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2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1540-1547, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607309

RESUMO

OBJECTIVE: To investigate the expression, mechanism and methylation level of miR-28-5p in multiple myeloma (MM), so as to provide the expirement basis for searching new targeted therapy. METHODS: RT-PCR was used to detect the expression levels of miR-28-5p and potential target CCND1 in CD138+ cells of the patients with MM and bone marrow mononuclear cells of patients with iron defficiency anemia(IDA) as control, Methylation-specific PCR(MSP) was used to detect methylation levels of CpG island in LPP/miR-28-5p promoter region and the correlation with other clinical indicators was analyzed. The 5-aza-2'-deoxycytidine (5-Aza-dC,DAC) was used to treat MM cell line U266; after drug treatment,MSP was used to analyze the methylation status of the CpG islands in LPP/miR-28-5p promoter; the qPCR was used to detect the expression levels of miR-28-5p,and the regulatory mechanism of miR-28-5p expression was explored furtherly. RESULTS: The methylation level of CpG island in LPP/miR-28-5p promoter region of MM patients was significantly higher than that of IDA patients. The relative expression level of miR-28-5p in MM patients was significantly lower than that of IDA patients. The relative expression level of miR-28-5p in newly diagnosed MM patients was higher than that in relapsed/progressive patients. The miR-28-5p target CCND1 was expressed at high levels in MM patients with LPP / miR-28-5p methylation, the expression level of miR-28-5p in MM patients correlated with ß2-MG concentration. 5-aza-dc could significantly inhibit the growth of U266 cell line, arrest the cell cycle in G1 phase, inhibit the biosynthesis of cellular RNA and protein and promote cell apoptosis. At the same time, up-regulation of miR-28-5p expression was found. CONCLUSION: The expression of miR-28-5p in MM patients is regulated by methylation of CpG islands in the promoter region of the genome.miR-28-5p may act as a tumor suppressor gene, and its low expression may be involved in the occurrence and development of MM, suggesting that miR-28-5p may become a new target for the treatment of MM.


Assuntos
MicroRNAs/genética , Mieloma Múltiplo , Linhagem Celular Tumoral , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Mieloma Múltiplo/genética
3.
Rinsho Ketsueki ; 60(9): 1236-1242, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597849

RESUMO

Recent technology advances in genomic analysis have unraveled the genomic complexity and evolutionary process of multiple myeloma (MM). Hyperdiploidy or IgH translocations t (4;14), t (11;14), t (6;14), t (14;16), and t (14;20), leading to ectopic overexpression of MMSET/FGFR3, CCND1, CCND3, MAF, and MAFB, respectively, are initiating events. Subsequent secondary events, such as gene copy number alterations, and gene somatic mutations, participate in tumor progression in a branching pattern consistent with Darwin's evolutionary model. Copy number alterations, such as 1q21 amplification and del (17p), have been associated with adverse outcomes. N/KRAS mutations are most commonly found in around 20% of patients, but numerous gene mutations are infrequent. Pathological and clinical relevance of gene mutations combined with cytogenetic abnormalities are currently under investigation. Additionally, detailed genomic analysis of individual patients using targeted-sequencing panels has been facilitated, and efforts toward personalized therapy based on molecular features have begun. This paper outlines MM molecular pathology and its clinical application in Japanese patients.


Assuntos
Mieloma Múltiplo/genética , Aberrações Cromossômicas , Dosagem de Genes , Humanos , Japão , Translocação Genética
5.
Medicine (Baltimore) ; 98(33): e16711, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415363

RESUMO

BACKGROUND: Multiple myeloma (MM) is a clonal plasma cell malignancy associated with hypercalcemia, bone lesions, and renal failure. The prognostic significance of the mutation of miRNAs, one kind of small noncoding RNA molecules that can modulate gene expression, should be confirmed in non-Hodgkin lymphomas (NHL). This study aimed to identify the prognostic value of miRNAs in patients with MM. METHODS: A meta-analysis was performed to estimate the pooled hazard ratios and their corresponding 95% confidence intervals for the associations between levels of miRNA expression (predictive factors) and outcomes in patients with MM. We systematically searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases (final search conducted January 1, 2018) to identify eligible studies. Eligible studies were included by certain inclusion and exclusion criteria, whose quality was assessed by Newcastle-Ottawa Scale. RESULTS: After performing the literature search and review, 10 relevant studies, including 1214 cases, were identified. The results of our meta-analysis revealed that upregulated miR-92a level and downregulated miR-16, miR-25, miR-744, miR-15a, let-7e, and miR-19b expression were associated with poor prognosis in MM. CONCLUSIONS: This study identified miRNAs could serve as potential prognostic biomarkers in MM. Given the limited research available, the clinical application of these findings has yet to be verified.


Assuntos
MicroRNAs/metabolismo , Mieloma Múltiplo/genética , Biomarcadores Tumorais/metabolismo , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Masculino , Mutação , Prognóstico , Modelos de Riscos Proporcionais , Regulação para Cima
6.
Orv Hetil ; 160(24): 944-951, 2019 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-31433233

RESUMO

Introduction: Plasma cell myeloma is a hematological malignancy with heterogeneous genomic landscape and diverse clinical course. Recurrent chromosomal and subchromosomal aberrations commonly occur in this entity and are associated with the pathogenesis and progression of the disease. The identification of these alterations aids genetic characterization, classification and prognostication of patients. Aim: Molecular cytogenetic investigations of plasma cell myeloma patients treated at the University of Pécs Clinical Center and János Balassa County Hospital of Tolna County, Szekszárd, between 2005 and 2018 were evaluated in our study. Method: 231 patients were screened for genetic aberrations using fluorescence in situ hybridization. Translocations involving the immunoglobulin heavy chain gene, losses of 1p and 17p chromosome arms, gains of 1q chromosome arm and unbalanced aberrations of chromosome 13 were investigated. Losses and gains of 1p, 1q, 5q, 12p, 13q, 16q and 17p chromosome arms were analyzed using multiplex ligation-dependent probe amplification in 42 patients. During the investigated period, 116 bone marrow karyotyping was also performed. Results: In total, 233 genetic aberrations were identified using our targeted approaches; the frequency of specific aberrations correlated with data of the recent literature. Concordance of results gained by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification was 96.2% by analyzing the same chromosome arms. The latter technique revealed 21 additional genetic aberrations in 16/42 patient samples (38%) as compared to fluorescence in situ hybridization. Conclusions: Our results suggest that the combined application of the two molecular cytogenetic methods may facilitate a more detailed characterization of genetic aberrations of plasma cell myeloma patients in Hungary. Orv Hetil. 2019; 160(24): 944-951.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Mieloma Múltiplo/genética , Humanos , Hungria/epidemiologia , Hibridização in Situ Fluorescente , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/patologia
7.
Nat Commun ; 10(1): 3835, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444325

RESUMO

The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Here we report a catalog and hierarchy of driver lesions using sequences from 67 MM genomes serially collected from 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups with distinct sets of co-operating events. Focusing on whole genome sequencing data, complex structural events emerge as major drivers, including chromothripsis and a novel replication-based mechanism of templated insertions, which typically occur early. Hyperdiploidy also occurs early, with individual trisomies often acquired in different chronological windows during evolution, and with a preferred order of acquisition. Conversely, positively selected point mutations, whole genome duplication and chromoplexy events occur in later disease phases. Thus, initiating driver events, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of evolution that are biologically relevant but heterogeneous across patients.


Assuntos
Carcinogênese/genética , Genoma Humano/genética , Modelos Genéticos , Mieloma Múltiplo/genética , Adulto , Idoso , Teorema de Bayes , Medula Óssea/patologia , Cromossomos Humanos/genética , Cromotripsia , Replicação do DNA , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Filogenia , Mutação Puntual , Fatores de Tempo , Sequenciamento Completo do Genoma
9.
Mol Med Rep ; 20(3): 2159-2166, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322175

RESUMO

Ribonucleotide reductase M2 (RRM2) is one of the two subunits that comprise ribonucleotide reductase (RR), the enzyme that catalyzes the conversion of ribonucleotide 5'­diphosphates into 2'­deoxyribonucleotides, which are required for DNA synthesis. RRM2 is a stress response factor important for the development of several tumors. However, its role in multiple myeloma (MM) remains to be fully elucidated. The present study aimed to investigate the role of RRM2 in MM. The expression of RRM2 in patients with MM was analyzed using the Oncomine database. The results demonstrated that RRM2 expression was higher in MM compared with healthy subjects. Reverse transcription­quantitative polymerase chain reaction and western blot results revealed that RRM2 expression was decreased following transfection with a small interfering RNA targeting RRM2 into NCI­H929 cells. RR activity and Cell Counting Kit­8 assays demonstrated that RRM2 silencing reduced RR activity and inhibited cell proliferation. Annexin V­propidium iodide staining indicated that the percentage of apoptotic NCI­H929 cells was increased following RRM2 silencing compared with that in the control group. Increased phosphorylation of H2AX indicated that RRM2 silencing may activate the DNA­damage response pathway in NCI­H929 cells. Western blot analysis revealed that protein levels of the apoptosis­associated factor Bcl­2 were reduced, whereas Bax, cleaved caspase­3 and cleaved poly(ADP­ribose) polymerase 1 were upregulated following RRM2 silencing compared with the control group. In addition, the results demonstrated that RRM2 silencing may inhibit target gene expression in the Wnt/ß­catenin signaling pathway by increasing the phosphorylation of glucose synthase kinase 3ß. These findings indicated that RRM2 may be involved in the proliferation and apoptosis of MM cells via the Wnt/ß­catenin signaling pathway, suggesting that RRM2 may represent a novel therapeutic target for MM.


Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Ribonucleosídeo Difosfato Redutase/genética , Via de Sinalização Wnt , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Mieloma Múltiplo/metabolismo , Interferência de RNA , Regulação para Cima
10.
Mol Med Rep ; 20(3): 2410-2418, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322176

RESUMO

The aim of the present study was to investigate the effect of bortezomib on heat shock protein 27 (HSP27) in multiple myeloma (MM) and provide a potential new target for clinical treatment. Peripheral blood was collected from 50 normal subjects and 50 patients with newly diagnosed MM and the expression of HSP27 was detected by ELISA. The changes of HSP27 after conventional vincristine, doxorubicin and dexamethasone (VAD) chemotherapy, and bortezomib plus VAD were compared. The effect of bortezomib on U266 cell proliferation and apoptosis was detected using a Cell Counting Kit­8 assay and Annexin V­FITC/propidium iodide double staining with flow cytometry. The content of HSP27 following bortezomib treatment was determined by ELISA. Western blot analysis and reverse transcription­quantitative PCR were used to detect the mRNA and protein expression of HSP27, Bax and Bcl­2. HSP27 expression was increased in patients with MM compared with healthy control subjects, and the expression was increased as the cancer progressed (P<0.05). Compared with the VAD chemotherapy group, the bortezomib plus VAD chemotherapy regimen significantly inhibited the expression of HSP27 (P<0.05), and the content of HSP27 was decreased in patients in which treatment was effective compared to those patients that exhibited disease progression (P<0.05). The efficacy of the treatment regimes was not associated with age or gender. Compared with the control group, bortezomib or OGX­427 (HSP27 inhibitor) treatment inhibited U266 cell proliferation, promoted U266 cell apoptosis (P<0.05) and significantly decreased HSP27 expression (P<0.05). Furthermore, the expression of HSP27 and Bcl­2 was significantly decreased, while the expression of Bax was increased by bortezomib and OGX­427 (P<0.05). There was no significant difference between the bortezomib and OGX­427 group in the in vitro analysis. HSP27 was positively correlated with Bcl­2 expression and negatively correlated with Bax expression in U266 cells. In conclusion, bortezomib promotes the apoptosis of MM cells, potentially by downregulating the expression of HSP27, providing a potential novel target for the clinical treatment of multiple myeloma.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Bortezomib/uso terapêutico , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Mieloma Múltiplo/tratamento farmacológico , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Proteínas de Choque Térmico/análise , Humanos , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/análise , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia
11.
Nat Commun ; 10(1): 2969, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278357

RESUMO

Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data.


Assuntos
Análise Mutacional de DNA/normas , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Mieloide Aguda/genética , Mieloma Múltiplo/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Biologia Computacional/métodos , Biologia Computacional/normas , Análise Mutacional de DNA/métodos , Conjuntos de Dados como Assunto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Mutação , Guias de Prática Clínica como Assunto , Sequenciamento Completo do Genoma/métodos , Sequenciamento Completo do Genoma/normas
12.
Int J Mol Sci ; 20(13)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266187

RESUMO

Extracellular vesicles (EVs) represent a heterogeneous group of membranous structures shed by all kinds of cell types, which are released into the surrounding microenvironment or spread to distant sites through the circulation. Therefore, EVs are key mediators of the communication between tumor cells and the surrounding microenvironment or the distant premetastatic niche due to their ability to transport lipids, transcription factors, mRNAs, non-coding regulatory RNAs, and proteins. Multiple myeloma (MM) is a hematological neoplasm that mostly relies on the bone marrow (BM). The BM represents a highly supportive niche for myeloma establishment and diffusion during the formation of distant bone lesions typical of this disease. This review represents a survey of the most recent evidence published on the role played by EVs in supporting MM cells during the multiple steps of metastasis, including travel and uptake at distant premetastatic niches, MM cell engraftment as micrometastasis, and expansion to macrometastasis thanks to EV-induced angiogenesis, release of angiocrine factors, activation of osteolytic activity, and mesenchymal cell support. Finally, we illustrate the first evidence concerning the dual effect of MM-EVs in promoting both anti-tumor immunity and MM immune escape, and the possible modulation operated by pharmacological treatments.


Assuntos
Neoplasias Ósseas/secundário , Vesículas Extracelulares/metabolismo , Mieloma Múltiplo/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Comunicação Celular , Progressão da Doença , Vesículas Extracelulares/genética , Humanos , Mieloma Múltiplo/genética , Evasão Tumoral , Microambiente Tumoral
13.
Hematology ; 24(1): 533-537, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31280705

RESUMO

OBJECTIVE: Buffy coat and ficoll of bone marrow (BM) are viable options for the study of minimal residual disease (MRD) in multiple myeloma (MM). As yet, there is no data about the superiority of either sample types. Herein, we aimed to address this issue. METHODS: Forty pairs of ficolled BMs and BM buffy coats of 19 MM patients were studied for MRD by allele-specific oligonucleotide real-time quantitative PCR, with patient-specific primers/probes whenever appropriate. RESULTS: There were 41 pairs of MRD data for comparison analysis due to one patient with biclonal disease. MRD levels in ficolls and buffy coats were highly concordant (rs = 0.936, P < 0.0001), with 31 (76%) and seven (17%) pairs being concomitantly MRD-positive or -negative. On the other hand, apart from the 16 pairs being both MRD-negative, or -positive but not quantifiable in ficolls and buffy coats, majority (n = 22, 88%) had higher MRD levels in ficolled BMs than BM buffy coats. Furthermore, in 17 pairs, in which MRD was quantifiable in both, MRD levels in ficolled BMs were 3.1 times those of BM buffy coats (median, 567/105 vs. 184/105, P = 0.001). CONCLUSION: Taken together, ficolled BM is more sensitive than BM buffy coat for MRD detection in MM, hence should be recommended.


Assuntos
Exame de Medula Óssea/métodos , Separação Celular/métodos , Centrifugação/métodos , Ficoll , Mieloma Múltiplo/patologia , Centrifugação com Gradiente de Concentração/métodos , Células Clonais , Primers do DNA , DNA de Neoplasias/análise , DNA de Neoplasias/isolamento & purificação , Rearranjo Gênico , Genes de Imunoglobulinas , Humanos , Leucócitos Mononucleares , Mieloma Múltiplo/genética , Neoplasia Residual , Células-Tronco Neoplásicas , Plasmócitos , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Manejo de Espécimes
14.
Acta Med Acad ; 48(1): 57-67, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31264433

RESUMO

The aim of this review is to summarize the current knowledge of genomic information in multiple myeloma. Multiple myeloma is a genetically complex plasma cell neoplasm that evolves from pre-malignant stages following genomic evolution leading to the proliferation of malignant plasma cells and the production of monoclonal immunoglobulin. The outcomes of patients with myeloma have dramatically improved over the past decade with the introduction of novel agents. Nevertheless, the disease is considered incurable and displays considerable heterogeneity in clinical presentation, course and survival. This heterogeneity can often be traced to cytogenetic abnormalities in the malignant clone. Accordingly, a large body of literature has examined the impact of genomics on myeloma and risk stratification based on cytogenetics has been adopted. In this review, we will focus on the cytogenetics of multiple myeloma and the prognostic significance as well as possible predictive implications. We will briefly review the existing methodologies relevant to myeloma but explore in greater depth the more novel molecular tools as applied to this disease. CONCLUSION: The field of genomics in multiple myeloma is rapidly evolving however more translational research is needed to accurately use genomic data as a tool of precision medicine.


Assuntos
Aberrações Cromossômicas , Genômica , Mieloma Múltiplo/genética , Citogenética , Humanos , Mieloma Múltiplo/diagnóstico , Prognóstico
15.
Cell Mol Life Sci ; 76(19): 3723-3744, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31147752

RESUMO

Starting from their role exerted on osteoblast and osteoclast differentiation and activity pathways, microRNAs (miRNAs) have been recently identified as regulators of different processes in bone homeostasis. For this purpose, in a recent review, we highlighted, as deregulated miRNAs could be involved in different bone diseases such as osteoporosis. In addition, recent studies supported the concept that osteoporosis-induced bone alterations might offer a receptive site for cancer cells to form bone metastases, However, to date, no data on specific-shared miRNAs between osteoporosis and bone metastases have been considered and described to clarify the evidence of this link. The main goal of this review is to underline as deregulated miRNAs in osteoporosis may have specific roles in the development of bone metastases. The review showed that several circulating osteoporotic miRNAs could facilitate tumor progression and bone-metastasis formation in several tumor types, i.e., breast cancer, prostate cancer, non-small-cell lung cancer, esophageal squamous cell carcinoma, and multiple myeloma. In detail, serum up-regulation of pro-osteoporotic miRNAs, as well as serum down-regulation of anti-osteoporotic miRNAs are common features of all these tumors and are able to promote bone metastasis. These results are of key importance and could help researcher and clinicians to establish new therapeutic strategies connected with deregulation of circulating miRNAs and able to interfere with pathogenic processes of osteoporosis, tumor progressions, and bone-metastasis formation.


Assuntos
Neoplasias Ósseas/secundário , MicroRNA Circulante/metabolismo , Osteoporose/genética , Animais , Neoplasias Ósseas/complicações , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/metabolismo , Mieloma Múltiplo/genética , Osteoporose/complicações , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
16.
Ann Hematol ; 98(10): 2463-2465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240468
17.
Cancer Sci ; 110(8): 2600-2606, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31218784

RESUMO

The t(11;14)/CCND1-IGH, t(4;14)/NSD2(MMSET)-IGH, and t(14;16)/IGH-MAF gene rearrangements detected by fluorescence in situ hybridization (FISH) are used for risk stratification in patients with multiple myeloma (MM). Compared with conventional FISH techniques using fresh cells, immunohistochemistry (IHC) is much more cost- and time-efficient, and can be readily applied to routinely prepared formalin-fixed, paraffin-embedded (FFPE) materials. In this study, we performed tissue FISH and IHC employing FFPE specimens, and examined the usefulness of IHC as a tool for detecting CCND1, NSD2, and MAF gene rearrangements. CD138 signals were used to identify plasma cells in tissue FISH and IHC analyses. With cohort 1 (n = 70), we performed tissue FISH and subsequently IHC, and determined IHC cut-off points. In this cohort, the sensitivity and specificity for the 3 molecules were ≥.90 and ≥.96, respectively. With cohort 2, using MM cases with an unknown gene status (n = 120), we performed IHC, and the gene status was estimated using the cut-off points determined with cohort 1. The subsequent FISH analysis showed that the sensitivity and specificity for the 3 molecules were ≥.92 and ≥.98, respectively. CCND1, NSD2, and MAF gene rearrangements were estimated accurately by IHC, suggesting that conventional FISH assays can be replaced by IHC.


Assuntos
Ciclina D1/genética , Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas c-maf/genética , Proteínas Repressoras/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
18.
Expert Opin Drug Saf ; 18(7): 563-571, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31070945

RESUMO

INTRODUCTION: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases. AREAS COVERED: A literature search on 'HDAC inhibitors' and 'multiple myeloma' was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data. EXPERT OPINION: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.


Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/efeitos adversos , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/genética , Humanos , Mieloma Múltiplo/genética , Panobinostat/administração & dosagem , Panobinostat/efeitos adversos , Resultado do Tratamento
19.
Oncol Rep ; 42(1): 291-300, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115560

RESUMO

The present study aimed to investigate the role of miR­181a in multiple myeloma (MM) cell lines. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was used to detect the expression of microRNA (miR)­181a. The MM cell line RPMI 8226 stably transduced with miR­181a mimics or inhibitor was established via lentiviral vectors. A Cell Counting Kit­8 proliferation assay, flow cytometry and a Transwell assay were conducted to assess cell proliferation, cell cycle, apoptosis and invasion. The role of miR­181a in MM tumor formation in vivo was assessed using a SCID Berge xenograft tumor model. The potential target genes of miR­181a were predicted using bioinformatic tools, and the expression of a potential target gene of miR­181a, neuro­-oncological ventral antigen­1 (NOVA1) was detected by RT­qPCR. miR­181a was determined to be significantly upregulated in MM cells (P<0.001). Following silencing of miR­181a via lentiviral­mediated transduction, RPMI 8226 cells exhibited a significant decrease in the number of S phase cells, and proliferative and invasive abilities. In addition, apoptosis was significantly promoted. A total of nine cross­target genes were pre­selected via bioinformatics software, including NOVA1. The results revealed that miR­181a inhibitor suppressed the expression of NOVA1 (t=26.951, P=0.001). In the xenograft tumor model of SCID Berge mice, miR­181a knock down significantly inhibited tumor growth. Conversely, these effects were reversed in response to miR­181 mimics. In summary, miR­181a was determined to be upregulated in MM cells, and may affect the biological function of cancer cells. The underlying mechanism may comprise the regulation of downstream target genes; however, further investigation is required.


Assuntos
MicroRNAs/genética , Mieloma Múltiplo/patologia , Regulação para Cima , Idoso , Animais , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Transplante de Neoplasias , Proteínas de Ligação a RNA/genética
20.
Oncol Res ; 27(8): 957-964, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31046873

RESUMO

Arylidene analogs are well proven for biological activities. FCY-302, a novel small molecule belonging to this class, was screened for its biological efficacy in leukemia and myeloma cells. FCY-302 selectively inhibited proliferation of cancer cells with GI50 values of 395.2 nM, 514.6 Nm, and 642.4 nM in HL-60, Jurkat, and RPMI-8226 cells, respectively. The compound also increased sub-G0 peak in the cancer cell cycle and favored apoptosis determined by annexin V assay. The compound decreased the antiapoptotic Bcl-2 levels and increased proapoptotic Bax proteins in leukemia and myeloma cell lines. FCY-302 attenuated the mitochondrial membrane-bound Na+/K+ ATPase, Ca2+ ATPase, and Mg2+ ATPase enzyme activities and significantly decreased activities of antioxidant enzymes like SOD, CAT, GR, and GST in all the three cancer cells tested. Our findings suggest that FCY-302 inhibits the proliferation of leukemia and myeloma cancer cells by altering key mitochondrial and antioxidant enzymes, eventually driving them to apoptosis. These results drive focus on FCY-302 and its analogs to be developed as potential small molecules with bioactivities against cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Leucemia/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HL-60 , Humanos , Células Jurkat , Leucemia/genética , Leucemia/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/enzimologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética
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