1. Introduction
Multiple myeloma (MM) is a neoplastic disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow, monoclonal protein in the blood and/or urine, and evidence of specific end-organ damage including hypercalcemia, renal failure, anemia, and osteolytic bone lesions [ 1 , 2 ]. The disease is almost always preceded by an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS), with or without an identified intervening stage of smoldering multiple myeloma (SMM) [ 3 , 4 ].
MM is the second most common hematological malignancy in adults and accounts for about 1.8% of all cancers and 10% of all blood ones in the United States with an annual incidence of 7.0 per 100,000 [ 4 ]. It affects mainly the older population with a median age of patients at diagnosis of 69 years, is more common in men and among people of African American descent [ 5 ]. Despite the significant progress in available therapies and the improvement in the outcome of patients, MM remains an incurable disease with a 5-year relative survival rate of 53.9% [ 5 , 6 , 7 ].
The overall approach to MM treatment has dramatically changed over the last two decades. New classes of drugs have been added to the traditional armamentarium (corticosteroids, alkylating agents, and anthracyclines), and, along with high-dose chemotherapy followed by autologous hemopoietic stem cell transplantation, have led to a longer-lasting clinical response in these patients. Novel agents include proteasome inhibitors, immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide), histone deacetylase inhibitors (panobinostat), monoclonal antibodies directed against CD38 (daratumumab and isatuximab) or signaling lymphocytic activation molecule F7 (SLAMF7, elotuzumab), and nuclear export inhibitors (selinexor) [ 8 , 9 ]. Currently, MM therapy is based on regimens that combine agents having different mechanisms of action.
Proteasome inhibitors (PIs) have been proved to be effective in MM patients and include the first-in-class PI bortezomib, the second-generation inhibitor carfilzomib, and ixazomib, the first oral PI [ 10 ]. These drugs target the 26S proteasome, a multi-subunit ATP-dependent enzymatic complex of the ubiquitin-proteasome system (UPS), the major protein degradation pathway in eukaryotic cells [ 10 ]. The proteasome is made up of a barrel-shaped core particle consisting of four stacked heptameric rings, referred to as the 20S proteasome, and two 19S regulatory particles at the extremities [ 10 ]. Proteasome substrates include misfolded, damaged, or mutant proteins and short-lived regulatory proteins that need to be removed for proper cellular function [ 10 ]. The accumulation of aberrantly folded proteins in the endoplasmic reticulum (ER) lumen can affect ER homeostasis and lead to a condition referred to as ER stress [ 10 ]. One pathway of relieving ER stress is the ER-associated degradation (ERAD) by which unfolded/misfolded proteins undergo retrotranslocation to the cytosol and are degraded by UPS [ 11 , 12 ]. By inhibiting the 26S proteasome, PIs halt ERAD and cause protein overload within the ER [ 11 , 12 ]. MM cells, because of their high protein turnover due to immunoglobulin overproduction, are particularly susceptible to proteasome inhibition [ 13 ]. Other proven mechanisms of anti-myeloma activity of PIs include the induction of oxidative stress due to excessive production of reactive oxygen species, which further exacerbates protein misfolding but also damages DNA, inevitably leading to cell death [ 14 ].
2. Bortezomib: The First-in-Class Proteasome Inhibitor
The introduction of bortezomib (also known as PS 341 and Velcade ™ ), approved by the US Food and Drug Administration (FDA) in 2003, represented a breakthrough in the treatment of MM. The drug is currently indicated for both newly diagnosed and relapsed and/or refractory forms of MM [ 15 , 16 ] and can be used in combination with other agents in stem cell-eligible patients, both in induction and in consolidation or maintenance therapy, as well as in patients not eligible for stem cell transplantation [ 8 , 17 ]. Bortezomib is a reversible boronic acid dipeptide which binds primarily the β5 subunit and, to a lesser extent, the β2 and β1 subunits of the catalytic 20S proteasome, blocking its chymotrypsin-like, trypsin-like and caspase-like activities, respectively [ 18 , 19 ]. Evidence that point mutations in the gene encoding the proteasome β5 subunit ( PSMB5 ) result in bortezomib resistance suggests that this subunit is the clinically relevant target of the drug [ 20 , 21 , 22 ].
Besides inducing ER stress in MM cells [ 23 , 24 ], bortezomib prevents the degradation of an inhibitory molecule IκB with the consequent suppression of transcription factor nuclear factor-κB (NF-κB) pathway, which regulates the expression of genes involved in cell growth and survival, cell cycle regulation, angiogenesis, inflammation, interactions between tumor cells and bone marrow stromal cells, and anti-apoptotic mechanisms [ 25 ]. Other proposed mechanisms of cellular toxicity induced by bortezomib are the direct induction of caspase-mediated apoptosis via the activation of the c-Jun NH2-terminal kinase (JNK) pathway and the phosphorylation of p53, and the cell-cycle G1 arrest via increased levels of cyclin-dependent kinase inhibitors p27 and p21 [ 26 , 27 ] ( Figure 1 ).
Despite being among the most widely used and highly effective treatment options for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with a negative impact on the quality of life and outcome of the patients ( Figure 2 ). The drug is available for intravenous injection or subcutaneous use [ 28 ]. Based on data from the multicenter phase II open-label, single-arm (SUMMIT) trial, which led to the FDA approval of the drug, the most frequently reported all-grade side effects were asthenic conditions including fatigue and weakness (52%), nausea (55%), diarrhea (44%), thrombocytopenia (40%), peripheral neuropathy (31%), vomiting (27%), anorexia (25%), pyrexia (22%) and anemia (21%) [ 29 ]. The major grade 3 adverse reactions included thrombocytopenia (28%), fatigue (12%), neuropathy (12%), and neutropenia (11%), and fourteen percent of the patients experienced at least one episode of severe toxicity (grade 4), most commonly hematologic including thrombocytopenia (3%) and neutropenia (3%) [ 29 ]. The major adverse effects reported in the following APEX phase III trial were consistent in type and frequency with those previously described [ 30 ].
Among non-hematological toxicities of bortezomib in MM treated patients, peripheral neuropathy received close attention while cardiac and skeletal muscle adverse events have been little considered. This review provides a detailed overview of the neuromuscular and cardiovascular unwanted effects of bortezomib. We focus on the molecular mechanisms responsible for drug toxicity in these tissues, summarizing the key data from clinical studies and from in vivo and in vitro experimental models.
3. Peripheral Neuropathy: The Key Dose-Limiting Toxicity
Peripheral neuropathy represents one of the most common, unpredictable, and dose-limiting non-hematologic adverse events of MM treatment with bortezomib, which often requires dose modification, delay, or discontinuation of the drug. Bortezomib-induced peripheral neuropathy (BIPN) negatively affects clinical endpoints with a detrimental effect on the quality of life of patients and is associated with a significant economic impact, which adds up to the costs directly related to disease therapy [ 31 , 32 ].
BIPN is a length-dependent predominant sensory painful neuropathy with the potential involvement of both large and small nerve fibers. It is clinically characterized by paraesthesia and numbness with symmetric “glove and stocking” distribution, and by neuropathic pain, mostly affecting fingertips and toes [ 31 ]. Neurological examination reveals distal multimodal sensory loss and reduced or absent deep tendon reflexes while peripheral nerve motor impairment is usually subclinical [ 33 ]. Symptoms of autonomic dysfunction, including orthostatic hypotension, postural dizziness, syncope, diarrhea, paralytic ileus, and urinary disturbances have been reported [ 34 , 35 , 36 ] and are likely due to bortezomib toxicity of the pre- and post-ganglionic autonomic nerve fibers of the sympathetic and parasympathetic nervous system [ 34 , 37 , 38 ]. Nerve conduction studies reveal a predominantly axonal or mixed polyneuropathy, although primarily demyelinating features have been occasionally reported [ 39 , 40 , 41 , 42 , 43 ]. Needle electromyography may record neurogenic motor unit potentials with active denervation in the distal muscles of the lower extremities [ 31 ]. Usually, cerebrospinal fluid analysis is not informative [ 31 ]. In a handful of individual case series or single case reports, bortezomib was associated with prominent and progressive motor neuropathy [ 38 , 40 , 41 , 43 , 44 , 45 , 46 , 47 ]. This condition has been ascribed to an immune-mediated mechanism for the frequent finding of albumin-cytological dissociation in the cerebrospinal fluid and for the favorable response to corticosteroids, intravenous immunoglobulin, or plasma exchange [ 38 , 40 , 41 , 43 , 45 , 46 , 47 ]. Moreover, in a few patients, a vasculitis process has been observed on nerve pathological examination [ 38 , 47 ].
A retrospective analysis of 8218 MM patients included in phase 3 randomized control trials with bortezomib reported an overall incidence of peripheral neuropathy (all grades) ranging from 8.4% to 80.5% (median 37.8%) and of severe neuropathy (grades 3 and 4) ranging from 1% to 33.2% (median 8%) [ 48 ]. The incidence and the severity of the neuropathy were similar for both newly diagnosed and relapsed MM patients [ 48 , 49 ]. Due to neurotoxicity, the drug was reduced in 12% and discontinued in 5% of the patients [ 50 ].
The incidence and severity of peripheral neuropathy depend on the cumulative drug dose, the dosing schedule, and the route of administration. Neurotoxicity generally develops within the first cycles of treatment using the standard dose and schedule, and reaches a plateau after five 3-week cycles at a cumulative dose of 42 mg/m 2 in relapsed MM or after three 6-week cycles at a cumulative dose of 45 mg/m 2 in newly diagnosed MM [ 33 , 50 ]. There is no evidence of new cumulative neurotoxicity upon retreatment with bortezomib [ 51 , 52 ]. The once per week and the subcutaneous bortezomib administration are associated with a significantly lower rate of neuropathy compared to the twice per week regimen and the intravenous route, without efficacy reduction [ 49 , 53 , 54 , 55 ]. Despite its frequency and severity, BIPN presents a potentially favorable outcome. Dose reduction, modification in the route or schedule of administration, and ultimately withdrawal of therapy can improve and sometimes resolve the neuropathy [ 56 , 57 ]. The median time to recovery is approximately three months [ 49 , 58 , 59 ]. However, neurotoxicity can be an adverse event that continues to affect patients after treatment has ceased, and up to 30% of patients may be left with persistent neuropathy [ 33 , 60 ]. BIPN is not preventable, and the treatment approach is limited to symptomatic therapies aiming at reducing neuropathic pain [ 61 ]. Immune therapy should be considered if there is any evidence of immune-mediated neuropathy.
Possible predisposing factors for the development of the treatment-emergent neuropathy have been identified. A pre-existing neuropathy significantly increases the risk of developing BIPN [ 31 , 58 , 62 , 63 ]. The peripheral nerve involvement may depend on previous chemotherapy or can be related to the hematologic disease itself [ 49 ]. Clinical signs of peripheral neuropathy or subclinical neurophysiological abnormalities have been observed in up to 54% of patients with previously untreated symptomatic MM [ 64 ]. It is not clear if the combination of thalidomide, a neurotoxic agent, and bortezomib results in a higher susceptibility to peripheral nerve toxicity [ 48 ]. Advanced age has been proposed as a risk factor for drug-induced peripheral neuropathy [ 65 , 66 ]; however, this relationship was not confirmed in larger trials [ 50 , 58 ] suggesting that elderly patients without any significant comorbidities should be treated with the optimal bortezomib dose [ 33 ]. Diabetes and impairment of renal function have been ruled out as predisposing factors for neuropathy [ 49 ]. Intriguingly, neurotoxicity is more frequent in patients with MM than in those with other malignancies, suggesting that the disease itself may have a role in the development of neuropathy in bortezomib-treated patients [ 49 ].
The pathogenesis of BIPN is not yet fully elucidated. In vivo and in vitro experimental studies have been designed to characterize the pathological features of the neuropathy and to understand the mechanisms through which bortezomib exerts its toxicity on the peripheral nervous system.
Due to the absence of the blood-brain barrier that bortezomib cannot cross, peripheral axons and dorsal root ganglia (DRG) of primary sensory neurons are selectively vulnerable, whereas the motoneurons in the anterior horn of the spinal cord are usually spared [ 67 , 68 ]. As mentioned above, bortezomib-treated patients, in most cases, present a sensory neuropathy and neuropathic pain with impairment of afferent large myelinated Aβ fibers as well as of small, thinly myelinated Aδ and unmyelinated C fibers [ 69 , 70 ]. Severely reduced autonomic nerve fiber densities were also observed in skin biopsies of treated patients suggesting that bortezomib can cause neuropathy involving somatic as well as autonomic small fibers with a length-dependent pattern [ 34 ].
Animal models for BIPN reproduce the findings observed in the clinical setting. Neuropathological examination of peripheral nerves from adult rats exposed to bortezomib three times per week for 8 weeks or twice per week for 4 weeks and from mice receiving bortezomib twice per week for 6 weeks documented morphological abnormalities and/or reduction of myelinated and unmyelinated fibers with possible concurrent impairment of DRG of sensory neurons and satellite cells [ 68 , 71 , 72 , 73 , 74 ]. Pathological changes in sensory nerves consisted of vacuolization and disorganization of fiber axoplasm [ 71 ]. Alterations of Schwann cells and myelin sheaths have also been described in both rat and mice models, although bortezomib mainly induces an axonopathy without significant impairment of internodal myelin structure [ 75 , 76 , 77 ]. As already mentioned, in rare cases, bortezomib can also induce neuropathy with predominant demyelinating features based on electrodiagnostic and histopathological findings [ 39 , 40 , 41 , 47 ].
Different hypotheses have been raised on the molecular mechanisms underlying these alterations. It has been suggested that mitochondria are one of the main targets of bortezomib in the peripheral nervous system. In the rat model of BIPN, swollen and enlarged mitochondria were observed in axons, Schwann cells, DRG satellite cells, and occasionally in DRG neurons, associated with a dysfunction in mitochondrial respiration with reduced complex I and II enzyme activities and ATP production [ 76 , 78 , 79 ]. Impaired mitochondrial function can induce the formation of reactive oxygen species and, as in MM cells [ 80 ], a dysregulation of intracellular Ca2+ homeostasis, both mechanisms being potentially neurotoxic [ 81 ]. Moreover, reduced ATP production could impair the function of the Na+-K+-ATPase-dependent pump with early negative effects on axonal membrane excitability, thus contributing to the neuropathic pain [ 82 ]. Despite the mechanisms leading to mitochondrial defects remain unknown, their dysfunction is considered an indirect effect of cytosolic proteasome inhibition rather than an off-target effect of bortezomib [ 78 , 79 ]. The “mitotoxicity hypothesis” has been proposed also for other chemotherapeutic agents, such as taxanes and platinum agents [ 83 , 84 ].
It has been shown that some drugs act on microtubule depolymerization and polymerization with the consequent disruption of processes necessary for cell survival, including intracellular transport, cell motility, maintenance of cell structure, and mitosis [ 85 ]. In vitro studies showed impaired axonal growth and axonal degeneration in neonatal and adult primary neuron cultures treated with MG132 and lactacystin, two other 26S proteasome inhibitors [ 86 , 87 ]. Bortezomib has been demonstrated to induce increased tubulin polymerization and stabilization of microtubules in neuronal cell lines as well as in rat embryonic and adult DRG neurons [ 88 , 89 ]. The mechanism promoting tubulin polymerization does not derive from a direct microtubule-binding as occurs for paclitaxel [ 85 ], but it is probably due to a selectively increased level of MAP2, a microtubule-associated protein [ 88 ] as a result of proteasome inhibition. The altered microtubule dynamics result in decreased neurite elongation and impaired axonal transport of mitochondria in mice and rat DRG neuronal cultures, respectively [ 90 , 91 ]. In addition, bortezomib can affect another major component of the cytoskeleton, the actin filaments, as observed in mouse neural stem cells [ 92 ].
Besides the effects on mitochondria and cytoskeleton, bortezomib acts at the nuclear level in primary sensory neurons, without affecting their survival [ 67 , 93 ]. In DRG neurons of adult Sprague-Dawley rats treated with low doses of bortezomib, nuclei were displaced in an eccentric position and resulted in irregular shape and altered polarity [ 93 ]. Ultrastructural analysis of DRG neurons documented a partial chromatolysis with dissolution of Nissl Bodies and retention of polyadenylated RNAs in nuclear granules, suggesting that bortezomib could interfere with mRNA processing, thus causing impairment of protein synthesis [ 67 ]. In support of this, reduced expression of the brain-derived neurotrophic factor (BDNF), a neuronal growth factor that is crucial for neuronal survival and repair, was observed in dysfunctional neurons [ 93 ].
Recently, a dysregulation of the sphingolipid metabolism, which may contribute to the development of neuropathic pain was demonstrated in the dorsal horn of the spinal cord from rats exposed to bortezomib [ 94 ]. These findings highlight that bortezomib affects different intracellular processes.
Several clinical and histopathological data suggest that also inflammation might be a relevant factor in the onset and course of BIPN [ 38 , 40 , 47 ]. A small-sized multicentre phase II trial reported a shift in the T helper type 1 (Th1)/ T helper type 2 (Th2) cytokine balance towards Th2 dominance with elevated levels of interleukin-6 (IL-6) in the peripheral blood of patients who developed a painful neuropathy during treatment with bortezomib [ 95 ]. The role of immunity in bortezomib-induced neurotoxicity, however, remains controversial since mice immunocompromised by X-ray irradiation before bortezomib treatment displayed the same peripheral neuropathy of immunocompetent mice [ 72 ]. Conversely, in animal models of bortezomib-induced neuropathy, the increased expression of TNF-α, a proinflammatory cytokine associated with the development of neuropathic pain [ 96 , 97 , 98 , 99 ], has been observed in the neurons of DRG and spinal dorsal horn [ 100 , 101 , 102 ]. Blockade of TNF-α signaling prevents the loss of myelinated and unmyelinated peripheral nerve fibers [ 100 ] and can hamper the onset of neuropathic pain in animal models for this condition [ 101 , 102 , 103 , 104 ]. One of the main mechanisms of action of bortezomib in cancer cells is the inhibition of the NF- κ B pathway by blocking the proteasome degradation of its negative regulator IkB with consequently reduced production of proinflammatory cytokines including TNF-α [ 105 , 106 ]. In contrast to cancer cells, bortezomib seems to activate NF- κ B in DRG neurons of treated mice independently of the presence of its natural inhibitor, thus leading to an upregulation of proinflammatory cytokines [ 100 ]. Indeed, neuropathy is significantly less severe in mice with impaired NF- κ B activation than in wild-type animals [ 107 ].
4. Cardiovascular Toxicity: The Low Rate and Reversible Side Effect
There are ambiguous and conflicting data on the influence of bortezomib on cardiac function and its potential cardiotoxicity is still a matter of debate. This partly depends on whether the drug is used in patients with significant cardiovascular disease risk factors and on previous exposure to known cardiotoxic chemotherapeutic agents such as anthracyclines, making it difficult to determine if a single or a combination of factors cause the cardiac events [ 108 , 109 ]. However, since bortezomib has been approved to be used in the clinical setting, many reports have been published addressing its cardiovascular toxicity [ 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 ]. The cardiovascular adverse events so far associated with bortezomib treatment include heart failure, that is the most frequently reported cardiac side effect [ 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ], conduction disorders such as complete atrioventricular block [ 110 , 121 , 122 , 123 ], arrhythmias including atrial fibrillation [ 110 , 124 ], ischemic heart disease [ 125 ], pericardial effusion [ 112 , 126 ] and orthostatic hypotension [ 27 , 115 ].
A systematic review and meta-analysis of 25 prospective phase II and phase III trials evaluating bortezomib in the treatment of different malignancies including MM, lymphoma, Waldenström macroglobulinemia, non-small cell lung cancer, and ovarian cancer concluded that it does not significantly increase the risk of cardiac adverse events as compared to control medications, with an incidence of all grade and high-grade cardiotoxicity in all patients of 3.8% and 2.3% respectively [ 127 ]. The overall cardiac safety profile of bortezomib was confirmed in a later retrospective analysis of patients included in the phase 2 registration study for the US and EU regulatory approval and in all phase 3 studies that led to the US and EU regulatory approval [ 128 ]. The study showed no significant differences in the incidence of cardiovascular toxicities between bortezomib- and non-bortezomib based arms. The incidence of grade ≥3 heart failure was 1.2–4.7%, with a low incidence of grade ≥3 ischemic heart disease (0.4–2.7%), arrhythmias (0.6–4.1%), and cardiac death (0–1.4%) [ 128 ]. In a recent prospective observational study, 17% of 30 patients with relapsed MM receiving bortezomib manifested cardiovascular adverse events confirming a low rate of cardiac toxicity of this drug compared to carfilzomib [ 129 ]. Cardiac complications usually occur within the first three months of treatment and mostly in patients with multiple cardiovascular risk factors, raising the possibility of a synergistic effect [ 129 , 130 ]. Cardiovascular side effects often improve with the withdrawal of the therapy, but medication, hospitalization, and pacemaker implantation may be required [ 110 , 112 , 115 ].
In the heart, the ubiquitin-proteasome system (UPS) is important in different intracellular pathways and its dysfunction has been suggested to play a pathogenetic role in cardiac diseases including cardiomyopathies, heart failure, ischemia-reperfusion injury, and atherosclerosis [ 131 , 132 , 133 , 134 ]. In vitro studies demonstrated that bortezomib at submicromolar concentrations inhibits reversibly the chymotrypsin-like proteasomal activity also in primary neonatal rat cardiomyocytes besides cancer cells [ 135 , 136 ]. Hence, it is reasonable to suppose that the drug could induce cardiac damage.
Cardiovascular effects of bortezomib have been addressed in several in vivo studies that led to contradictory results. Left ventricular systolic and diastolic function was preserved and no distinct morphological myocardial abnormalities were detected in adult male rabbits exposed to bortezomib alone for 10 weeks [ 136 ]. Conversely, male Wistar rats treated thrice weekly with bortezomib for 3 weeks developed a reversible cardiac dysfunction with a significant decrease in left ventricular ejection fraction and showed myocardial changes with scattered enlarged and vacuolated cardiomyocytes [ 137 ]. Bortezomib treatment induced left ventricular hypertrophy in 10-week-old mice subjected to sham surgery and resulted in heart failure and premature death in animals with aortic constriction [ 138 , 139 ]. Interestingly, three-month-old female pigs exposed for 12 weeks to MLN273, a proteasome inhibitor structurally and functionally related to bortezomib [ 140 , 141 , 142 ], developed hypertrophic-restrictive cardiomyopathy with a significant increase of myocardial perivascular and interstitial fibrosis [ 143 ].
The pathogenic mechanisms potentially involved in bortezomib-induced cardiovascular toxicity remain largely to be elucidated. Myocardial cells are post-mitotic terminally differentiated cells with finely tuned metabolism and function, and limited capacity for division and proliferation. Quality control of structural and functional proteins and efficient removal of damaged cellular components play a key role in maintaining myocardial viability and regulating its functions [ 144 ]. In rat cardiomyoblast H9c2 cells, bortezomib, by inhibiting proteasomal activity, causes the accumulation of polyubiquitinated proteins which, in turn, leads to ER stress and compensatory autophagy [ 137 ]. MG262, a boronic acid-based proteasome inhibitor [ 142 ], through the activation of the calcineurin-NFAT pathway, promotes the translocation of the nuclear factor of activated T-cells (NFAT) into the nucleus in neonatal rat ventricular myocytes with significant changes in the cell morphology [ 138 ]. It has also been suggested that the inhibition of the proteasome by bortezomib in primary neonatal rat ventricular myocytes can lead to the activation of caspase-3 and caspase-7 and, consequently, to cellular apoptosis [ 135 ]. Mitochondria have been identified as another possible intracellular, and probably indirect target of cardiotoxicity because bortezomib inhibits complex V of the mitochondrial respiratory chain that results in a marked drop in ATP synthesis in the heart of treated rats and a decreased cell shortening of primary rat left ventricular myocytes [ 137 ]. Functional changes paralleled the structural alterations of the mitochondria, which became pleomorphic and enlarged containing concentric cristae and electron-dense inclusions and with a tendency to form large intermyofibrillar clusters leading to misalignment of the myofibrillar network [ 137 ]. Both the functional and morphological changes in this rat model of cardiotoxicity were reversible with full recovery after bortezomib discontinuation, suggesting that it does not induce irreversible damage of cardiomyocytes, in agreement with the improvement of heart function observed in MM patients after drug withdrawal [ 137 ]. Moreover, bortezomib-mediated mitochondrial dysfunction might be further explained by a recently described process of extraction of misfolded proteins from mitochondria, and their subsequent degradation in proteasomes altogether called mitochondria-associated degradation (MAD) [ 145 ]. Similarly to ERAD, inhibition of proteasome leads to accumulation of misfolded and damaged proteins in mitochondria resulting in their dysfunction.
It has been proposed that bortezomib-induced vascular effects could be partly responsible for its potential cardiotoxicity. Thrombotic microangiopathy has been recently described in patients treated with bortezomib, suggesting its possible direct microvascular toxicity to the endothelium [ 146 ]. In vitro studies demonstrated that bortezomib at clinically achievable concentrations exerts anti-angiogenic effects on endothelial cells derived from the bone marrow of MM patients and human umbilical vascular endothelial cells (HUVEC) [ 147 ]. Bortezomib mediates anti-angiogenesis both directly by inducing cell cycle arrest at G2 to M transition and indirectly through the down-regulation of the expression of genes involved in the angiogenic cascade, including VEGF and IL-6, with consequent growth inhibition and increased permeability of vascular endothelial cells [ 147 , 148 ]. The reversible peptide aldehyde MG132 [ 142 ] reduces in vitro the number of endothelial progenitor cells and negatively affects their function by inducing their apoptosis and impairing the endothelial nitric oxide synthase/nitric oxide (eNOS/NO) pathway [ 149 , 150 ]. Moreover, in female pigs, the chronic inhibition of proteasome by MLN273 can lead to endothelial dysfunction and coronary atherosclerosis with reduced myocardial perfusion response and increased microvascular permeability [ 141 , 143 ]. These data are supported by human studies that showed decreased proteasomal activity and accumulation of ubiquitinated substrates in carotid and coronary symptomatic unstable atherosclerotic plaques [ 151 , 152 ]. Therefore, bortezomib could affect the physiological properties of blood vessels and hasten or aggravate an already present vascular damage, as it happens in coronary heart disease.
Finally, the impairment of both the sympathetic and parasympathetic nerve fibers [ 34 , 37 ] could contribute to the conduction disorders and arrhythmias occasionally reported and participate in the postural hypotension observed in bortezomib treated patients [ 27 ].
5. Muscle Toxicity: The Neglected Adverse Event
Patients with MM can develop several neurological complications caused either by the disease itself or by the toxic effects of the medications used to treat it. The involvement of skeletal muscle is considered very rare in MM and has been reported in the concurrent immunoglobulin light chain (AL) amyloidosis or as the result of long-lasting corticosteroid therapy [ 153 ]. Based on initial data from the phase II SUMMIT and CREST studies in relapsed and/or refractory MM, muscle weakness is a frequent adverse effect of bortezomib therapy, with the incidence of any grade and grade 3 events in patients of 11% and 4–5%, respectively [ 29 , 154 ]. Despite these elevated rates of weakness in patients, a detailed description and evaluation of skeletal muscle involvement with bortezomib was lacking in the literature. Recently, a small-sized single-center prospective study on 24 newly diagnosed symptomatic MM patients pointed out that bortezomib treatment may cause a myopathy [ 155 ]. Seven out of 14 patients receiving bortezomib complained of difficulty in climbing stairs and rising from a chair and developed a symmetrical proximal lower limb muscle weakness involving predominantly thigh flexors. All patients had serum creatine kinase (CK) within the normal reference range. Nerve conduction studies were normal, and needle electromyography (EMG) recorded myopathic features including small, polyphasic units, and fast recruitment. Bortezomib-induced myopathy was an early complication occurring within the four 3-week cycles of therapy and did not progress, remaining confined to the legs. Muscle weakness was potentially reversible, with 43% of patients experiencing symptom resolution in a median of 3.6 months with drug interruption. The mechanisms underlying the pathogenesis of muscle injury in these patients has not been fully clarified. A muscle biopsy from a symptomatic MM patient treated with bortezomib revealed abnormalities compatible with a metabolic myopathy characterized on morphological grounds by the accumulation of lipid droplets in several muscle fibers and by mitochondrial alterations consisting of swelling and cristae loss at ultrastructural examination [ 155 ]. These pathological findings were reproduced in an in vitro model, indeed, primary human myoblasts exposed to bortezomib within the dose range found in the plasma of treated patients presented excessive storage of lipid droplets together with structural and functional mitochondrial abnormalities, and without being affected by cytotoxic effects of the drug [ 155 ]. In line with one of the main mechanisms of cardio- and neurotoxicity induced by bortezomib [ 76 , 78 , 79 , 80 , 81 , 137 , 156 ], in vitro findings were consistent with the ability of the drug to impair the mitochondria whose dysfunction may lead to an increase in intracellular lipid content in skeletal muscle [ 155 ]. Myogenin, a muscle-specific transcription factor [ 157 ], has also been suggested as a possible intracellular target for bortezomib-induced muscle toxicity. It has been observed that the treatment of C2C12 mouse myoblast cell line with bortezomib at clinically relevant doses led to myogenin down-regulation with the consequent inhibition of myotubes formation and cell cycle arrest at the G2/M phase [ 158 ].
Due to the possible clinical relevance of bortezomib-induced muscle toxicity, our group developed an experimental mouse model to further elucidate the mechanisms responsible for muscle damage. Adult female mice were treated with bortezomib at a dose of 1 mg/kg twice weekly for 7 or 14 days and morphological studies including light microscopy and transmission electron microscopy were performed on skeletal muscle tissue (see File S1 (Supplementary Materials) for the detail description of Materials and Methods). One week after the administration of bortezomib, chymotrypsin-like activity of the proteasome was markedly reduced in blood and skeletal muscle of treated mice compared to the control group ( Figure 3 ). After 14 days of treatment, the chymotrypsin-like activity partially recovered but still was significantly lower in blood as well as in the muscle tissue of mice receiving the drug than in control mice ( Figure 3 ). Histological analysis did not show morphological changes of vastus lateralis, gastrocnemius, and tibialis anterioris muscles in mice exposed to bortezomib for one or two weeks ( Figure 4 ). Neither necrotic or regenerating muscle fibers nor increased perimysial or endomysial connective tissue was observed in hematoxylin and eosin (H&E) and modified Gomori trichrome ( Figure 4 ). All other histochemical stainings including nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR), cytochrome c oxidase (COX), succinate dehydrogenase (SDH), Periodic acid Schiff (PAS) and Sudan black were normal. The ultrastructural analysis of muscles obtained from bortezomib-treated mice, however, revealed morphological abnormalities of mitochondria, which were enlarged and had a significantly higher cristae density, more commonly in the subsarcolemmal compartment ( Figure 5 ). Moreover, the lateral sacs of sarcoplasmic reticulum were in various stages of dilation but retained their triadic structure ( Figure 5 ). All these changes were more evident in mice after 14 days of treatment. Neither storage of lipid droplets nor morphological evidence of apoptosis or necrosis was observed in any muscle samples. These findings indicate that bortezomib may exert a toxic effect on mitochondria in skeletal muscle fibers in healthy C57BL/6 mice, suggesting that “mitotoxicity” could represent a common mechanism responsible for the toxicity induced by the PI in the different tissues, including peripheral nerve and heart. Further studies are needed to clarify whether the changes of mitochondrial morphology observed in muscles of bortezomib-treated mice result in their functional impairment and to identify the exact intracellular targets of bortezomib in skeletal muscle.
6. Conclusions
Bortezomib has shown remarkable clinical benefits in the treatment of MM but is associated with various adverse events that may lead to early discontinuation of the therapy. Despite peripheral neuropathy is recognized as the main non-hematologic dose-limiting adverse effect, cardiovascular and muscular complications are relatively common and potentially reversible. Therefore, their identification and management are crucial to provide an optimal therapeutic strategy and improve long-term outcomes. Patients treated with bortezomib should undergo cardiac surveillance and be carefully monitored by a neurologist for neuromuscular signs and/or symptoms.
In vivo and in vitro studies have documented a significant alteration of the morphology and/or function of mitochondria in peripheral nerves as well as in cardiac and skeletal muscle, suggesting that they might be a common target of bortezomib toxicity in these tissues. The mechanisms underlying the drug-induced mitochondrial defects are partially known, hampering the development of effective therapeutic strategies able to prevent or reverse them, without interfering with the anti-tumor activity. Modulators of oxidative phosphorylation, ROS scavengers, compounds that boost endogenous antioxidant responses, and drugs preventing the mitochondrial p53 accumulation or able to modulate the mitochondrial metabolism may be suitable for managing the effects of bortezomib on mitochondria [ 159 ]. However, single small-sized studies that evaluated the efficacy of acetyl-L-carnitine, methylcobalamin, and a nutraceutical compound (docosahexaenoic acid, α-lipoic acid, vitamin C, and vitamin E) for the prevention of bortezomib-related peripheral neuropathy do not allow to draw firm conclusions on their therapeutic benefits [ 78 , 160 , 161 ]. Hopefully, available experimental models will help us to further clarify the pathophysiology of mitochondrial toxicity induced by bortezomib, providing valuable information for possible strategies aimed at overcoming these effects.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/12/9/2540/s1 , File S1: The detail description of Materials and Methods.
Click here for additional data file.
Author Contributions
E.P., V.G., G.M.W., M.M., P.T., G.T., D.N. and G.V.: review and study design, analysis/interpretation of data and drafting/revising the manuscript; G.M.W., M.M. and D.N.: acquisition of data, analysis/interpretation of data and drafting/revising the manuscript; P.T. and G.T.: analysis/interpretation of data and drafting/revising the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Rajkumar S.V. Dimopoulos M.A. Palumbo A. Blade J. Merlini G. Mateos M.-V. Kumar S. Hillengass J. Kastritis E. Richardson P. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol. 2014 15 e538 e548 10.1016/S1470-2045(14)70442-5 25439696
2. Palumbo A. Anderson K. Multiple Myeloma N. Engl. J. Med. 2011 364 1046 1060 10.1056/NEJMra1011442 21410373
3. Landgren O. Kyle R.A. Pfeiffer R.M. Katzmann J.A. Caporaso N.E. Hayes R.B. Dispenzieri A. Kumar S. Clark R.J. Baris D. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: A prospective study Blood 2009 113 5412 5417 10.1182/blood-2008-12-194241 19179464 PMC2689042
4. Kumar S.K. Rajkumar V. Kyle R.A. van Duin M. Sonneveld P. Mateos M.-V. Gay F. Anderson K.C. Multiple myeloma Nat. Rev. Dis. Primer 2017 3 17046 10.1038/nrdp.2017.46 28726797
5. Howlader N. Noone A.M. Krapcho M. Miller D. Brest A. Yu M. Ruhl J. Tatalovich Z. Mariotto A. Lewis D.R. SEER Cancer Statistics Review, 1975–2017 National Cancer Institute Bethesda, MD, USA 2020
6. Kumar S.K. Dispenzieri A. Lacy M.Q. Gertz M.A. Buadi F.K. Pandey S. Kapoor P. Dingli D. Hayman S.R. Leung N. Continued improvement in survival in multiple myeloma: Changes in early mortality and outcomes in older patients Leukemia 2014 28 1122 1128 10.1038/leu.2013.313 24157580 PMC4000285
7. Gandolfi S. Laubach J.P. Hideshima T. Chauhan D. Anderson K.C. Richardson P.G. The proteasome and proteasome inhibitors in multiple myeloma Cancer Metastasis Rev. 2017 36 561 584 10.1007/s10555-017-9707-8 29196868
8. Bird S.A. Boyd K. Multiple myeloma: An overview of management Palliat. Care Soc. Pract. 2019 13 10.1177/1178224219868235 32215370 PMC7065505
9. Pinto V. Bergantim R. Caires H.R. Seca H. Guimarães J.E. Vasconcelos M.H. Multiple Myeloma: Available Therapies and Causes of Drug Resistance Cancers 2020 12 407 10.3390/cancers12020407 PMC7072128 32050631
10. Sherman D.J. Li J. Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease Molecules 2020 25 671 10.3390/molecules25030671 PMC7037493 32033280
11. Walter P. Ron D. The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation Science 2011 334 1081 1086 10.1126/science.1209038 22116877
12. Ri M. Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma Int. J. Hematol. 2016 104 273 280 10.1007/s12185-016-2016-0 27169614
13. Adams J. The proteasome: A suitable antineoplastic target Nat. Rev. Cancer 2004 4 349 360 10.1038/nrc1361 15122206
14. Mitsiades N. Mitsiades C.S. Richardson P.G. Poulaki V. Tai Y.-T. Chauhan D. Fanourakis G. Gu X. Bailey C. Joseph M. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: Therapeutic applications Blood 2003 101 2377 2380 10.1182/blood-2002-06-1768 12424198
15. Mateos M.-V. Ludwig H. Bazarbachi A. Beksac M. Bladé J. Boccadoro M. Cavo M. Delforge M. Dimopoulos M.A. Facon T. Insights on Multiple Myeloma Treatment Strategies HemaSphere 2019 3 e163 10.1097/HS9.0000000000000163 31723802 PMC6745941
16. Kumar S.K. Callander N.S. Hillengass J. Liedtke M. Baljevic M. Campagnaro E. Castillo J.J. Chandler J.C. Cornell R.F. Costello C. NCCN Guidelines Insights: Multiple Myeloma, Version 1.2020 J. Natl. Compr. Cancer Netw. 2019 17 1154 1165 10.6004/jnccn.2019.0049 31590151
17. Rajkumar S.V. Kumar S. Multiple Myeloma: Diagnosis and Treatment Mayo Clin. Proc. 2016 91 101 119 10.1016/j.mayocp.2015.11.007 26763514 PMC5223450
18. Manasanch E.E. Orlowski R.Z. Proteasome inhibitors in cancer therapy Nat. Rev. Clin. Oncol. 2017 14 417 433 10.1038/nrclinonc.2016.206 28117417 PMC5828026
19. Groll M. Berkers C.R. Ploegh H.L. Ovaa H. Crystal Structure of the Boronic Acid-Based Proteasome Inhibitor Bortezomib in Complex with the Yeast 20S Proteasome Structure 2006 14 451 456 10.1016/j.str.2005.11.019 16531229
20. Barrio S. Stühmer T. Da-Viá M. Barrio-Garcia C. Lehners N. Besse A. Cuenca I. Garitano-Trojaola A. Fink S. Leich E. Spectrum and functional validation of PSMB5 mutations in multiple myeloma Leukemia 2019 33 447 456 10.1038/s41375-018-0216-8 30026573
21. Allmeroth K. Horn M. Kroef V. Miethe S. Müller R.-U. Denzel M.S. Bortezomib resistance mutations in PSMB5 determine response to second-generation proteasome inhibitors in multiple myeloma Leukemia 2020 10.1038/s41375-020-0989-4 PMC7932915 32690882
22. Lü S. Wang J. The resistance mechanisms of proteasome inhibitor bortezomib Biomark. Res. 2013 1 13 10.1186/2050-7771-1-13 24252210 PMC4177604
23. Oakes S.A. Papa F.R. The Role of Endoplasmic Reticulum Stress in Human Pathology Annu. Rev. Pathol. Mech. Dis. 2015 10 173 194 10.1146/annurev-pathol-012513-104649 PMC5568783 25387057
24. Ito S. Proteasome Inhibitors for the Treatment of Multiple Myeloma Cancers 2020 12 265 10.3390/cancers12020265 31979059 PMC7072336
25. Li Z.-W. Chen H. Campbell R.A. Bonavida B. Berenson J.R. NF-kB in the pathogenesis and treatment of multiple myeloma Curr. Opin. Hematol. 2008 15 391 399 10.1097/MOH.0b013e328302c7f4 18536579
26. Hideshima T. Mitsiades C. Akiyama M. Hayashi T. Chauhan D. Richardson P. Schlossman R. Podar K. Munshi N.C. Mitsiades N. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341 Blood 2003 101 1530 1534 10.1182/blood-2002-08-2543 12393500
27. Rajkumar S.V. Richardson P.G. Hideshima T. Anderson K.C. Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer J. Clin. Oncol. 2005 23 630 639 10.1200/JCO.2005.11.030 15659509
28. Tan C.R.C. Abdul-Majeed S. Cael B. Barta S.K. Clinical Pharmacokinetics and Pharmacodynamics of Bortezomib Clin. Pharmacokinet. 2019 58 157 168 10.1007/s40262-018-0679-9 29802543
29. Richardson P.G. Barlogie B. Berenson J. Singhal S. Jagannath S. Irwin D. Rajkumar S.V. Srkalovic G. Alsina M. Alexanian R. A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma N. Engl. J. Med. 2003 348 2609 2617 10.1056/NEJMoa030288 12826635
30. Richardson P.G. Sonneveld P. Schuster M.W. Irwin D. Stadtmauer E.A. Facon T. Harousseau J.-L. Ben-Yehuda D. Lonial S. Goldschmidt H. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma N. Engl. J. Med. 2005 352 2487 2498 10.1056/NEJMoa043445 15958804
31. Argyriou A.A. Iconomou G. Kalofonos H.P. Bortezomib-induced peripheral neuropathy in multiple myeloma: A comprehensive review of the literature Blood 2008 112 1593 1599 10.1182/blood-2008-04-149385 18574024
32. Song X. Wilson K.L. Kagan J. Panjabi S. Cost of peripheral neuropathy in patients receiving treatment for multiple myeloma: A US administrative claims analysis Ther. Adv. Hematol. 2019 10 10.1177/2040620719839025 30967926 PMC6444783
33. Argyriou A.A. Cavaletti G. Bruna J. Kyritsis A.P. Kalofonos H.P. Bortezomib-induced peripheral neurotoxicity: An update Arch. Toxicol. 2014 88 1669 1679 10.1007/s00204-014-1316-5 25069804
34. Giannoccaro M.P. Donadio V. Gomis Pèrez C. Borsini W. Di Stasi V. Liguori R. Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: An immunofluorescence study Neurol. Sci. 2011 32 361 363 10.1007/s10072-010-0475-2 21290160
35. Mele G. Coppi M.R. Melpignano A. Quarta G. Paralytic ileus following “subcutaneous bortezomib” therapy: Focus on the clinical emergency—Report of two cases Clin. Exp. Med. 2016 16 99 101 10.1007/s10238-015-0337-6 25600700
36. Shah M.H. Phase II Study of the Proteasome Inhibitor Bortezomib (PS-341) in Patients with Metastatic Neuroendocrine Tumors Clin. Cancer Res. 2004 10 6111 6118 10.1158/1078-0432.CCR-04-0422 15447997
37. Stratogianni A. Tosch M. Schlemmer H. Weis J. Katona I. Isenmann S. Haensch C.A. Bortezomib-induced severe autonomic neuropathy Clin. Auton. Res. 2012 22 199 202 10.1007/s10286-012-0164-8 22532274
38. Mauermann M.L. Blumenreich M.S. Dispenzieri A. Staff N.P. A case of peripheral nerve microvasculitis associated with multiple myeloma and bortezomib treatment Muscle Nerve 2012 46 964 970 10.1002/mus.23493 23225391
39. Chaudhry V. Cornblath D.R. Polydefkis M. Ferguson A. Borrello I. Characteristics of bortezomib- and thalidomide-induced peripheral neuropathy J. Peripher. Nerv. Syst. 2008 13 275 282 10.1111/j.1529-8027.2008.00193.x 19192067 PMC3741683
40. Ravaglia S. Corso A. Piccolo G. Lozza A. Alfonsi E. Mangiacavalli S. Varettoni M. Zappasodi P. Moglia A. Lazzarino M. Immune-mediated neuropathies in myeloma patients treated with bortezomib Clin. Neurophysiol. 2008 119 2507 2512 10.1016/j.clinph.2008.08.007 18829381
41. Thawani S.P. Tanji K. De Sousa E.A. Weimer L.H. Brannagan T.H. Bortezomib-Associated Demyelinating Neuropathy—Clinical and Pathologic Features J. Clin. Neuromuscul. Dis. 2015 16 202 209 10.1097/CND.0000000000000077 25996966
42. Filosto M. Rossi G. Pelizzari A.M. Buzio S. Tentorio M. Broglio L. Mancuso M. Rinaldi M. Scarpelli M. Padovani A. A high-dose bortezomib neuropathy with sensory ataxia and myelin involvement J. Neurol. Sci. 2007 263 40 43 10.1016/j.jns.2007.05.023 17612569
43. Singh M. Thomas V.M. Mulay S. Bortezomib-induced motor neuropathy: A case report J. Oncol. Pharm. Pract. 2020 10.1177/1078155220904153 32054409
44. Gupta S. Pagliuca A. Devereux S. Mufti G.J. Schey S. Life-threatening motor neurotoxicity in association wih bortezomib Haematologica 2006 91 1001 16757419
45. Jeter A. Kang Y. Immune modulation therapy in the management of bortezomib-induced peripheral neuropathy Exp. Hematol. Oncol. 2012 1 20 10.1186/2162-3619-1-20 23211009 PMC3514086
46. Schmitt S. Goldschmidt H. Storch-Hagenlocher B. Pham M. Fingerle-Rowson G. Ho A.D. Neben K. Inflammatory autoimmune neuropathy, presumably induced by bortezomib, in a patient suffering from multiple myeloma Int. J. Hematol. 2011 93 791 794 10.1007/s12185-011-0847-2 21553020
47. Saifee T.A. Elliott K.J. Lunn M.P. Blake J. Reilly M.M. Rabin N. Yong K.L. D’Sa S. Brandner S. Bortezomib-induced inflammatory neuropathy J. Peripher. Nerv. Syst. 2010 15 366 368 10.1111/j.1529-8027.2010.00287.x 21199108
48. Li T. Timmins H.C. King T. Kiernan M.C. Goldstein D. Park S.B. Characteristics and risk factors of bortezomib induced peripheral neuropathy: A systematic review of phase III trials Hematol. Oncol. 2020 10.1002/hon.2706 31873944
49. Velasco R. Alberti P. Bruna J. Psimaras D. Argyriou A.A. Bortezomib and other proteosome inhibitors—Induced peripheral neurotoxicity: From pathogenesis to treatment J. Peripher. Nerv. Syst. 2019 24 10.1111/jns.12338 31647153
50. Richardson P.G. Briemberg H. Jagannath S. Wen P.Y. Barlogie B. Berenson J. Singhal S. Siegel D.S. Irwin D. Schuster M. Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib J. Clin. Oncol. 2006 24 3113 3120 10.1200/JCO.2005.04.7779 16754936
51. Knopf K.B. Duh M.S. Lafeuille M.-H. Gravel J. Lefebvre P. Niculescu L. Ba-Mancini A. Ma E. Shi H. Comenzo R.L. Meta-Analysis of the Efficacy and Safety of Bortezomib Re-Treatment in Patients With Multiple Myeloma Clin. Lymphoma Myeloma Leuk. 2014 14 380 388 10.1016/j.clml.2014.03.005 25023616
52. Vidisheva A.P. Wang J. Spektor T.M. Bitran J.D. Lutzky J. Tabbara I.A. Ye J.Z. Ailawadhi S. Stampleman L.V. Steis R.G. Safety of BTZ retreatment for patients with low-grade peripheral neuropathy during the initial treatment Support. Care Cancer 2017 25 3217 3224 10.1007/s00520-017-3732-6 28455546
53. Bringhen S. Larocca A. Rossi D. Cavalli M. Genuardi M. Ria R. Gentili S. Patriarca F. Nozzoli C. Levi A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients Blood 2010 116 4745 4753 10.1182/blood-2010-07-294983 20807892
54. Ye Z. Chen J. Xuan Z. Yang W. Chen J. Subcutaneous bortezomib might be standard of care for patients with multiple myeloma: A systematic review and meta-analysis Drug Des. Devel. Ther. 2019 13 1707 1716 10.2147/DDDT.S198117 31190749 PMC6529723
55. Mu S. Ai L. Qin Y. Hu Y. Subcutaneous versus Intravenous Bortezomib Administration for Multiple Myeloma Patients: A Meta-analysis Curr. Med. Sci. 2018 38 43 50 10.1007/s11596-018-1844-y 30074150
56. Terpos E. Kleber M. Engelhardt M. Zweegman S. Gay F. Kastritis E. van de Donk N.W.C.J. Bruno B. Sezer O. Broijl A. European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications Haematologica 2015 100 1254 1266 10.3324/haematol.2014.117176 26432383 PMC4591757
57. Richardson P.G. Delforge M. Beksac M. Wen P. Jongen J.L. Sezer O. Terpos E. Munshi N. Palumbo A. Rajkumar S.V. Management of treatment-emergent peripheral neuropathy in multiple myeloma Leukemia 2012 26 595 608 10.1038/leu.2011.346 22193964
58. Dimopoulos M.A. Mateos M.-V. Richardson P.G. Schlag R. Khuageva N.K. Shpilberg O. Kropff M. Spicka I. Palumbo A. Wu K.L. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: Subanalysis of the phase 3 VISTA study: Reversibility of PN with VMP in newly diagnosed MM Eur. J. Haematol. 2011 86 23 31 10.1111/j.1600-0609.2010.01533.x 20874823
59. Richardson P.G. Sonneveld P. Schuster M.W. Stadtmauer E.A. Facon T. Harousseau J.-L. Ben-Yehuda D. Lonial S. Goldschmidt H. Reece D. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: Impact of a dose-modification guideline Br. J. Haematol. 2009 144 895 903 10.1111/j.1365-2141.2008.07573.x 19170677
60. Boyette-Davis J.A. Cata J.P. Zhang H. Driver L.C. Wendelschafer-Crabb G. Kennedy W.R. Dougherty P.M. Follow-Up Psychophysical Studies in Bortezomib-Related Chemoneuropathy Patients J. Pain 2011 12 1017 1024 10.1016/j.jpain.2011.04.008 21703938 PMC3164390
61. Ibrahim E.Y. Ehrlich B.E. Prevention of chemotherapy-induced peripheral neuropathy: A review of recent findings Crit. Rev. Oncol. Hematol. 2020 145 102831 10.1016/j.critrevonc.2019.102831 31783290 PMC6982645
62. Lanzani F. Mattavelli L. Frigeni B. Rossini F. Cammarota S. Petrò D. Jann S. Cavaletti G. Role of a pre-existing neuropathy on the course of bortezomib-induced peripheral neurotoxicity J. Peripher. Nerv. Syst. 2008 13 267 274 10.1111/j.1529-8027.2008.00192.x 19192066
63. Badros A. Goloubeva O. Dalal J.S. Can I. Thompson J. Rapoport A.P. Heyman M. Akpek G. Fenton R.G. Neurotoxicity of bortezomib therapy in multiple myeloma: A single-center experience and review of the literature Cancer 2007 110 1042 1049 10.1002/cncr.22921 17654660
64. Richardson P.G. Xie W. Mitsiades C. Chanan-Khan A.A. Lonial S. Hassoun H. Avigan D.E. Oaklander A.L. Kuter D.J. Wen P.Y. Single-Agent Bortezomib in Previously Untreated Multiple Myeloma: Efficacy, Characterization of Peripheral Neuropathy, and Molecular Correlations With Response and Neuropathy J. Clin. Oncol. 2009 27 3518 3525 10.1200/JCO.2008.18.3087 19528374 PMC2717758
65. Corso A. Mangiacavalli S. Varettoni M. Pascutto C. Zappasodi P. Lazzarino M. Bortezomib-induced peripheral neuropathy in multiple myeloma: A comparison between previously treated and untreated patients Leuk. Res. 2010 34 471 474 10.1016/j.leukres.2009.07.022 19674790
66. Mateos M.-V. Hernández J.-M. Hernández M.-T. Gutiérrez N.-C. Palomera L. Fuertes M. Díaz-Mediavilla J. Lahuerta J.-J. de la Rubia J. Terol M.-J. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: Results of a multicenter phase 1/2 study Blood 2006 108 2165 2172 10.1182/blood-2006-04-019778 16772605
67. Casafont I. Berciano M.T. Lafarga M. Bortezomib Induces the Formation of Nuclear poly(A) RNA Granules Enriched in Sam68 and PABPN1 in Sensory Ganglia Neurons Neurotox. Res. 2010 17 167 178 10.1007/s12640-009-9086-1 19609631
68. Carozzi V.A. Canta A. Oggioni N. Sala B. Chiorazzi A. Meregalli C. Bossi M. Marmiroli P. Cavaletti G. Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies Exp. Neurol. 2010 226 301 309 10.1016/j.expneurol.2010.09.004 20832406
69. Cata J.P. Weng H.-R. Burton A.W. Villareal H. Giralt S. Dougherty P.M. Quantitative Sensory Findings in Patients With Bortezomib-Induced Pain J. Pain 2007 8 296 306 10.1016/j.jpain.2006.09.014 17175202
70. Terkelsen A.J. Karlsson P. Lauria G. Freeman R. Finnerup N.B. Jensen T.S. The diagnostic challenge of small fibre neuropathy: Clinical presentations, evaluations, and causes Lancet Neurol. 2017 16 934 944 10.1016/S1474-4422(17)30329-0 29029847
71. Meregalli C. Canta A. Carozzi V.A. Chiorazzi A. Oggioni N. Gilardini A. Ceresa C. Avezza F. Crippa L. Marmiroli P. Bortezomib-induced painful neuropathy in rats: A behavioral, neurophysiological and pathological study in rats Eur. J. Pain 2010 14 343 350 10.1016/j.ejpain.2009.07.001 19695912
72. Carozzi V.A. Renn C.L. Bardini M. Fazio G. Chiorazzi A. Meregalli C. Oggioni N. Shanks K. Quartu M. Serra M.P. Bortezomib-Induced Painful Peripheral Neuropathy: An Electrophysiological, Behavioral, Morphological and Mechanistic Study in the Mouse PLoS ONE 2013 8 e72995 10.1371/journal.pone.0072995 24069168 PMC3772181
73. Bruna J. Udina E. Alé A. Vilches J.J. Vynckier A. Monbaliu J. Silverman L. Navarro X. Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice Exp. Neurol. 2010 223 599 608 10.1016/j.expneurol.2010.02.006 20188093
74. Bruna J. Alé A. Velasco R. Jaramillo J. Navarro X. Udina E. Evaluation of pre-existing neuropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mouse model J. Peripher. Nerv. Syst. 2011 16 199 212 10.1111/j.1529-8027.2011.00346.x 22003935
75. Shin Y.K. Jang S.Y. Lee H.K. Jung J. Suh D.J. Seo S.-Y. Park H.T. Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib-induced peripheral neuropathy Glia 2010 58 1961 1976 10.1002/glia.21065 20830808
76. Cavaletti G. Gilardini A. Canta A. Rigamonti L. Rodriguez-Menendez V. Ceresa C. Marmiroli P. Bossi M. Oggioni N. D’Incalci M. Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat Exp. Neurol. 2007 204 317 325 10.1016/j.expneurol.2006.11.010 17214983
77. Gilardini A. Avila R.L. Oggioni N. Rodriguez-Menendez V. Bossi M. Canta A. Cavaletti G. Kirschner D.A. Myelin structure is unaltered in chemotherapy-induced peripheral neuropathy NeuroToxicology 2012 33 1 7 10.1016/j.neuro.2011.10.010 22079976
78. Zheng H. Xiao W.H. Bennett G.J. Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy Exp. Neurol. 2012 238 225 234 10.1016/j.expneurol.2012.08.023 22947198
79. Jannuzzi A.T. Arslan S. Yilmaz A.M. Sari G. Beklen H. Méndez L. Fedorova M. Arga K.Y. Karademir Yilmaz B. Alpertunga B. Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib Redox Biol. 2020 32 101502 10.1016/j.redox.2020.101502 32244176 PMC7115161
80. Landowski T.H. Megli C.J. Nullmeyer K.D. Lynch R.M. Dorr R.T. Mitochondrial-Mediated Disregulation of Ca 2+ Is a Critical Determinant of Velcade (PS-341/Bortezomib) Cytotoxicity in Myeloma Cell Lines Cancer Res. 2005 65 3828 3836 10.1158/0008-5472.CAN-04-3684 15867381
81. Sullivan P.G. Dragicevic N.B. Deng J.-H. Bai Y. Dimayuga E. Ding Q. Chen Q. Bruce-Keller A.J. Keller J.N. Proteasome Inhibition Alters Neural Mitochondrial Homeostasis and Mitochondria Turnover J. Biol. Chem. 2004 279 20699 20707 10.1074/jbc.M313579200 14742431
82. Nasu S. Misawa S. Nakaseko C. Shibuya K. Isose S. Sekiguchi Y. Mitsuma S. Ohmori S. Iwai Y. Beppu M. Bortezomib-induced neuropathy: Axonal membrane depolarization precedes development of neuropathy Clin. Neurophysiol. 2014 125 381 387 10.1016/j.clinph.2013.07.014 23973385
83. Xiao W.H. Bennett G.J. Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin Pain 2012 153 704 709 10.1016/j.pain.2011.12.011 22244441 PMC3288606
84. Xiao W.H. Zheng H. Zheng F.Y. Nuydens R. Meert T.F. Bennett G.J. Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat Neuroscience 2011 199 461 469 10.1016/j.neuroscience.2011.10.010 22037390 PMC3237950
85. Jordan M.A. Wilson L. Microtubules as a target for anticancer drugs Nat. Rev. Cancer 2004 4 253 265 10.1038/nrc1317 15057285
86. Klimaschewski L. Hausott B. Ingorokva S. Pfaller K. Constitutively expressed catalytic proteasomal subunits are up-regulated during neuronal differentiation and required for axon initiation, elongation and maintenance J. Neurochem. 2006 96 1708 1717 10.1111/j.1471-4159.2006.03694.x 16539686
87. Laser H. Mack T.G.A. Wagner D. Coleman M.P. Proteasome inhibition arrests neurite outgrowth and causes "dying-back" degeneration in primary culture J. Neurosci. Res. 2003 74 906 916 10.1002/jnr.10806 14648596
88. Poruchynsky M.S. Sackett D.L. Robey R.W. Ward Y. Annunziata C. Fojo T. Proteasome inhibitors increase tubulin polymerization and stabilization in tissue culture cells: A possible mechanism contributing to peripheral neuropathy and cellular toxicity following proteasome inhibition Cell Cycle 2008 7 940 949 10.4161/cc.7.7.5625 18414063 PMC9416319
89. Meregalli C. Chiorazzi A. Carozzi V.A. Canta A. Sala B. Colombo M. Oggioni N. Ceresa C. Foudah D. La Russa F. Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy Cell Cycle 2014 13 612 621 10.4161/cc.27476 24335344
90. Alé A. Bruna J. Herrando M. Navarro X. Udina E. Toxic Effects of Bortezomib on Primary Sensory Neurons and Schwann Cells of Adult Mice Neurotox. Res. 2015 27 430 440 10.1007/s12640-014-9514-8 25588865
91. Staff N.P. Podratz J.L. Grassner L. Bader M. Paz J. Knight A.M. Loprinzi C.L. Trushina E. Windebank A.J. Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons NeuroToxicology 2013 39 124 131 10.1016/j.neuro.2013.09.001 24035926 PMC3844018
92. Karademir B. Sari G. Jannuzzi A.T. Musunuri S. Wicher G. Grune T. Mi J. Hacioglu-Bay H. Forsberg-Nilsson K. Bergquist J. Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib Sci. Rep. 2018 8 16318 10.1038/s41598-018-34507-3 30397214 PMC6218500
93. Palanca A. Casafont I. Berciano M.T. Lafarga M. Proteasome inhibition induces DNA damage and reorganizes nuclear architecture and protein synthesis machinery in sensory ganglion neurons Cell. Mol. Life Sci. 2014 71 1961 1975 10.1007/s00018-013-1474-2 24061536 PMC11113442
94. Stockstill K. Doyle T.M. Yan X. Chen Z. Janes K. Little J.W. Braden K. Lauro F. Giancotti L.A. Harada C.M. Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain J. Exp. Med. 2018 215 1301 1313 10.1084/jem.20170584 29703731 PMC5940258
95. Mangiacavalli S. Corso A. De Amici M. Varettoni M. Alfonsi E. Lozza A. Lazzarino M. Emergent T-helper 2 profile with high interleukin-6 levels correlates with the appearance of bortezomib-induced neuropathic pain: Correspondence Br. J. Haematol. 2010 149 916 918 10.1111/j.1365-2141.2010.08138.x 20201942
96. Hung A.L. Lim M. Doshi T.L. Targeting cytokines for treatment of neuropathic pain Scand. J. Pain 2017 17 287 293 10.1016/j.sjpain.2017.08.002 29229214 PMC5774983
97. Stemkowski P.L. Smith P.A. Sensory Neurons, Ion Channels, Inflammation and the Onset of Neuropathic Pain Can. J. Neurol. Sci. 2012 39 416 435 10.1017/S0317167100013937 22728849
98. Myers R.R. Shubayev V.I. The ology of neuropathy: An integrative review of the role of neuroinflammation and TNF-α axonal transport in neuropathic pain J. Peripher. Nerv. Syst. 2011 16 277 286 10.1111/j.1529-8027.2011.00362.x 22176142 PMC4444223
99. Leung L. Cahill C.M. TNF-α and neuropathic pain—A review J. Neuroinflamm. 2010 7 27 10.1186/1742-2094-7-27 PMC2861665 20398373
100. Alé A. Bruna J. Morell M. van de Velde H. Monbaliu J. Navarro X. Udina E. Treatment with anti-TNF alpha protects against the neuropathy induced by the proteasome inhibitor bortezomib in a mouse model Exp. Neurol. 2014 253 165 173 10.1016/j.expneurol.2013.12.020 24406455
101. Zhang J. Su Y.-M. Li D. Cui Y. Huang Z.-Z. Wei J.-Y. Xue Z. Pang R.-P. Liu X.-G. Xin W.-J. TNF-α-mediated JNK activation in the dorsal root ganglion neurons contributes to Bortezomib-induced peripheral neuropathy Brain. Behav. Immun. 2014 38 185 191 10.1016/j.bbi.2014.01.020 24530998
102. Li Z.-Y. Zhang Y.-P. Zhang J. Zhang S.-B. Li D. Huang Z.-Z. Xin W.-J. The possible involvement of JNK activation in the spinal dorsal horn in bortezomib-induced allodynia: The role of TNF-α and IL-1β J. Anesth. 2016 30 55 63 10.1007/s00540-015-2077-x 26373954
103. Li C. Deng T. Shang Z. Wang D. Xiao Y. Blocking TRPA1 and TNF-α Signal Improves Bortezomib-Induced Neuropathic Pain Cell. Physiol. Biochem. 2018 51 2098 2110 10.1159/000495828 30522101
104. Chiorazzi A. Canta A. Meregalli C. Carozzi V. Sala B. Oggioni N. Monbaliu J. Antibody Against Tumor Necrosis Factor-α Reduces Bortezomib-induced Allodynia in a Rat Model Anticancer Res. 2013 33 5453 5459 24324081
105. Hideshima T. Richardson P. Chauhan D. Palombella V.J. Elliott P.J. Adams J. Anderson K.C. The Proteasome Inhibitor PS-341 Inhibits Growth, Induces Apoptosis, and Overcomes Drug Resistance in Human Multiple Myeloma Cells Cancer Res. 2001 61 3071 3076 11306489
106. Karin M. Nuclear factor-κB in cancer development and progression Nature 2006 441 431 436 10.1038/nature04870 16724054
107. Alé A. Bruna J. Calls A. Karamita M. Haralambous S. Probert L. Navarro X. Udina E. Inhibition of the neuronal NFκB pathway attenuates bortezomib-induced neuropathy in a mouse model NeuroToxicology 2016 55 58 64 10.1016/j.neuro.2016.05.004 27211850
108. Cole D.C. Frishman W.H. Cardiovascular Complications of Proteasome Inhibitors Used in Multiple Myeloma Cardiol. Rev. 2018 26 122 129 10.1097/CRD.0000000000000183 29077585
109. Kistler K.D. Kalman J. Sahni G. Murphy B. Werther W. Rajangam K. Chari A. Incidence and Risk of Cardiac Events in Patients With Previously Treated Multiple Myeloma Versus Matched Patients Without Multiple Myeloma: An Observational, Retrospective, Cohort Study Clin. Lymphoma Myeloma Leuk. 2017 17 89 96.e3 10.1016/j.clml.2016.11.009 28025038
110. Orciuolo E. Buda G. Cecconi N. Galimberti S. Versari D. Cervetti G. Salvetti A. Petrini M. Unexpected cardiotoxicity in haematological bortezomib treated patients Br. J. Haematol. 2007 138 396 397 10.1111/j.1365-2141.2007.06659.x 17561972
111. Gupta A. Pandey A. Sethi S. Bortezomib-Induced Congestive Cardiac Failure in a Patient with Multiple Myeloma Cardiovasc. Toxicol. 2012 12 184 187 10.1007/s12012-011-9146-7 21952908
112. Bockorny M. Chakravarty S. Schulman P. Bockorny B. Bona R. Severe Heart Failure after Bortezomib Treatment in a Patient with Multiple Myeloma: A Case Report and Review of the Literature Acta Haematol. 2012 128 244 247 10.1159/000340050 22964848
113. Meseeha M.G. Kolade V.O. Attia M.N. Partially reversible bortezomib-induced cardiotoxicity: An unusual cause of acute cardiomyopathy J. Community Hosp. Intern. Med. Perspect. 2015 5 28982 10.3402/jchimp.v5.28982 26653686 PMC4677580
114. Voortman J. Giaccone G. Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: A case report BMC Cancer 2006 6 129 10.1186/1471-2407-6-129 16689991 PMC1475607
115. Honton B. Despas F. Dumonteil N. Rouvellat C. Roussel M. Carrie D. Galinier M. Montastruc J.L. Pathak A. Bortezomib and heart failure: Case-report and review of the French Pharmacovigilance database Fundam. Clin. Pharmacol. 2014 28 349 352 10.1111/fcp.12039 23781941
116. Hacihanefioglu A. Tarkun P. Gonullu E. Acute severe cardiac failure in a myeloma patient due to proteasome inhibitor bortezomib Int. J. Hematol. 2008 88 219 222 10.1007/s12185-008-0139-7 18633693
117. Jerkins J. Bortezomib-induced Severe Congestive Heart Failure Cardiol. Res. 2010 10.4021/cr105e PMC5358234 28352372
118. Chakraborty R. Mukkamalla S.K.R. Calderon N. Bortezomib induced reversible left ventricular systolic dysfunction: A case report and review of literature BJMP 2013 6 a631
119. Foley P.W. Hamilton M.S. Leyva F. Myocardial scarring following chemotherapy for multiple myeloma detected using late gadolinium hyperenhancement cardiovascular magnetic resonance J. Cardiovasc. Med. 2010 11 386 388 10.2459/JCM.0b013e32832f3ff2 19584744
120. Subedi A. Sharma L.R. Shah B.K. Bortezomib-induced acute congestive heart failure: A case report and review of literature Ann. Hematol. 2014 93 1797 1799 10.1007/s00277-014-2026-z 24599584
121. Dasanu C.A. Complete heart block secondary to bortezomib use in multiple myeloma J. Oncol. Pharm. Pract. 2011 17 282 284 10.1177/1078155210367839 20406745
122. Lee W.-S. Kim D.-H. Shin S.-H. Woo S.-I. Kwan J. Park K.-S. Park S.-D. Yi H.-G. Jeon S.-H. Complete Atrioventricular Block Secondary to Bortezomib Use in Multiple Myeloma Yonsei Med. J. 2011 52 196 10.3349/ymj.2011.52.1.196 21155055 PMC3017698
123. Diwadkar S. Patel A.A. Fradley M.G. Bortezomib-Induced Complete Heart Block and Myocardial Scar: The Potential Role of Cardiac Biomarkers in Monitoring Cardiotoxicity Case Rep. Cardiol. 2016 2016 3456287 10.1155/2016/3456287 26942019 PMC4749759
124. Berenson J.R. Matous J. Swift R.A. Mapes R. Morrison B. Yeh H.S. A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma Clin. Cancer Res. 2007 13 1762 1768 10.1158/1078-0432.CCR-06-1812 17363530
125. Takamatsu H. Yamashita T. Kotani T. Sawazaki A. Okumura H. Nakao S. Ischemic heart disease associated with bortezomib treatment combined with dexamethasone in a patient with multiple myeloma Int. J. Hematol. 2010 91 903 906 10.1007/s12185-010-0586-9 20458563
126. Burkhart T. Keith M.C.L. Lenneman C.A.G. Fernando R.R. Bortezomib-Induced Cardiac Tamponade in a 49-Year-Old Man Tex. Heart Inst. J. 2018 45 260 263 10.14503/THIJ-17-6242 30374242 PMC6183647
127. Xiao Y. Yin J. Wei J. Shang Z. Incidence and Risk of Cardiotoxicity Associated with Bortezomib in the Treatment of Cancer: A Systematic Review and Meta-Analysis PLoS ONE 2014 9 e87671 10.1371/journal.pone.0087671 24489948 PMC3906186
128. Laubach J.P. Moslehi J.J. Francis S.A. San Miguel J.F. Sonneveld P. Orlowski R.Z. Moreau P. Rosiñol L. Faber E.A. Voorhees P. A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: Towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma Br. J. Haematol. 2017 178 547 560 10.1111/bjh.14708 28466536 PMC6812508
129. Cornell R.F. Ky B. Weiss B.M. Dahm C.N. Gupta D.K. Du L. Carver J.R. Cohen A.D. Engelhardt B.G. Garfall A.L. Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma J. Clin. Oncol. 2019 37 1946 1955 10.1200/JCO.19.00231 31188726 PMC9798911
130. Koulaouzidis G. Lyon A.R. Proteasome Inhibitors as a Potential Cause of Heart Failure Heart Fail. Clin. 2017 13 289 295 10.1016/j.hfc.2016.12.001 28279415
131. Shukla S.K. Rafiq K. Proteasome biology and therapeutics in cardiac diseases Transl. Res. 2019 205 64 76 10.1016/j.trsl.2018.09.003 30342797 PMC6372329
132. Portbury A.L. Ronnebaum S.M. Zungu M. Patterson C. Willis M.S. Back to your heart: Ubiquitin proteasome system-regulated signal transduction J. Mol. Cell. Cardiol. 2012 52 526 537 10.1016/j.yjmcc.2011.10.023 22085703 PMC3294005
133. Gilda J.E. Gomes A.V. Proteasome dysfunction in cardiomyopathies: Proteasome dysfunction in cardiomyopathies J. Physiol. 2017 595 4051 4071 10.1113/JP273607 28181243 PMC5471412
134. Li Y.-F. Wang X. The role of the proteasome in heart disease Biochim. Biophys. Acta BBA Gene Regul. Mech. 2011 1809 141 149 10.1016/j.bbagrm.2010.09.001 20840877 PMC3021001
135. Hasinoff B.B. Patel D. Wu X. Molecular Mechanisms of the Cardiotoxicity of the Proteasomal-Targeted Drugs Bortezomib and Carfilzomib Cardiovasc. Toxicol. 2017 17 237 250 10.1007/s12012-016-9378-7 27388042
136. Pokorna Z. Jirkovsky E. Hlavackova M. Jansova H. Jirkovska A. Lencova-Popelova O. Brazdova P. Kubes J. Sotakova-Kasparova D. Mazurova Y. In vitro and in vivo investigation of cardiotoxicity associated with anticancer proteasome inhibitors and their combination with anthracycline Clin. Sci. 2019 133 1827 1844 10.1042/CS20190139 31409729
137. Nowis D. Mączewski M. Mackiewicz U. Kujawa M. Ratajska A. Wieckowski M.R. Wilczyński G.M. Malinowska M. Bil J. Salwa P. Cardiotoxicity of the Anticancer Therapeutic Agent Bortezomib Am. J. Pathol. 2010 176 2658 2668 10.2353/ajpath.2010.090690 20519734 PMC2877829
138. Tang M. Li J. Huang W. Su H. Liang Q. Tian Z. Horak K.M. Molkentin J.D. Wang X. Proteasome functional insufficiency activates the calcineurin–NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts Cardiovasc. Res. 2010 88 424 433 10.1093/cvr/cvq217 20601385 PMC2972684
139. Carrier L. Too much of a good thing is bad: Proteasome inhibition induces stressed hearts to fail Cardiovasc. Res. 2010 88 389 390 10.1093/cvr/cvq315 20889761
140. Bonuccelli G. Sotgia F. Capozza F. Gazzerro E. Minetti C. Lisanti M.P. Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice Cell Cycle 2007 6 1242 1248 10.4161/cc.6.10.4182 17495527
141. Herrmann J. Saguner A.M. Versari D. Peterson T.E. Chade A. Olson M. Lerman L.O. Lerman A. Chronic Proteasome Inhibition Contributes to Coronary Atherosclerosis Circ. Res. 2007 101 865 874 10.1161/CIRCRESAHA.107.152959 17823377
142. Kisselev A.F. Goldberg A.L. Proteasome inhibitors: From research tools to drug candidates Chem. Biol. 2001 8 739 758 10.1016/S1074-5521(01)00056-4 11514224
143. Herrmann J. Wohlert C. Saguner A.M. Flores A. Nesbitt L.L. Chade A. Lerman L.O. Lerman A. Primary proteasome inhibition results in cardiac dysfunction Eur. J. Heart Fail. 2013 15 614 623 10.1093/eurjhf/hft034 23616520 PMC3661018
144. Gavazzoni M. Vizzardi E. Gorga E. Bonadei I. Rossi L. Belotti A. Rossi G. Ribolla R. Metra M. Raddino R. Mechanism of cardiovascular toxicity by proteasome inhibitors: New paradigm derived from clinical and pre-clinical evidence Eur. J. Pharmacol. 2018 828 80 88 10.1016/j.ejphar.2018.03.022 29550338
145. Mårtensson C.U. Priesnitz C. Song J. Ellenrieder L. Doan K.N. Boos F. Floerchinger A. Zufall N. Oeljeklaus S. Warscheid B. Mitochondrial protein translocation-associated degradation Nature 2019 569 679 683 10.1038/s41586-019-1227-y 31118508
146. Yui J.C. Van Keer J. Weiss B.M. Waxman A.J. Palmer M.B. D’Agati V.D. Kastritis E. Dimopoulos M.A. Vij R. Bansal D. Proteasome inhibitor associated thrombotic microangiopathy: Proteasome inhibitor associated TMA Am. J. Hematol. 2016 91 E348 E352 10.1002/ajh.24447 27286661
147. Roccaro A.M. Hideshima T. Raje N. Kumar S. Ishitsuka K. Yasui H. Shiraishi N. Ribatti D. Nico B. Vacca A. Bortezomib Mediates Antiangiogenesis in Multiple Myeloma via Direct and Indirect Effects on Endothelial Cells Cancer Res. 2006 66 184 191 10.1158/0008-5472.CAN-05-1195 16397231
148. Tamura D. Arao T. Tanaka K. Kaneda H. Matsumoto K. Kudo K. Aomatsu K. Fujita Y. Watanabe T. Saijo N. Bortezomib potentially inhibits cellular growth of vascular endothelial cells through suppression of G2/M transition Cancer Sci. 2010 101 1403 1408 10.1111/j.1349-7006.2010.01544.x 20367638 PMC11159993
149. Wei Q. Xia Y. Proteasome Inhibition Down-regulates Endothelial Nitric-oxide Synthase Phosphorylation and Function J. Biol. Chem. 2006 281 21652 21659 10.1074/jbc.M602105200 16737962
150. Hu X.-S. Du C.-Q. Yang L. Yao X.-Y. Hu S.-J. Proteasome inhibitor MG132 suppresses number and function of endothelial progenitor cells: Involvement of nitric oxide synthase inhibition Int. J. Mol. Med. 2010 25 10.3892/ijmm_00000356 20127043
151. Herrmann J. Edwards W.D. Holmes D.R. Shogren K.L. Lerman L.O. Ciechanover A. Lerman A. Increased ubiquitin immunoreactivity in unstable atherosclerotic plaques associated with acute coronary syndromes J. Am. Coll. Cardiol. 2002 40 1919 1927 10.1016/S0735-1097(02)02564-0 12475450
152. Versari D. Herrmann J. Gössl M. Mannheim D. Sattler K. Meyer F.B. Lerman L.O. Lerman A. Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis Arterioscler. Thromb. Vasc. Biol. 2006 26 2132 2139 10.1161/01.ATV.0000232501.08576.73 16778122
153. Muchtar E. Derudas D. Mauermann M. Liewluck T. Dispenzieri A. Kumar S.K. Dingli D. Lacy M.Q. Buadi F.K. Hayman S.R. Systemic Immunoglobulin Light Chain Amyloidosis–Associated Myopathy: Presentation, Diagnostic Pitfalls, and Outcome Mayo Clin. Proc. 2016 91 1354 1361 10.1016/j.mayocp.2016.06.027 27712634
154. Jagannath S. Barlogie B. Berenson J. Siegel D. Irwin D. Richardson P.G. Niesvizky R. Alexanian R. Limentani S.A. Alsina M. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma Br. J. Haematol. 2004 127 165 172 10.1111/j.1365-2141.2004.05188.x 15461622
155. Guglielmi V. Nowis D. Tinelli M. Malatesta M. Paoli L. Marini M. Manganotti P. Sadowski R. Wilczynski G.M. Meneghini V. Bortezomib-Induced Muscle Toxicity in Multiple Myeloma J. Neuropathol. Exp. Neurol. 2017 76 620 630 10.1093/jnen/nlx043 28863457
156. Arastu-Kapur S. Anderl J.L. Kraus M. Parlati F. Shenk K.D. Lee S.J. Muchamuel T. Bennett M.K. Driessen C. Ball A.J. Nonproteasomal Targets of the Proteasome Inhibitors Bortezomib and Carfilzomib: A Link to Clinical Adverse Events Clin. Cancer Res. 2011 17 2734 2743 10.1158/1078-0432.CCR-10-1950 21364033
157. Zammit P.S. Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis Semin. Cell Dev. Biol. 2017 72 19 32 10.1016/j.semcdb.2017.11.011 29127046
158. Xing S.S. Shen C.C. Godard M.P. Wang J.J. Yue Y.Y. Yang S.T. Zhao Q. Zhang S.B. Wang T.X. Yang X.L. Bortezomib inhibits C2C12 growth by inducing cell cycle arrest and apoptosis Biochem. Biophys. Res. Commun. 2014 445 375 380 10.1016/j.bbrc.2014.02.008 24525132 PMC3971480
159. Jiacheng M. Kavelaars A. Dougherty P.M. Heijnen C.J. Beyond Symptomatic Relief for Chemotherapy-Induced Peripheral Neuopathy:targeting the source Cancer 2018 124 2289 2298 10.1002/cncr.31248 29461625 PMC5991994
160. Maschio M. Zarabla A. Maialetti A. Marchesi F. Giannarelli D. Gumenyuk S. Pisani F. Renzi D. Galiè E. Mengarelli A. Prevention of Bortezomib-Related Peripheral Neuropathy with Docosahexaenoic acid and α-Lipoic Acid in Patients with Multiple Myeloma: Preliminary Data Integr. Cancer Ther. 2018 17 1115 1124 10.1177/1534735418803758 30295079 PMC6247541
161. Callander N. Markovina S. Eickhoff J. Hutson P. Campell T. Hematti P. Go R. Hegeman R. Longo W. Williams E. Acetyl-L-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubin and low-dose dexamethasone: A study from the Wisconsin Ocology Network Cancer Chemother. Pharmacol. 2014 74 875 882 10.1007/s00280-014-2550-5 25168296 PMC4175433