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Table of Contents

    Topic review

    Myeloma Cell Death

    Subjects: Cell Biology
    View times: 15
    Submitted by: Brigitte Sola


    Multiple myeloma (MM) is a neoplastic disease of plasma cells, characterized by a complex array of clinical manifestations. Despite extensive efforts and progress in the care of MM patients, the disease is still fatal because of de novo or acquired resistance of malignant cells to standard chemotherapies. In turn, new therapies and/or combination therapies are urgently needed. Reactive oxygen species (ROS) are unstable and highly reactive chemical molecules, able to alter the main structural components of cells, such as proteins and lipids, and thus, modifying cell fates. ROS levels are tightly controlled in normal cells both for their production and degradation. In turn, an unbalance of the redox status might be exploited to induce cell death. This is indeed the case for myeloma cells even those that are resistant, opening new perspectives for refractory or relapsed MM patients. 

    1. Introduction

    Multiple myeloma (MM) is a plasma cell malignancy characterized by the accumulation of clonal cells in the bone marrow and the overproduction of monoclonal immunoglobulin causing the clinical features of the disease: hypercalcemia, renal failure, anemia and bone lesions, collectively known as CRAB symptoms. Moreover, plasma cells are prone to produce large amounts of immunoglobulins, causing an endoplasmic reticulum stress, the unbalance of redox homeostasis and the production of intracellular ROS [1]. The disease progresses from benign monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma to overt aggressive MM and ultimately plasma cell leukemia. Over the past twenty years, MM patients outcome has been improved through the use of new drugs as well as new therapeutic approaches [2][3][4][5]. For elderly patients, not eligible to autologous transplantation, the use of proteasome inhibitors (PIs), immunomodulators (IMiDs), monoclonal antibodies, histone deacetylase (HDAC) inhibitors and more recently, check-point inhibitors and their various combinations have improved substantially MM patients survival. However, most MM patients are refractory or relapse (R/R) after one or more treatment regimens and the disease is still fatal [3][5][6].
    The first-in-class PI, bortezomib (BTZ) and several second-generation PIs (carfilzomib (CFZ), ixazomib) are efficient drugs, currently used for newly diagnosed patients and R/R patients alone or associated with other agents [7]. By targeting subunits of the ubiquitin/proteasome system (UPS), the major cell regulator of protein degradation, PIs cause a proteotoxic stress that activates the apoptotic function of the unfolded protein response (UPR) [8]. Indeed, after UPS inhibition, misfolded proteins accumulate in the endoplasmic reticulum (ER) generating an ER stress and activating the UPR. The survival of MM cells is highly dependent on the UPR, and inefficient or prolonged UPR activation signals apoptosis [9][10][11]. Another important mechanism of BTZ cytotoxicity in MM cells is the generation of an oxidative stress that has been long considered as a byproduct of the ER stress. The production of ROS depends on ER-resident protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreduction (ERO1) enzymes as well as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) complexes and mitochondrial electron transport chain (ETC) [12]. The ERO1 flavoprotein consumes oxygen and generates hydrogen peroxide (H2O2). Under ER stress, the activity of these enzymes is increased and generates higher amounts of ROS and, in turn, an oxidative stress. Moreover, BTZ treatment induces an adaptative antioxidant response by depleting intracellular glutathione (GSH), activating CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) and transcription factor 4 (ATF4), two antioxidant transcription factors, and the nuclear factor-erythroid 2 p45-related factor 2 (NRF2), the key controller of detoxification genes [13].
    Although BTZ and more generally PIs have achieved excellent therapeutic effects, innate resistance can be observed in drug-naive patients and acquired resistance may appear during the course of the treatment [14]. Indeed, during the progression of the disease, complex genetic alterations occur that contribute to the development of a resistant phenotype. The upregulation of the 20S proteasome subunits [15][16], the paradoxical downregulation of the 19S proteasome subunits [17], and the overexpression of efflux pumps [18] are among the main reported mechanisms of acquired resistance. However, the modulation of UPR, the alteration of apoptosis/autophagy signaling and metabolic changes contribute also largely to PI resistance. Indeed, a high glycolytic activity and/or the rewiring of glucose metabolism through the pentose phosphate pathway (PPP) and the serine synthesis pathway (SSP), an increased mitochondrial activity and fatty acid oxidation, are associated with PIs resistance [19][20][21]. A proteomic analysis comparing naive and R/R MM patients characterized four sets of relevant proteins including proteasomal proteins, apoptosis signaling proteins, proteins regulating the inflammation response, and factors regulating the redox status [22]. Moreover, the tumor microenvironment (TME) within the bone marrow facilitates tumor cells proliferation as well as drug resistance. This is due, at least in part, to a metabolic reprogramming of mesenchymal stromal and immune cells favoring the defense against ROS [23][24].

    2. Unbalancing ROS in Multiple Myeloma

    The rational for manipulating the redox status of MM cells to induce their death and/or to alleviate their resistance is an old concept [25]. This is based on the observation that the oxidative metabolism in myeloma vs normal plasma cells is fundamentally different. Theoretically, either oxidant or antioxidant treatment could exacerbate an oxidative stress and in turn, cell death. Indeed, myeloma cell death is obtained either by decreasing ROS levels or by increasing them (Table 1). ROS are synthesized in MM cells at least in part by the NOX complex activity [26]. Moreover, compared to normal bone marrow plasma cells, patients with MGUS, or a smoldering myeloma, NOX2 (encoded by CYBB) is the only catalytic subunit expressed in MM patients along with the p40phox (NCF4) and p22phox (CYBA) regulatory subunits [27]. Although a pan-NOX inhibitor, VAS3947 has a strong anti-MM activity, it shows adverse effects when combined with BTZ [27].
    The effects due to pro-oxidant strategies are more documented. Increasing the intracellular ROS level can be achieved either by their direct production or by inhibiting antioxidant defenses.

    2.1. Drugs That Target Glutathione Metabolism

    TP53 mutations/deletions are present in most cancers and associated with resistance to therapies. In turn, molecules acting downstream of p53, inducing the transcription of p53 targets such as p21CIP, BAX, PUMA, and NOXA and reactivating cell death have been selected. In MM cells, TP53 mutations/deletions are rare but increase with disease progression and associate with a bad prognosis. p53-modulating agents such as CP-31398, PRIMA-1 (p53 reactivation and induction of massive apoptosis-1), or APR-246 (PRIMA-1Met) induce ROS-mediated apoptosis of MM regardless the TP53 status [28][29][30][31][32]. At the molecular level, APR-246 induces ROS production by depleting GSH cell content [28][31]. Interestingly, APR-246 synergizes BSO, an irreversible inhibitor of the GSH synthesis. Another report indicated that caffeic acid phenetyl ester (CAPE), a phenolic compound, induces apoptosis through an oxidative stress caused by glutathione depletion [33].
    Table 1. Drugs targeting redox metabolism in MM preclinical models.
    Effects on ROS Level Drug/Combination Effects Preclinical Model Reference
    Decreasing VAS3947 NOX2i 1 HMCL [27]
    Increasing APR-246 GSH depletion HCML
    Primary cell
    In vivo
      CAPE GSH HCML [33]
      APR-246/BSO GSH depletion/γGCSi In vivo [28]
      APR-246/auranofin GSHdepletion/TXNRD1i r HCMLs
    Primary cells
      Auranofin TXNRD1i HCMLs [34]
      Auranofin/ZnPP IX TXNRD1i/HO1i HCMLs [35]
      PX-12 TXNi HCMLs [36]
      Auranofin/BTZ TXNi/PI HCMLs [27]
      Lenalidomide/BTZ TXNi/PI HCMLs [37]
      LCS-1 SOD1i HCMLs
    Primary cells
    In vivo
      2-methoxyestradiol/BTZ SOD2i/PI HCMLs [39]
      Disulfiram/BTZ SOD1i/PI HCMLs [40]
      Scutellarein/BTZ SOD2i/PI HCMLs [41]
      CCF642/BTZ PDIi/PI HCMLs
    In vivo
      E64FC26 PDIi HCMLs
    In vivo
      L-asparaginase/CFZ AA depletion/PI HCMLs [45]
      DPI/HK2-ASO/PER Mitochondria complex I/HK2i/FAOi HCMLs
    In vivo
      SR18292 PCG-1αi HCMLs
    Primary cells

    2.2. Drugs That Target Antioxidant Enzymes

    MM cells display increased expression of TXN and TXNRD1 involved in the protection against oxidative stress. Moreover, antioxidant genes are overexpressed in myeloma patients, including those with a poor prognosis, and MM cell lines when compared to normal plasma cells [27]. As expected, the targeting of antioxidant enzymes could be beneficial for MM patients.

    2.2.1. Thioredoxin System Inhibitors (Auranofin and Other Gold Compounds)

    As described before, the thioredoxin system comprising TXN and TXNRD1 is one of the major antioxidant systems in MM cells. In turn, TXN and TXNRD1 inhibition results in ROS-induced apoptosis [48][36]. Gold compounds have a high affinity for thiol and selenol groups and auranofin is very efficient to induce MM cells death, including PI-resistant cells and those with p53 deficiency [27][48][31][34][36]. TXN inhibition activates mitophagy, the selective degradation of mitochondria by autophagy, and negatively regulates the AKT/mTOR and ERK1/2 survival signaling pathways [36]. TNXRD1 inhibition impacts the NFκB signaling pathway [34]. Importantly, auranofin combined with BTZ alleviates the chemoresistance mediated by the tumor microenvironment [27]. A bis-chelated tetrahedral gold(I) phosphine complex seems even more powerful than auranofin to induce ROS-mediated apoptosis [49]. However, TNXRD1 inhibition could be compensated by the overexpression of HO1 through the NRF2 signaling pathway [35]. HO1 pharmacological inhibition using zinc protoporphyrin IX restores BTZ sensitivity [35]. A number of drugs targeting TXN and TXNRD1 and inducing ROS, have been described in the past decade [12], but their ability to synergize with PI in MM patients remains to be established. Nevertheless, the targeting of multiple antioxidant systems could be essential for an efficient anti-MM strategy.
    The IMiDs, lenalidomide and pomalidomide, are thalidomide analogs. They inhibit TXNRD1 that leads to an accumulation of cytotoxic H2O2 levels [37]. In contrast with auranofin and gold compounds, the cytotoxicity of IMiDs necessitates cereblon (CRBN), the substrate receptor the CUL4-RING E3 ligase complex [50]. Indeed, IMiDs/CRBN complexes are retained in the cells and change the redox status by inhibiting H2O2 degradation. Thus, MM cells with a low antioxidant capacity display increased sensitivity to IMiD-mediated cell death [50].

    2.2.2. Superoxide Dismutase (SOD1/2) Inhibitors

    Both SOD1 and SOD2 enzymes are overexpressed in MM cells and cell lines compared to normal plasma cells and mediate BTZ-resistance [27][40][39][38]. The inhibition of SOD1 with disulfiram and SOD2 with 2-methoxyestradiol induces apoptosis of both BTZ-sensitive and -resistant MM cells [40][39]. Among the various mechanisms of BTZ resistance, the 19S associated-ubiquitin receptor Rpn13 plays a major role since its inhibition restores BTZ sensitivity [51]. SOD1 is the mediator of Rpn13 signaling and in turn, SOD1 inhibition using the LCS-1 inhibitor, induces a ROS-mediated MM cell death including BTZ-resistant cells [38]. Scutellarein, a flavone extracted from a traditional Chinese medicinal herb, induces a mitochondrial-mediated apoptosis in the MM cells by activating SOD2. This leads to ROS accumulation and synergistic effects combined with BTZ [41].

    2.3. Other ROS-Inducing Drugs

    PDIs are ER-resident oxidoreductase enzymes that ensure the proper folding of nascent polypeptide chains by forming bonds between cysteine residues. PDIs are overexpressed in MM [43]. The inhibition of PDIs induces the accumulation of misfolded or unfolded proteins, an ER stress, and an oxidative stress. Moreover, both pathways are enhanced in response to PIs [42][43][44]. In turn, the concomitant inhibition of PDIs and UPR further enhances the proteotoxic/ER stress and oxidative stress, and the apoptotic response.
    Amino acid depletion triggered by L-asparaginase (ASNase) after hydrolysis of glutamine (glutaminolysis) sensitizes MM cells to CFZ [45]. This occurs via NRF2 upregulation, increased mitochondrial ROS generation and mitochondrial dysfunction. Deregulating the protein and amino acid synthesis programs allows PI-resistant MM cells to enter apoptosis [45].
    OXPHOS genes are often overexpressed in MM cells and associated with a poor prognosis [47]. This is due to the overexpression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In turn, OXPHOS genes are enriched in MM patients with high PGC-1α level and the PGC-1α inhibitor ST18292 exerts efficient antimyeloma effects trough ROS production [52].

    3. Global Alteration of MM Metabolism

    More generally, several metabolic pathways are altered in MM cells offering a plethora of potent targets (Figure 3) [52]. MM cells are particularly dependent on glycolysis. GLUT1/4 glucose transporters are expressed on MM cells and their activity is necessary for cell survival [53][54]. Ritonavir, a HIV protease inhibitor reversibly binds GLUT4 and induces MM cell apoptosis [55]. HK2, the first rate-limiting enzyme of the glycolysis cascade is expressed on MM cells at diagnosis and its overexpression is associated with poor prognosis [56][46]. HK2 converts glucose into G6P. The targeting of HK2 by the small molecule 3-bromopyruvate (3-BP) is efficient for killing MM cells [57]. Interestingly, the knockdown of HK2 by an antisense oligonucleotide (ASO) associated with DPI or metformin as mitochondrial complex I inhibitor, and perhexiline as β-oxidation inhibitor induces specifically tumor cell death [46]. The targeting of ENO1 that mediates the conversion 2-phospho-D-glycerate to phosphoenolpyruvate at the final step of the glycolytic pathway, also induces MM cell death. ENO1 is overexpressed in MM samples [58][59]. Other glycolytic enzymes such as phosphofructokinase (PFK), pyruvate kinase M2 (PKM2), and lactate dehydrogenase (LDHA) are also highly expressed in MM cells becoming attracting targets [56][60].
    Significant amounts of lactate are produced in MM cells confirming that the oxidative glycolysis is fully functional, but lactate is also produced by the stromal cells within the TME. Lactate enters MM cells through the MCT1 transporter and fuels OXPHOS [61]. The inhibition of MCT1 by the α-cyano-4-hydroxycinnamic acid reduces lactate incorporation and causes apoptosis [61]. Recently, phosphatase of regenerating liver 3 (PRL3), an interleukin-6-induced oncogenic phosphatase, has been shown essential for the metabolic changes of myeloma cells. PRL3 exerts pleiotropic effects. It promotes glucose uptake and glycolytic flux through the upregulation of glycolytic enzymes, and regulates the SSP leading to an increase in GSH intracellular content [59]. PRL3 is highly expressed in MM cells and correlates with poor prognosis and unfavorable outcome [62].
    As much as glucose, glutamine is used as an energy provider and MM cells are addicted to glutamine [63]. Alanine/serine/cysteine-preferring transporter 2 (ASCT2), L-type amino acid transporter (LAT1), and sodium-coupled neutral amino acid transporter 1 (SNAT1) are the glutamine transporters expressed on MM cells [63]. Although ASCT2, LAT1, and SNAT1 inhibitors have been assessed on several types of tumors, to our knowledge there is no data on myeloma. Glutamine synthase (GS) is lacking in MM cells, therefore MM cells are dependent on glutamine uptake. By contrast, glutaminase 1 (GLS1) expression is increased [63]. In turn, the inhibition GLS1 that catalyzes glutamine, by benzophenanthridinone (BPI) induces MM apoptosis [64]. An increased glutamine anaplerosis toward TCA cycle is observed in malignant MM cells and this increase is even more marked in comparison with MGUS and overt myeloma [65]. Importantly and different from normal plasma cells in this regard, glycolysis and OXPHOS compensate each other as well as glycolysis and glutaminolysis [55].
    Metabolic reprogramming in MM cells is also necessary for cells to adapt their TME. We have previously seen that glutamine, lactate, and probably other metabolites enter MM cells from the TME and in turn, change profoundly the cell metabolism. Furthermore, mitochondria are trafficking between MM cells and mesenchymal stromal cells through tumor-derived nanotubes [66]. The enhanced OXPHOS of MM cells could be the outcome of massive mitochondria acquisition and metabolism reprogramming. Although NOX2 could drive mitochondria transfer from stromal cells to tumor cells as shown for leukemic blasts [67], we have reported that a pan-NOX inhibitor induces MM cell death but shows adverse effect when combined with BTZ [27]. Alternatively, NOX inhibitors could be associated with drugs that have no impact on ROS production rather modifying glycolysis or glutaminolysis. Hypoxia is also a hallmark of the bone marrow niche and HIF-1α and HIF-2α that are stabilized in MM cells control glycolysis through the upregulation of genes coding for glycolytic enzymes and redox homeostasis.
    The vulnerability of MM cells to fatty acid metabolism is less studied. Fatty acid synthase (FASN) is overexpressed in MM patients and the inhibition of β-oxidation as well as de novo fatty acid synthesis induces MM cell death including BTZ-resistant cells [68]. Disruption of fatty acid oxidation confers sensitivity to CFZ [69]. Moreover, PI-resistant MM cells increase lipogenesis as a mechanism of resistance [19]. Perhexiline (PER) as a β-oxidation inhibitor synergizes with HK2-antisens oligonucleotide (ASO) for inducing cell death. Cell death is even dramatically enhanced with the triple combination PER/DPI/HK2-ASO [46]. Obesity is a risk factor for MM and bone marrow-resident adipocytes sustain MM growth [70]. By analogy with leukemias, a metabolic shift from glycolysis to enhanced β-oxidation could impact on MM survival [71].
    Interestingly, diet and nutrition are linked to risk factors for multiple myeloma [72][73]. Dietary factors may affect inflammation and endogenous growth factors pathways (e.g., IL6, insulin-like growth factor) thereby playing an important role in MM pathogenesis and in patients’ survival [74]. Moreover, diet may also impact the risk of developing MGUS, the premalignant condition of MM [75].
    The growth of MM cells within their bone marrow niche necessitates a metabolic shift that shapes the TME toward a hypoxic, acidic, and nutrients-poor milieu [76]. In turn, TME becomes unfavorable for immune cells including T cells and NK cells to exert their antitumor effects. TME displays also tumor-promoting activity by allowing the polarization of M2 macrophages and inhibiting regulatory T cells (Tregs). Several recent reviews are dedicated to this theme [77][76][78][79], we rapidly report here some important clues. The PD-1/PD-L1 pathway controls, at least in part, the maintenance of immune surveillance within the TME [80]. PD-L1 expression is increased in MM cells and associated with disease progression. Although several regulatory pathways are involved in the regulation of PD-L1 level such as JAK/STAT, PI3K/AKT, and ERK/MAPK pathways [81], it is worth noting that HIF-1α directly regulates positively CD274 gene (encoding PD-L1) transcription [82]. The increased expression of PD-L1 increases cell resistance to cytotoxic T-cell-mediated lysis [83]. Other immune-suppressive cells such as MDSCs [84] and TAMs [85] express high levels of PD-L1. One can imagine that the presence of hypoxic niches in the bone marrow drives the stabilization of HIF-1α that favors PD-L1 expression also in these cells. Moreover, hypoxia inhibits the killing potential of NK cells favoring immune evasion [86]. As described for melanoma cells, the acidity within the TME imposed by an enhanced glycolysis could impact tumor infiltrating lymphocytes (TILs) in promoting anergy and macrophages polarization supporting tumor growth [87][88]. These immunosuppressive pathways should be considered for efficient anti-myeloma therapy.

    4. Autophagy and Ferroptosis Are Forms of Death Controlled by MM Metabolism

    Due to their function of immunoglobulin synthesis, MM cells are addicted to UPS and to another protein degradation pathway, macroautophagy referred to as autophagy [89]. Autophagy is the cell mechanism of self-destruction for clearing organelles and compensate proteasome deficiency to degrade ubiquitinylated proteins. SQSTM1 is the autophagy cargo receptor that bridges ubiquitinylated proteins and autophagosomes and is a critical mediator of autophagy and PI-resistance [90]. In BTZ- and CFZ-resistant cells, SQSTM1 is overexpressed through the activation of NRF2 and this affects the fatty acid oxidation and in turn the level of NADPH [69]. The simultaneous inhibition of UPS and autophagy by hydroxychloroquine induces a synergistic cytotoxicity [91]. Furthermore, FAM46C that encodes a non-canonical poly(A) polymerase is mutated in almost 20% of MM patients. FAM46C sustains ER biogenesis in MM cells and this activity is controlled by autophagy through an inhibitory interaction with SQSTM1 [92]. This SQSTM1/FAM46C interplay could be exploited to increase PI efficacy and alleviate PI resistance.
    Another type of cell death has been described recently for MM cells: ferroptosis [93]. Ferroptosis is an iron-dependent programmed cell death characterized by a high lipid peroxidation and accumulation of ROS that occurs mainly through intracellular GSH depletion and decreased activity of GPX4 [94]. One way to reduce GSH level is to inhibit the Xc- antiporter that allows cysteine to enter cells (Figure 3). Starheim and coworkers have reported previously that inhibiting Xc- activity induces MM cell death including BTZ-resistant cells. However, in this report the nature of cell death was not examined. GPX4 is a key regulator of ferroptosis inhibiting the formation of lipid peroxide. GPX4, highly expressed in MM cells, is targeted by FTY720 leading to MM ferroptosis [93]. It appears that autophagy and apoptosis play a role in the occurrence of ferroptosis [94]. Although such interplay has not been reported for MM cells, it opens new perspectives for combinatory therapies.

    5. Conclusions

    MM cells have increased ROS levels in comparison to plasma cells, their normal counterparts. This high level of ROS contributes to the initiation, promotion, and progression of MM disease, as well as, resistance to chemotherapy. Therefore, increasing ROS to highly toxic levels may provide a unique tool to kill myeloma cells. This approach seems very efficient since ROS-inducing agents co-operate with PIs (and probably other drugs) and induce MM cell apoptosis including those that are PI-resistant. However, to our knowledge, despite preclinical evidences, no clinical trials using either drugs targeting antioxidant enzymes or depleting glutathione are currently ongoing (www.clinicaltrials.gov). One main concern is to know what are the effects of pro-oxidants on the MM cancer-stem cell (CSC). MM-CSCs is a rare subpopulation of cells that has the capacity for self-renewal and tumor initiation. CSCs are responsible for drug resistance and disease relapse [95]. Although the phenotype of MM CSC is still debated, by analogy with other hemopathies and solid tumors, CSCs likely, synthesize low levels of ROS and in turn, are little impacted by pro-oxidants. Indeed, pro-oxidants inhibit tumor cells proliferation but may have limited impact on cancer-stem cells that synthesize low ROS levels [96]. Moreover, in the perspective of an anti-myeloma immunotherapy, the complex network of immune cells, non-immune cells, and MM cells in their niche, including their redox status, should be better understood.
    Interestingly, several unrelated drugs are acting by modulating the redox status. Melphalan is an alkylating agent; its toxicity is due to a redox imbalance and melphalan resistance is linked to modulation of metabolic pathways as well as oxidative stress [97][98][99]. The depletion of intracellular GSH by BSO significantly enhances melphalan activity [97][98]. The next-generation melphalan pro-drug melflufen (melphalan flufenamide ethyl ester) is an alkylating agent that has shown its high efficacy. It was recently approved by the FDA for use in combination with dexamethasone in R/R MM patients [100]. Melflufen enters cells where it is targeted by aminopeptidases resulting in its trapping in organelles and membranes allowing its accumulation. In pre-clinical models, it has been shown that it generates ROS [101]. HDAC inhibitors, which regulate gene expression by inhibiting the deacetylation of histone proteins, have been shown to exert a wide array of antitumor effects including cell cycle arrest and cell death by generating ROS [102][103].
    Metabolism changes in MM cells show their vulnerability. For efficient killing of myeloma tumor cells, the design of metabolic targets and the choice of new combinations must take into account the modifications of metabolism imposed by the TME as well as the redox status of MM cells themselves.

    The entry is from 10.3390/cancers13102411


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