ABSTRACT
This systematic review examines the relationship with multiple myeloma (MM) risk for sunlight and vitamin D related exposures, including vitamin D supplementation, circulating 25-hydroxyvitamin D concentration, personal ultraviolet B radiation exposure, ambient solar irradiance and vitamin D receptor (VDR) gene polymorphisms We conducted a search for terms related to multiple myeloma, vitamin D, vitamin D receptor, ultraviolet radiation, sunlight, and single nucleotide polymorphism (SNP) using Ovid MEDLINE, Ovid EMBASE, Web of Science and Cochrane CENTRAL. Studies were assessed for risk of bias and quality using the RoB 2.0, ROBINS-E or Q-Genie tools. We identified 13 eligible studies: one randomised controlled trial, two cohort studies, and ten case-control studies, including one nested case-control study and one meta-analysis of genome-wide association studies. We conducted a qualitative synthesis; quantitative synthesis was not appropriate due to study heterogeneity and the small number of studies identified. There was insufficient evidence to support an effect of any sunlight or vitamin D related exposure on MM risk. No polymorphisms in VDR were found to be strongly related to risk for people of European ancestry. Of the identified studies, many had high risk of bias or were of lower quality. Few studies have investigated the association between sunlight and vitamin D related exposures and multiple myeloma risk. The scarcity of high-quality studies makes it difficult to evaluate potential effects of these exposures on MM risk. Further research is necessary to investigate the influence of vitamin D related exposures on risk of multiple myeloma..
Subject(s)
Multiple Myeloma , Receptors, Calcitriol , Humans , Case-Control Studies , Genome-Wide Association Study , Multiple Myeloma/etiology , Multiple Myeloma/genetics , Polymorphism, Single Nucleotide , Receptors, Calcitriol/genetics , Sunlight/adverse effects , Ultraviolet Rays , Vitamin D/geneticsABSTRACT
The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR action in myeloma. Here, we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that plays a role in improved myeloma cell killing. We show that the GR agonist dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells. In a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk likely arises from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR-MR homodimerization, while leaving GR-GR homodimerization intact. Unbiased transcriptomics analyses reveal that c-myc and many of its target genes are downregulated most by combined Dex-Spi treatment. Proteomics analyses further identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex-Spi downregulated genes and proteins that may predict prognosis in the CoMMpass myeloma patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies for glucocorticoid-based dose-reduction.
Subject(s)
Glucocorticoids , Multiple Myeloma , Humans , Glucocorticoids/pharmacology , Receptors, Mineralocorticoid/genetics , Dexamethasone/pharmacology , Dexamethasone/metabolism , Dexamethasone/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Spironolactone/therapeutic useABSTRACT
Previous studies have shown the potential of immunogenic cell death-related modalities in myeloma. The significance of IL5RA in myeloma and immunogenic cell death remains unknown. We analyzed IL5RA expression, the gene expression profile, and secretory protein genes related to IL5RA level using GEO data. Immunogenic cell death subgroup classification was performed using the ConsensusClusterPlus and pheatmap R package. Enrichment analyses were based on GO/KEGG analysis. After IL5RA-shRNA transfection in myeloma cells, cell proliferation, apoptosis, and drug sensitivity were detected. P < 0.05 was considered statistically significant. IL5RA was upregulated in myeloma and progressed smoldering myeloma. We observed enrichment in pathways such as the PI3K-Akt signaling pathway, and Natural killer cell mediated cytotoxicity in the high-IL5RA group. IL5RA was also closely associated with secretory protein genes such as CST6. We observed the enrichment of cellular apoptosis and hippo signaling pathway on differential genes in the immunogenic cell death cluster. Furthermore, IL5RA was associated with immune infiltration, immunogenic cell death-related genes, immune-checkpoint-related genes, and m6A in myeloma. In vitro and in vivo experiments showed the involvement of IL5RA in apoptosis, proliferation, and drug resistance of myeloma cells. IL5RA shows the potential to be an immunogenic cell death-related predictor for myeloma.
Subject(s)
Multiple Myeloma , Humans , Hippo Signaling Pathway , Immunogenic Cell Death , Interleukin-5 Receptor alpha Subunit/genetics , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/geneticsABSTRACT
Taurine upregulated gene 1 (TUG1) has been implicated in the onset and progression of various malignancies. The current study aimed to evaluate the biological function and potential mechanisms of TUG1 in multiple myeloma (MM) progression. TUG1 knockdown in MM cells was investigated in vitro and in vivo to evaluate the role of TUG1. We also predicted the transcription factor (TF) that bound to TUG1 together with the downstream target genes of the TUG1-TF interaction, and evaluated the regulatory mechanism of TUG1 in cell assays. TUG1 knockdown reduced the cell's proliferative and migratory capabilities while increasing apoptosis and bortezomib sensitivity in vitro and inhibiting tumorigenesis in vivo. TUG1 was found in the nucleus of MM cells and was found to be positively regulated by the TF-YY1. Further in vitro mechanistic investigations indicated that the YY1-TUG1 complex targeted YOD1 to regulate MM progression.
Subject(s)
MicroRNAs , Multiple Myeloma , RNA, Long Noncoding , Humans , Apoptosis/genetics , Bortezomib/pharmacology , Cell Line, Tumor , Cell Proliferation/genetics , Endopeptidases/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , RNA, Long Noncoding/genetics , Taurine , Thiolester Hydrolases/genetics , YY1 Transcription Factor/geneticsABSTRACT
Some cytogenetic abnormalities (CAs) are associated with poorer prognosis in multiple myeloma (MM); proteasome inhibitors appear to benefit patients with high-risk CAs. We evaluated 2247 MM patients from the TOURMALINE-MM1/-MM2/-MM3/-MM4 trials to assess the PFS benefit of ixazomib plus lenalidomide-dexamethasone (Rd) vs placebo-Rd (TOURMALINE-MM1/-MM2) or ixazomib vs placebo (TOURMALINE-MM3/-MM4) in specific high-risk CAs. After a pooled median follow-up of 25.6 months, the hazard ratio (HR) for PFS with ixazomib- vs placebo-based therapy for high-risk patients was 0.74 (95% confidence interval [CI]: 0.59-0.93; median PFS [mPFS] 17.8 vs 13.2 months), and 0.70 (95% CI: 0.62-0.80; mPFS 26.3 vs 17.6 months) for complementary standard-risk patients. The HR for expanded high-risk patients was 0.75 (95% CI: 0.64-0.87; mPFS 18.1 vs 14.1 months), and 0.71 (95% CI: 0.59-0.85; mPFS 36.1 vs 21.4 months) for complementary standard-risk patients. The HR for PFS with ixazomib- vs placebo-based therapy was 0.68 in patients with t(4;14) (95% CI: 0.48-0.96; mPFS 22.4 vs 13.2 months), and 0.77 for patients with amp1q21 (95% CI: 0.63-0.93; mPFS 18.8 vs 14.5 months). A PFS benefit was demonstrated with ixazomib- vs placebo-based therapy regardless of cytogenetic status, with greatest benefit observed in patients with t(4;14) and amp1q21.
Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Lenalidomide/therapeutic use , Dexamethasone/adverse effects , Boron Compounds/adverse effects , Chromosome Aberrations , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Multiple myeloma (MM) is a pernicious plasma cell disorder and has a poor prognosis. N6-methyladenosine (m6A) is an abundant epigenetic RNA modification and is important in cancer progression. Nevertheless, the function of m6A and its regulator METTL3 in MM are rarely reported. Here, we identified the m6A "writers", METTL3, was enhanced in MM and found that Yin Yang 1 (YY1) and primary-miR-27a-3p were the potential target for METTL3. METTL3 promoted primary-miR-27a-3p maturation and YY1 mRNA stability in an m6A manner. YY1 also was found to facilitate miR-27a-3p transcription. METTL3 affected the growth, apoptosis, and stemness of MM cells through accelerating the stability of YY1 mRNA and the maturation of primary-miR-27a-3p in vitro and in vivo. Our results reveal the key function of the METTL3/YY1/miR-27a-3p axis in MM and may provide fresh insights into MM therapy.
Subject(s)
Methyltransferases , MicroRNAs , Multiple Myeloma , YY1 Transcription Factor , Humans , Carcinogenesis , Cell Transformation, Neoplastic , Methyltransferases/genetics , Methyltransferases/metabolism , MicroRNAs/genetics , Multiple Myeloma/genetics , YY1 Transcription Factor/genetics , YY1 Transcription Factor/metabolismABSTRACT
Multiple myeloma (MM) is a plasma cell malignancy that, despite recent advances in therapy, continues to pose a major challenge to hematologists. Currently, different classes of drugs are applied to treat MM, among others, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Most of them participate in an interplay with the immune system, hijacking its effector functions and redirecting them to anti-MM activity. Therefore, adjuvant therapies boosting the immune system may be potentially beneficial in MM therapy. Vitamin D (VD) and vitamin K (VK) have multiple so called "non-classical" actions. They exhibit various anti-inflammatory and anti-cancer properties. In this paper, we investigated the influence of VD and VK on epigenetic alterations associated with the proliferative potential of MM cells and the development of BTZ resistance. Our results showed that the development of BTZ resistance is associated with a global decrease in DNA methylation. On the contrary, both control MM cells and BTZ-resistant MM cells exposed to VD alone and to the combination of VD and VK exhibit a global increase in methylation. In conclusion, VD and VK in vitro have the potential to induce epigenetic changes that reduce the proliferative potential of plasma cells and may at least partially prevent the development of resistance to BTZ. However, further ex vivo and in vivo studies are needed to confirm the results and introduce new supplementation recommendations as part of adjuvant therapy.
Subject(s)
Multiple Myeloma , Vitamin D , Humans , Vitamin D/pharmacology , Bortezomib/pharmacology , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Vitamins , Vitamin K , DNA Methylation , Dietary SupplementsABSTRACT
Multiple myeloma (MM) remains an incurable hematological malignancy. Bortezomib (BTZ) is a proteasome inhibitor widely used in MM therapy whose potent activity is often hampered by the development of resistance. The immune system is vital in the pathophysiology of BTZ resistance. Vitamins D (VD) and K (VK) modulate the immune system; therefore, they are potentially beneficial in MM. The aim of the study was to evaluate the effect of BTZ therapy and VD and VK supplementation on the proliferation potential and gene expression profiles of MM cells in terms of the development of BTZ resistance. The U266 MM cell line was incubated three times with BTZ, VD and VK at different timepoints. Then, proliferation assays, RNA sequencing and bioinformatics analysis were performed. We showed BTZ resistance to be mediated by processes related to ATP metabolism and oxidative phosphorylation. The upregulation of genes from the SNORDs family suggests the involvement of epigenetic mechanisms. Supplementation with VD and VK reduced the proliferation of MM cells in both the non-BTZ-resistant and BTZ-resistant phenotypes. VD and VK, by restoring proper metabolism, may have overcome resistance to BTZ in vitro. This observation forms the basis for further clinical trials evaluating VD and VK as potential adjuvant therapies for MM patients.
Subject(s)
Antineoplastic Agents , Multiple Myeloma , Humans , Bortezomib/pharmacology , Bortezomib/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Transcriptome , Vitamins/therapeutic use , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic useABSTRACT
Recent studies have suggested the potency of berberine (BBR) for multiple cancer treatments, including multiple myeloma (MM). However, the direct target and underlying mechanism of BBR remain largely understood in MM. Here, we demonstrated that BBR inhibited cell proliferation and acted synergistically with bortezomib in MM.1S cells. BBR treatment induced MM cell cycle arrest by downregulating several cell cycle-related proteins. Murine double minute 2 (MDM2) as a BBR-binding protein was identified by surface plasmon resonance image (SPRi) analysis and molecular docking. Overexpression of MDM2 is associated with MM progression and a poor prognosis. Knockdown MDM2 by siRNA transfection can repress MM malignant progression and attenuate the BBR sensitivity to MM.1S cells. BBR treatment induced the degradation of MDM2 through the ubiquitin-proteasome system and reactivated P53/P21 in MM cells. Overall, our data has illustrated that MDM2, as a binding protein of BBR for the first time, may serve as a potential therapeutic option for MM.
Subject(s)
Berberine , Multiple Myeloma , Animals , Apoptosis , Berberine/pharmacology , Berberine/therapeutic use , Bortezomib/metabolism , Carcinogenesis , Cell Line, Tumor , Humans , Mice , Molecular Docking Simulation , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Proteasome Endopeptidase Complex/metabolism , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , RNA, Small Interfering , Tumor Suppressor Protein p53/genetics , UbiquitinABSTRACT
Multiple myeloma is one of the most hard-to-treat cancers among blood malignancies due to the high rate of drug resistance and relapse. The researchers are trying to find more effective drugs for treatment of the disease. Hence, the use of drugs targeting signaling pathways has become a powerful weapon. Overactivation of phosphatidylinositol 3-kinase signaling pathways is frequently observed in multiple myeloma cancer cells, which increases survival, proliferation, and even drug resistance in such cells. In recent years, drugs that inhibit the mediators involved in this biological pathway have shown promising results in the treatment of multiple myeloma. In the present study, we aimed to introduce phosphatidylinositol 3-kinase signaling inhibitors which include small molecules, herbal compounds, and microRNAs.
Subject(s)
MicroRNAs , Multiple Myeloma , Humans , MicroRNAs/genetics , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Neoplasm Recurrence, Local , Phosphatidylinositol 3-Kinases/metabolism , Signal TransductionABSTRACT
Multiple myeloma (MM) is a genetically heterogeneous malignancy characterized by variable treatment responses. Although numerous drugs have been approved in recent years, the ability to predict treatment response and tailor individual therapy is limited by the absence of robust predictive biomarkers. The goal of this clinical trial was to use ex vivo, high-throughput screening (HTS) of 170 compounds to predict response among patients with relapsed or refractory MM and inform the next treatment decisions. Additionally, we integrated HTS with multi-omic analysis to uncover novel associations between in vitro drug sensitivity and gene expression and mutation profiles. MATERIALS AND METHODS: Twenty-five patients with relapsed or refractory MM underwent a screening bone marrow or soft tissue biopsy. Sixteen patients were found to have sufficient plasma cells for HTS. Targeted next-generation sequencing was performed on plasma cell-free DNA from all patients who underwent HTS. RNA and whole-exome sequencing of bone marrow plasma cells were performed on eight and seven patients, respectively. RESULTS: Results of HTS testing were made available to treating physicians within a median of 5 days from the biopsy. An actionable treatment result was identified in all 16 patients examined. Among the 13 patients who received assay-guided therapy, 92% achieved stable disease or better. The expression of 105 genes and mutations in 12 genes correlated with in vitro cytotoxicity. CONCLUSION: In patients with relapsed or refractory MM, we demonstrate the feasibility of ex vivo drug sensitivity testing on isolated plasma cells from patient bone marrow biopsies or extramedullary plasmacytomas to inform the next line of therapy.
Subject(s)
High-Throughput Screening Assays , Multiple Myeloma/drug therapy , Aged , Drug Evaluation, Preclinical , Female , Humans , Male , Middle Aged , Multiple Myeloma/genetics , Treatment OutcomeABSTRACT
BACKGROUND: Bone marrow mesenchymal stem cells (BMMSCs) were proved to play a vital role in multiple myeloma (MM). Polygonatum sibiricum polysaccharide (PSP) was found to have anti-tumor pharmacological effects, yet its interaction with BMMSCs remained poorly understood. Therefore, we explore the effect of PSP on osteogenic differentiation of BMMSCs. METHODS: BMMSCs were isolated by density gradient centrifugation. CD90 and CD34 were detected by flow cytometry (FCM). Osteogenic marks were detected by quantitative real-time PCR (qRT-PCR) and Western blotting (WB). The vitality of cells treated with different concentrations of PSP was observed by Cell Counting Kit-8 (CCK-8). ALP staining kit was used to detect the activity of alkaline phosphatase (ALP). Alizarin red staining detected the formation of mineralized nodules. Osteoblast-associated genes were evaluated by qRT-PCR and WB. The phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) signaling pathways were tested by WB. RESULTS: The BMMSCs showed good growth under an inverted microscope. FCM showed that CD34 and CD45 was low-expressed, whereas CD44, CD90 and CD105 was highly expressed. Compared with the Control group, the expressions of Runx2 and ALP in cells were significantly increased. CCK-8 showed that different concentrations of PSP had no significant effect on the viability of BMMSCs. BMMSCs treated with 25 mg/l PSP were stained the most deeply by ALP. Mineralized nodules in PSP groups dramatically increased, and hit a peak under the action of 25 mg/l PSP. PSP up-regulated p-PI3K, p-AKT, and p-mTOR, but had no significant effect on PI3K, AKT, and mTOR. CONCLUSION: PSP induced osteogenic differentiation of BMMSCs from MM patients.
Subject(s)
Biomarkers, Tumor/genetics , Mesenchymal Stem Cells/cytology , Multiple Myeloma/pathology , Osteogenesis/drug effects , Polygonatum/chemistry , Polysaccharides/pharmacology , Alkaline Phosphatase/genetics , Cell Differentiation/drug effects , Cells, Cultured , Core Binding Factor Alpha 1 Subunit/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mesenchymal Stem Cells/chemistry , Mesenchymal Stem Cells/drug effects , Models, Biological , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Phosphatidylinositol 3-Kinase/metabolism , Phosphorylation/drug effects , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolismABSTRACT
Boosting the production of recombinant therapeutic antibodies is crucial in both academic and industry settings. In this work, we investigated the usage of varying signal peptides by antibody V-genes and their roles in recombinant transient production, systematically comparing myeloma and the native signal peptides of both heavy and light chains in 168 antibody permutation variants. We found that amino acids count and types (essential or non-essential) were important factors in a logistic regression equation model for predicting transient co-transfection protein production rates. Deeper analysis revealed that the culture media were often incomplete and that the supplementation of essential amino acids can improve the recombinant protein yield. While these findings are derived from transient HEK293 expression, they also provide insights to the usage of the large repertoire of antibody signal peptides, where by varying the number of specific amino acids in the signal peptides attached to the variable regions, bottlenecks in amino acid availability can be mitigated.
Subject(s)
Amino Acids/metabolism , Antibodies, Monoclonal, Humanized/biosynthesis , Antineoplastic Agents, Immunological/metabolism , Biotechnology , Immunoglobulin E/biosynthesis , Immunoglobulin Variable Region , Protein Engineering , Protein Sorting Signals , Trastuzumab/biosynthesis , Antibodies, Monoclonal, Humanized/genetics , Culture Media/metabolism , HEK293 Cells , Humans , Immunoglobulin E/genetics , Immunoglobulin Variable Region/genetics , Multiple Myeloma/genetics , Multiple Myeloma/immunology , Protein Sorting Signals/genetics , Recombinant Proteins/biosynthesis , Trastuzumab/genetics , WorkflowABSTRACT
Multiple myeloma (MM) is a plasma cell malignancy frequently accompanied with skeletal co-morbidity. Vitamin D (1,25(OH)2D) is an important mediator of skeletal homeostasis that mediates its effect by binding to vitamin D receptor (VDR), a steroid family receptor and modulates various downstream pathways. Multiple polymorphisms have been determined in VDR gene that witnessed significant association with cancer development and progression. Therefore, in this maiden study, we recruited 75 newly diagnosed MM patients and 75 control subjects. 25-hydroxy vitamin D (25(OH)D) levels were measured in all recruited study subjects. Further, PCR-RFLP was performed in DNA samples of recruited study subjects. Results demonstrated significantly decreased 25(OH)D levels in MM patients compared to controls. Additionally, decreased 25(OH)D levels in MM patients inversely associated with disease severity. Further, single nucleotide polymorphism (SNP) analysis of VDR gene showed significantly higher risk of MM disease development in Ffâ¯+â¯ff, Aaâ¯+â¯aa, and Bbâ¯+â¯bb genotypes. Additionally, FokI f, ApaI a and BsmI b alleles were significantly associated with MM occurrence. In conclusion, this study provided initial evidences of association between 25(OH)D insufficiency, VDR gene polymorphism and MM development. Thus, we suggest that a study involving assessment of 25(OH)D levels and VDR gene polymorphism in large patients' cohort might substantiate their role in MM development which would further provide impetus to give 25(OH)D supplementation along with conventional chemotherapeutic agents for myeloma treatment in future.
Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Multiple Myeloma/genetics , Receptors, Calcitriol/genetics , Adult , Alleles , Female , Genotype , Humans , Male , Middle Aged , Multiple Myeloma/pathology , Polymorphism, Single Nucleotide/genetics , Protein Isoforms/genetics , Vitamin D/analogs & derivatives , Vitamin D/geneticsABSTRACT
INTRODUCTION: Deletion of chromosome 17p [del(17p)] in patients with multiple myeloma is associated with a poor prognosis. Highdose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of treatment in this population. OBJECTIVES: The aim of the study was to compare the treatment outcomes with highdose chemotherapy and ASCT with standard treatment in patients with del(17p). PATIENTS AND METHODS: We collected data from 12 Polish centers between 2011 and 2017. The records of 97 patients with p53 deletion were assessed, including 29 individuals treated with ACST and 68 receiving standard treatment alone. RESULTS: During the followup, 45 patients died and the overall survival (OS) for the whole group was 33 months (range, 1-66 months), with a median progressionfree survival (PFS) of 13 months (range, 1-46 months). The prognostic factors of OS in a multivariable analysis were calcium levels at diagnosis within the reference range (hazard ratio [HR], 0.24; 95% CI, 0.12-0.48) and at least partial remission achieved after the firstline treatment (HR, 0.25; 95% CI, 0.12-0.51). Treatment with ASCT was an important factor in improving survival (HR, 3.23; 95% CI, 1.52-6.84). Abnormal kidney function at the time of diagnosis reduced the PFS (HR, 0.46; 95% CI, 0.22-0.94). When the analysis was limited only to patients who could be candidates for ASCT, the survival benefit of the procedure was lost (P = 0.21). CONCLUSIONS: Patients with multiple myeloma with del(17p) do not benefit from highdose chemotherapy followed by ACST.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 17 , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Proportional Hazards Models , Transplantation, Autologous , Treatment OutcomeABSTRACT
Heparanase is known to enhance the progression of many cancer types and is associated with poor patient prognosis. We recently reported that after patients with multiple myeloma were treated with high dose chemotherapy, the tumor cells that emerged upon relapse expressed a much higher level of heparanase than was present prior to therapy. Because tumor cells having stemness properties are thought to seed tumor relapse, we investigated whether heparanase had a role in promoting myeloma stemness. When plated at low density and grown in serum-free conditions that support survival and expansion of stem-like cells, myeloma cells expressing a low level of heparanase formed tumor spheroids poorly. In contrast, cells expressing a high level of heparanase formed significantly more and larger spheroids than did the heparanase low cells. Importantly, heparanase-low expressing cells exhibited plasticity and were induced to exhibit stemness properties when exposed to recombinant heparanase or to exosomes that contained a high level of heparanase cargo. The spheroid-forming heparanase-high cells had elevated expression of GLI1, SOX2 and ALDH1A1, three genes known to be associated with myeloma stemness. Inhibitors that block the heparan sulfate degrading activity of heparanase significantly diminished spheroid formation and expression of stemness genes implying a direct role of the enzyme in regulating stemness. Blocking the NF-κB pathway inhibited spheroid formation and expression of stemness genes demonstrating a role for NF-κB in heparanase-mediated stemness. Myeloma cells made deficient in heparanase exhibited decreased stemness properties in vitro and when injected into mice they formed tumors poorly compared to the robust tumorigenic capacity of cells expressing higher levels of heparanase. These studies reveal for the first time a role for heparanase in promoting cancer stemness and provide new insight into its function in driving tumor progression and its association with poor prognosis in cancer patients.
Subject(s)
Down-Regulation , Glucuronidase/genetics , Multiple Myeloma/pathology , Neoplastic Stem Cells/pathology , Aldehyde Dehydrogenase 1 Family/genetics , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Exosomes/enzymology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Multiple Myeloma/genetics , Neoplasm Transplantation , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/enzymology , Retinal Dehydrogenase/genetics , SOXB1 Transcription Factors/genetics , Spheroids, Cellular/cytology , Zinc Finger Protein GLI1/geneticsABSTRACT
Betulinic acid (BA), as a prospective natural compound, shows outstanding antitumor bioactivities against many solid malignancies. However, its mechanism against multiple myeloma (MM) remains elusive. Herein, for the first time, we studied the antitumor activity of BA against MM both in vivo and in vitro. We showed that BA mediated cytotoxicity in MM cells through apoptosis, S-phase arrest, mitochondrial membrane potential (MMP) collapse, and overwhelming reactive oxygen species (ROS) accumulation. Moreover, when the ROS scavenger N-acetyl cysteine (NAC) effectively abated elevated ROS, the BA-induced apoptosis was partially reversed. Our results revealed that BA-mediated ROS overproduction played a pivotal role in anticancer activity. Molecularly, we found that BA resulted in marked inhibition of the aberrantly activated NF-κB pathway in MM. As demonstrated by using the NF-κB pathway-specific activator TNF-α and the inhibitor BAY 11-7082, BA-mediated inhibition of the NF-κB pathway directly promoted the overproduction of ROS and, ultimately, cell death. Furthermore, BA also exerted enormous tumor-inhibitory effects via repressing proliferation and inhibiting the NF-κB pathway in our xenograft model. Overall, by blocking the NF-κB pathway that breaks redox homeostasis, BA, as a potent NF-κB inhibitor, is a promising therapeutic alternative for MM.
Subject(s)
Multiple Myeloma/drug therapy , NF-kappa B/metabolism , Triterpenes/therapeutic use , Animals , Apoptosis , Cell Cycle Checkpoints , Humans , Mice , Mice, Nude , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Pentacyclic Triterpenes , Reactive Oxygen Species , Triterpenes/pharmacology , Xenograft Model Antitumor Assays , Betulinic AcidABSTRACT
Despite advances in the treatment of multiple myeloma, the disease still remains incurable for the majority of patients. The overexpression of anti-apoptotic proteins (i.e., Bcl-2, Bcl-XL or Mcl-1) is a hallmark of cancer and favors tumor cell survival and resistance to therapy. The oral drug venetoclax is the first-in-class Bcl-2-specific BH3 mimetic. In myeloma, in vitro sensitivity to venetoclax is mainly observed in plasma cells harboring the t(11;14) translocation, a molecular subgroup associated with high Bcl-2 and low Mcl-1/Bcl-XL expression. In addition with Bcl-2 members expression profile, functional tests as BH3 profiling or in vitro BH3 mimetic drug testing also predict sensitivity to the drug. Phase 1 clinical trials recently confirmed the efficacy of venetoclax monotherapy in heavily pretreated myeloma patients, mostly in patients with t(11;14). In combination with the proteasome inhibitor bortezomib, venetoclax therapy was found to be feasible and allowed promising response rate in relapsed myeloma patients, independent of t(11;14) status. The present review summarizes the current knowledge, "from bench to bedside", about venetoclax for the treatment of multiple myeloma.
Subject(s)
Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Apoptosis/genetics , Biomarkers , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Clinical Trials, Phase I as Topic , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Molecular Targeted Therapy/methods , Multiple Myeloma/genetics , Mutation , Protein Binding , Protein Interaction Domains and Motifs/drug effects , Proto-Oncogene Proteins c-bcl-2/chemistry , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction/drug effects , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Treatment OutcomeABSTRACT
Mutational characterisation in extramedullary multiple myeloma (EM-MM) patients is challenging due to inaccessible EM plasmacytomas, unsafe nature of multiple biopsies and the spatial and temporal genomic heterogeneity apparent in MM (Graphical abstract). Conventional monitoring of disease burden is through serum markers and PET-CT, however these modalities are sometimes inadequate (serum markers), not performed in a timely manner (PET-CT) and uninformative for identifying mutations driving disease progression. DNA released into the blood by tumour cells (ctDNA) contains the predominant clones derived from the multiple disease foci. Blood-derived ctDNA can, therefore, provide a holistic illustration of the major drivers of disease progression. In this report, the utility of ctDNA, as an adjunct to currently available modalities in EM-MM, is presented for a patient with EM and oligosecretory (OS) disease. Whole exome sequencing of contemporaneously acquired tumour tissue and matched ctDNA samples revealed the presence of spatial and temporal genetic heterogeneity and the identification of pathways associated with drug resistance. Longitudinal monitoring of plasma samples revealed that ctDNA can be utilised to define the dynamic clonal evolution co-existent with disease progression and as an adjunct non-invasive marker of tumour burden.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , GTP Phosphohydrolases/genetics , Membrane Proteins/genetics , Multiple Myeloma/genetics , Plasmacytoma/genetics , Biomarkers, Tumor/blood , Circulating Tumor DNA/blood , Clonal Evolution , Disease Progression , Female , GTP Phosphohydrolases/blood , Hematopoietic Stem Cell Transplantation , Humans , Membrane Proteins/blood , Middle Aged , Multiple Myeloma/blood , Multiple Myeloma/diagnostic imaging , Multiple Myeloma/therapy , Mutation , Plasma Cells/metabolism , Plasma Cells/pathology , Plasmacytoma/blood , Plasmacytoma/diagnostic imaging , Plasmacytoma/therapy , Positron Emission Tomography Computed Tomography , Exome SequencingABSTRACT
BACKGROUND: Berberine downregulated miR-19a/92a cluster expression in multiple myeloma (MM) cells. METHODS: The cell viability of MM cells after berberine treatment was measured by CCK8 assay. qRT-PCR assay validated miR-19a/92a expression in multiple myeloma cells. TAM database analyzed miR-19a/92a-associated disease. miREnvironment database revealed that effects of environmental factors on the miR-19a/92a cluster. By targeting the seed region in the miRNA, the role of t-anti-miR-19a/92a cluster was evaluated by cell proliferation, migration, and colony formation. RESULTS: Berberine inhibited the cell viability of MM cells and downregulated the expression of miR-19a/92a. Seven kinds of hematological malignancies are closely associated with miR-19a/92a expression. By targeting the seed region of the miRNA, t-anti-miR-19a/92a significantly inhibits multiple myeloma cell proliferation, migration, and colony formation. CONCLUSION: Our findings may exhibit that miR-19a/92a cluster is a therapeutic target for MM and provide new mechanistic insight into the anti-MM effects of certain compounds in traditional Chinese herbal medicines.