous results on identification of affected proteins following BTZ and CFZ treatment using LC–MS based proteomics studies in human neuronal cells.…”

Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells

“…Recent studies have shown that bortezomib causes acute cytoskeletal damage, which is relevant in neural cell integrity. In addition, it has been demonstrated that bortezomib causes excessive protein carbonylation and destabilization of actin filaments [17]. Our current study provided interesting results that indicate a significant dysregulation of genes in neuronal cells, which may be characteristic for bortezomib activity (Figures 2, 3 and 8).…”

Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies

“…Likewise, Karademir et al showed that bortezomib causes high protein carbonylation and ubiquitinated-protein accumulation in neural stem cells, which could explain its associated neurotoxicity. Additionally, cardiomyoblastic cells exposed 24 h to carfilzomib showed also high protein carbonylation and ubiquitinated-protein accumulation, supporting the reported cardiotoxic side effects of carfilzomib in the clinic [107]. In a rat study, carfilzomib treatment resulted in a significant increase in heart MDA content, accompanied by a decrease in cardiac glutathione (GSH) levels and CAT enzyme activity.…”