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Vincristine (VCR) abrogates aggresome formation and in a combination treatment with bortezomib augments the exocytosis of endogenous misfolded proteins. (A) Peripheral myelin protein 22 (PMP22) is homogeneously distributed throughout the cytoplasm of RT4-D6P2T cells before treatment with bortezomib (left panel). After treatment with bortezomib (Bzb), PMP22 appears to undergo retrograde transport towards the MTOC where it forms perinuclear aggresomes (arrows, middle panel, green signals) and colocalises with γ-tubulin (arrows, middle panel, red signals). A merged image of both fluorophores is shown in the far right panel (yellow signal). (B) Following pretreatment with VCR, a microtubule depolymerisation agent, PMP22 signals are evident at multiple sites in a granular pattern of aggregates throughout the cytoplasm, most notably in the perikaryon. Cells pretreated with (C) suberoylanilide hydroxamic acid (SAHA), a known histone deacetylase inhibitor (HDACi), or (D) clonazepam (CZP), an anticonvulsant, and (E) 17-allylamino-17-demethoxy-geldanamycin (17-AAG), a HSP90 inhibitor, fail to form aggresomes, but instead form rounded structures outside of the cell (arrowheads), which are smaller than the perinuclear aggresomes. (F) Pretreatment with valproic acid (VPA) causes the appearance of similar rounded structures outside of the cells (arrowheads) in addition to juxtanuclear aggresomes (arrows).
Source publication
The proteasome inhibitor bortezomib has improved the survival of patients with multiple myeloma but bortezomib-induced peripheral neuropathy (BiPN) has emerged as a serious potential complication of this therapy. Animal studies suggest that bortezomib predominantly causes pathological changes in Schwann cells. A tractable system to evaluate combina...
Citations
... Autophagy is suppressed by phosphorylating ULK1 through mTOR. The HDAC inhibitor Vorinostat triggers autophagy in tumor cells through the production of ROS [164] . The combination of Suberoylanilide hydroxamic acid (Vorinostat), 17-allylamino-17-demethoxy-geldanamycin (Tanespimycin), and Clonazepam overcame the complication of peripheral neuropathy by inducing autophagy via HSP70 or LAMP-2A [165] . ...
Multiple myeloma (MM) is a type of hematological cancer that occurs when B cells become malignant. Various drugs such as proteasome inhibitors, immunomodulators, and compounds that cause DNA damage can be used in the treatment of MM. Autophagy, a type 2 cell death mechanism, plays a crucial role in determining the fate of B cells, either promoting their survival or inducing cell death. Therefore, autophagy can either facilitate the progression or hinder the treatment of MM disease. In this review, autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response (UPR), bone marrow microenvironment (BMME), drug resistance, hypoxia, DNA repair and transcriptional regulation, and apoptosis. The genes that are effective in each mechanism and research efforts on this subject were discussed in detail. Signaling pathways targeted by new drugs to benefit from autophagy in MM disease were covered. The efficacy of drugs that regulate autophagy in MM was examined, and clinical trials on this subject were included. Consequently, among the autophagy mechanisms that are effective in MM, the most suitable ones to be used in the treatment were expressed. The importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was emphasized. Ultimately, this review aims to provide a comprehensive overview of MM disease, encompassing autophagy mechanisms, drugs, clinical studies, and further studies.
... 50 nM BTZ for up to 18 h). 11,20) According to previous findings on BTZ pharmacokinetics, the blood concentration of BTZ reaches C max at around 200 nM within 30 min after injection. 17) In that regard, a concentration of 50-100 nM would suffice for analyzing acutely elicited adverse effects; however, the concentration then drops sharply to ≤5 nM within 3 h. ...
... In BTZ-treated SCs, the aggregation of misfolded protein is considered to trigger cellular metabolic disorder and secondarily induce endoplasmic reticulum stress. 11,20) which is associated with our data showing that BTZ-induced increase in mRNA expression of Dtim3, an endoplasmic reticulum stress marker. In an earlier report, cultured primary SCs that treated with a high dose of BTZ exhibited decreased numbers of myelin-related proteins. ...
... Demyelination in BTZ-treated rodent models has been firmly validated, whereas the irretrievable loss of SCs or only temporary dysfunction of myelination have yet to be demonstrated. 10,11,20) Our current study provides an alternative possibility to explore. In present study, BTZ increased MBP levels but decreased Mbp RNA levels in SCs, implying that abnormally accumulated myelin protein may become an autoimmune antigen that recruits immune cells to infiltrate, which has been reported in an in vivo model. ...
Peripheral neuropathy is one of the major adverse effects that limit the clinical application of bortezomib (BTZ). However, the underlying mechanisms of BTZ-induced peripheral neuropathy (BIPN) remain elusive. To examine cell types potentially involved in the development of BIPN, we used four purified cultures of cells of the peripheral nervous system: Schwann cells (SCs), satellite glial cells (SGCs), macrophages, and dorsal root ganglion (DRG) neurons. Administration of a low BTZ concentration (5 nM; similar to concentrations in clinical use) caused dedifferentiation of cultured SCs, returning mature SCs to an immature state. In cultured SGCs, BTZ increased glial fibrillary acidic protein (GFAP) levels without inducing the release of inflammatory cytokines or chemokines. In macrophages, BTZ caused little inflammatory response. Finally, in DRG neurons, BTZ strongly suppressed the expression levels of sensor and transducer ion channels without affecting cell morphology. Taken together, low concentrations of BTZ can cause SC dedifferentiation (i.e., demyelination), increased GFAP level in SGC, and decreased expression levels of sensor and transducer ion channels in DRG neurons (i.e., numbness feeling). Thus, we have reported, for the first time, specific effects of BTZ on peripheral nervous system cells, thereby contributing to a better understanding of the initiating mechanism of BIPN.
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... Autophagy can regulate the extent of neurotoxic brain injury caused by anti-tumor drugs. For example, the peripheral nervous system damage caused by bortezomib can also enhance the level of autophagy [81]. Bortezomib is a proteasome inhibitor that prevents the degradation of misfolded proteins in the nervous system, resulting in severe neurotoxicity. ...
Opinion statement
Autophagy is a physiological process that occurs in normal tissues. Under external environmental pressure or internal environmental changes, cells can digest part of their contents through autophagy in order to reduce metabolic pressure or remove damaged organelles. In cancer, autophagy plays a paradoxical role, acting as a tumor suppressor—by removing damaged organelles and inhibiting inflammation or by promoting genome stability and the tumor-adaptive responses—as a pro-survival mechanism to protect cells from stress. In this article, we review the autophagy-dependent mechanisms driving childhood central nervous system tumor cell death, malignancy invasion, chemosensitivity, and radiosensitivity. Autophagy inhibitors and inducers have been developed, and encouraging results have been achieved in autophagy modulation, suggesting that these might be potential therapeutic agents for the treatment of pediatric central nervous system (CNS) tumors.
... Although bortezomib treatment benefits MM, the bortezomib-induced peripheral neuropathy (BiPN) in MM patients is a novel issue. In another study, some candidate drugs were combined and treated with bortezomib to reduce BiPN [91]. They discovered that CMA could be a potential mechanism of aggregation clearance in Schwann cells in BiPN. ...
... The combined bortezomib treatment with suberoylanilide hydroxamic acid (SAHA), 17-allylamino-17-demethoxy-geldanamycin (17-AAG), or clonazepam (CZP) indued colocalization of LAMP2A, HSC70, and aggregated proteins in a rounded structure. In a phase I trial of the bortezomib combined treatment with SAHA for MM patients, the PN symptom was rarely reported [91]. PN has been identified in PD with the phosphorylated α-synuclein accumulation feature [110]. ...
Chaperone-mediated autophagy (CMA) is a protein degradation mechanism through lysosomes. By targeting the KFERQ motif of the substrate, CMA is responsible for the degradation of about 30% of cytosolic proteins, including a series of proteins associated with neurodegenerative diseases (NDs). The fact that decreased activity of CMA is observed in NDs, and ND-associated mutant proteins, including alpha-synuclein and Tau, directly impair CMA activity reveals a possible vicious cycle of CMA impairment and pathogenic protein accumulation in ND development. Given the intrinsic connection between CMA dysfunction and ND, enhancement of CMA has been regarded as a strategy to counteract ND. Indeed, genetic and pharmacological approaches to modulate CMA have been shown to promote the degradation of ND-associated proteins and alleviate ND phenotypes in multiple ND models. This review summarizes the current knowledge on the mechanism of CMA with a focus on its relationship with NDs and discusses the therapeutic potential of CMA modulation for ND.
... The effect of clonazepam was explored on BIPN, and the formation of aggregates was reported to be one of the reasons [52]. It was suggested that drugs eliminating these aggregates via chaperone-mediated autophagy could be useful. ...
Aim
To establish the role of inflammation in bortezomib induced peripheral neuropathy (BIPN).
Background
Peripheral neuropathy is the dose-limiting toxicity of bortezomib which can lead to discontinuation of the treatment. There are multiple mechanisms involved in the disposition of BIPN. However, the role of inflammatory mediators is still under investigation. The complete understanding of inflammatory markers in relation to BIPN can lead to the development of effective therapy for prophylaxis and treatment of peripheral neuropathy.
Objective
Based on the available data, postulate the role of inflammatory mediators in the development of peripheral neuropathy due to bortezomib.
Method
The “Pubmed” and “Google Scholar” were used as the search engines with terms like “peripheral neuropathy”, “bortezomib induced peripheral neuropathy” and “inflammation”. Original research, case reports and review articles were considered.
Results
Bortezomib use is associated with the development of peripheral neuropathy. This effect is due to the damage to Schwann cells and dorsal root ganglion neurons; mitochondrial damage; increased ion channel susceptibility; and higher infiltration of macrophages in the spinal cord. All these factors collectively increase the secretion of inflammatory mediators and lead to the development of neuropathic pain.
Conclusion
Targeting inflammatory mediators may be helpful in the treatment of bortezomib-induced peripheral neuropathy.
... A previous study demonstrated that recombinant adeno-associated virus augmenting the LAMP2A level protected dopaminergic neurons in the substantia nigra from α-synuclein-induced degeneration [117]. In addition, it has also been reported that various compounds, such as geldanamycin [118], 6-aminonicotinamide [119], glucose-6-phosphate dehydrogenase inhibitor [119], silymarin [120], chronic caffeine [121], manganese [122], trehalose [123], b-asarone [124], and other compounds extracted from natural medicinal plants [125], or even combination treatments with bortezomib and suberoylanilide hydroxamic acid (SAHA) [126], can increase LAMP2A levels and activate the CMA pathway. However, these compounds are not able to specifically regulate the CMA pathway and have many other targets. ...
Autophagy is an important function that mediates the degradation of intracellular proteins and organelles. Chaperone-mediated autophagy (CMA) degrades selected proteins and has a crucial role in cellular proteostasis under various physiological and pathological conditions. CMA dysfunction leads to the accumulation of toxic protein aggregates in the central nervous system (CNS) and is involved in the pathogenic process of neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. Previous studies have suggested that the activation of CMA to degrade aberrant proteins can provide a neuroprotective effect in the CNS. Recent studies have shown that CMA activity is upregulated in damaged neural tissue following acute neurological insults, such as cerebral infarction, traumatic brain injury, and spinal cord injury. It has been also suggested that various protein degradation mechanisms are important for removing toxic aberrant proteins associated with secondary damage after acute neurological insults in the CNS. Therefore, enhancing the CMA pathway may induce neuroprotective effects not only in neurogenerative diseases but also in acute neurological insults. We herein review current knowledge concerning the biological mechanisms involved in CMA and highlight the role of CMA in neurodegenerative diseases and acute neurological insults. We also discuss the possibility of developing CMA-targeted therapeutic strategies for effective treatments.
... Because the carriers of HLA-B*40:06 showed a high odds ratio A possible mechanism for the association of a specific HLA with BiPN development is hypothesized to be the alteration of inward systematic inflammatory processes, as reported previously. [19][20][21] According to these reports, Btz treatment could induce changes in the expression of genes and production of inflammatory cytokines in immunological cells. Therefore, it can be speculated that lymphocytes of any type with a specific HLA are susceptible to Btz-induced alteration of inflammatory processes, leading to the frequent onset or worsening of BiPN through a systematic inflammatory reaction. ...
Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients exhibit sub-optimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz-related toxicities and response to treatment. Eighty-two transplant-ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response (CR) was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA-B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA-B*40:06 and -DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA-DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). CR was achieved in patients carrying HLA-DQB1*03:02, -DQB1*05:01, and -DRB1*01:01-class II alleles. HLA genotyping may help predict Btz-induced toxicity and treatment efficacy in patients with MM, although this needs further validation.
... One such protein is peripheral myelin promoter 22 (PMP 22) that has been reported to be mis-expressed and aggregated within SCs especially in type 1 CMT (van Paassen et al., 2019). Treatment of SCs with rapamycin (Rangaraju and Notterpek, 2011), suberoylanilide hydroxamic acid (SAHA), 17-allylamino-17-demethoxy-geldanamycin (17-AAG) or clonazepam (Watanabe et al., 2010) facilitated autophagy, resulting in breakdown and disposal of these aggregated unfolded proteins in vitro. However, in vivo studies in a mouse model of CMT1A linked with PMP22 aggregation showed that although rapamycin promoted peripheral nerve myelination it did not improve the overall neuromuscular function in these animals (Nicks et al., 2014). ...
The central nervous system (CNS) has very limited capacity to regenerate after traumatic injury or disease. In contrast, the peripheral nervous system (PNS) has far greater capacity for regeneration. This difference can be partly attributed to variances in glial-mediated functions, such as axon guidance, structural support, secretion of growth factors and phagocytic activity. Due to their growth-promoting characteristic, transplantation of PNS glia has been trialed for neural repair. After peripheral nerve injuries, Schwann cells (SCs, the main PNS glia) phagocytose myelin debris and attract macrophages to the injury site to aid in debris clearance. One peripheral nerve, the olfactory nerve, is unique in that it continuously regenerates throughout life. The olfactory nerve glia, olfactory ensheathing cells (OECs), are the primary phagocytes within this nerve, continuously clearing axonal debris arising from the normal regeneration of the nerve and after injury. In contrast to SCs, OECs do not appear to attract macrophages. SCs and OECs also respond to and phagocytose bacteria, a function likely critical for tackling microbial invasion of the CNS via peripheral nerves. However, phagocytosis is not always effective; inflammation, aging and/or genetic factors may contribute to compromised phagocytic activity. Here, we highlight the diverse roles of SCs and OECs with the focus on their phagocytic activity under physiological and pathological conditions. We also explore why understanding the contribution of peripheral glia phagocytosis may provide us with translational strategies for achieving axonal regeneration of the injured nervous system and potentially for the treatment of certain neurological diseases.
... Although to date, there are not specific modulators of CMA, several compounds have demonstrated to alter key effectors of this process. On the one hand, compounds such as geldanamycin (Pedrozo et al., 2013), 6-aminonicotinamide (Finn et al., 2005), glucose-6-phosphate dehydrogenase inhibitor (Finn et al., 2005), silymarin (Tripathi et al., 2020), chronic caffeine (Luan et al., 2018), manganese (Yan et al., 2019), trehalose (Rusmini et al., 2019), β-Asarone (Huang et al., 2016) and other compounds extracted from natural medicinal plants (Wu et al., 2019a), or even combination treatments with bortezomib and suberoylanilide hydroxamic acid (SAHA; Watanabe et al., 2010) increase LAMP2A levels and thus, CMA activity. This therapeutic strategy could be beneficial for neurodegenerative diseases, where, as mentioned before, CMA activity is downregulated. ...
Brain aging is characterized by a time-dependent decline of tissue integrity and function, and it is a major risk for neurodegenerative diseases and brain cancer. Chaperone-mediated autophagy (CMA) is a selective form of autophagy specialized in protein degradation, which is based on the individual translocation of a cargo protein through the lysosomal membrane. Regulation of processes such as proteostasis, cellular energetics, or immune system activity has been associated with CMA, indicating its pivotal role in tissue homeostasis. Since first studies associating Parkinson’s disease (PD) to CMA dysfunction, increasing evidence points out that CMA is altered in both physiological and pathological brain aging. In this review article, we summarize the current knowledge regarding the impact of CMA during aging in brain physiopathology, highlighting the role of CMA in neurodegenerative diseases and glioblastoma, the most common and aggressive brain tumor in adults.
... In addition to synergistic anti-tumor effect, SAHA/bortezomib could potentially reduce the side effects of either drug alone. For instance, SAHA can reduce bortezomib-induced peripheral neuropathy by inducing autophagy of Schwann cells [49]. The administration of SAHA/bortezomib could also potentially create a room for the reduction of the dosage of chemotherapy for the patients. ...
Combination of suberoylanilide hydroxamic acid (SAHA) and bortezomib (SAHA/ bortezomib) was shown to synergistically induce killing of lymphoblastoid cell lines (LCL) and Burkitt lymphoma (BL) of type III or Wp-restricted latency, both of which express EBNA3A, -3B and -3C proteins. We hypothesize that SAHA/bortezomib can counteract the survival functions conferred by the EBNA3 proteins. We tested the effect of SAHA/bortezomib on the survival of BL cell lines containing EBNA3A, -3B or -3C knockout EBV with or without the respective revertant EBNA3 genes. Isobologram analysis showed that SAHA/bortezomib induced significantly greater synergistic killing of EBNA3C-revertant cells when compared with EBNA3C-knockout cells. Such differential response was not observed in either EBNA3A or -3B revertant versus their knockout pairs. Interestingly, EBNA3C-knockout cells showed significant G2/M arrest whilst EBNA3C-revertant cells and LCLs escaped G2/M arrest induced by SAHA/bortezomib and became more susceptible to the induction of apoptosis. In parallel, SAHA/bortezomib induced stronger expression of p21WAF1 but weaker expression of p-cdc25c, an M-phase inducer phosphatase, in EBNA3C-expressing cells when compared with EBNA3C-knockout cells. SAHA/bortezomib also induced greater growth suppression of EBNA3C-expressing xenografts (EBNA3C-revertant and LCL) than that of EBNA3C-knockout xenografts in SCID mice. In conclusion, our data showed that SAHA/bortezomib could synergistically induce killing of BL and LCL through counteracting the survival functions of EBNA3C, providing a strong basis for clinical testing of this drug combination in patients with EBV-associated lymphoproliferative diseases.
