Pathophysiological role of calcium channels and transporters in the multiple myeloma

AbstractMultiple myeloma (MM) is a common malignant tumor of plasma cells. Despite several treatment approaches in the past two decades, MM remains an aggressive and incurable disease in dire need of new treatment strategies. Approximately 70–80% of patients with MM have myeloma bone disease (MBD), often accompanied by pathological fractures and hypercalcemia, which seriously affect the prognosis of the patients. Calcium channels and transporters can mediate Ca2+ balance inside and outside of the membrane, indicating that they may be closely related to the prognosis of MM. Therefore, this review focuses on the roles of some critical calcium channels and transporters in MM prognosis, which located in the plasma membrane, endoplasmic reticulum and mitochondria. The goal of this review is to facilitate the identification of new targets for the treatment and prognosis of MM.

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Influence of metformin on HIF-1 pathway in multiple myeloma

Pharmacological Reports ◽

10.1007/s43440-020-00142-x ◽

2020 ◽

Vol 72 (5) ◽

pp. 1407-1417

Author(s):

Kinga A. Kocemba-Pilarczyk ◽

Sonia Trojan ◽

Barbara Ostrowska ◽

Małgorzata Lasota ◽

Paulina Dudzik ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Treatment Strategies ◽

Annexin V ◽

Growth And Survival ◽

Hypoxic Conditions ◽

New Treatment ◽

First Time ◽

Pcr Techniques

Abstract Background Multiple myeloma (MM) is defined as plasma cells malignancy, developing in the bone marrow. At the beginning of the disease, the malignant plasma cells are dependent on bone marrow microenvironment, providing growth and survival factors. Importantly, the recent studies pointed hypoxia as an important factor promoting progression of MM. In particular, hypoxia-triggered HIF-1 signaling was shown to promote chemoresistance, angiogenesis, invasiveness and induction of immature phenotype, suggesting that strategies targeting HIF-1 may contribute to improvement of anti-myeloma therapies. Methods The Western Blot and RT-PCR techniques were applied to analyze the influence of metformin on HIF-1 pathway in MM cells. To evaluate the effect of metformin on the growth of MM cell lines in normoxic and hypoxic conditions the MTT assay was used. The apoptosis induction in metformin treated hypoxic and normoxic cells was verified by Annexin V/PI staining followed by FACS analysis. Results Our results showed, for the first time, that metformin inhibits HIF-1 signaling in MM cells. Moreover, we demonstrated the effect of metformin to be mainly oxygen dependent, since the HIF-1 pathway was not significantly affected by metformin in anoxic conditions as well as after application of hypoxic mimicking compound, CoCl2. Our data also revealed that metformin triggers the growth arrest without inducing apoptosis in either normoxic or hypoxic conditions. Conclusions Taken together, our study indicates metformin as a promising candidate for developing new treatment strategies exploiting HIF-1 signaling inhibition to enhance the overall anti-MM effect of currently used therapies, that may considerably benefit MM patients.

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Animal Models of Multiple Myeloma Bone Disease

Frontiers in Genetics ◽

10.3389/fgene.2021.640954 ◽

2021 ◽

Vol 12 ◽

Author(s):

Syed Hassan Mehdi ◽

Sana Nafees ◽

Syed Jafar Mehdi ◽

Carol A. Morris ◽

Ladan Mashouri ◽

...

Keyword(s):

Multiple Myeloma ◽

Animal Models ◽

Bone Disease ◽

Plasma Cells ◽

Compression Fracture ◽

Bone Lesions ◽

Significant Treatment ◽

Myeloma Bone Disease ◽

Incurable Disease ◽

Cumulative Evidence

Multiple myeloma (MM) is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells (PCs) in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. It is the second most common hematological malignancy and considered an incurable disease despite significant treatment improvements. MM bone disease (MMBD) is defined as the presence of one or more osteolytic bone lesions or diffused osteoporosis with compression fracture attributable to the underlying clonal PC disorder. MMBD causes severe morbidity and increases mortality. Cumulative evidence shows that the interaction of MM cells and bone microenvironment plays a significant role in MM progression, suggesting that these interactions may be good targets for therapy. MM animal models have been developed and studied in various aspects of MM tumorigenesis. In particular, MMBD has been studied in various models, and each model has unique features. As the general features of MM animal models have been reviewed elsewhere, the current review will focus on the features of MMBD animal models.

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The role of angiogenesis in multiple myeloma treatment

Diagnostyka Laboratoryjna ◽

10.5604/01.3001.0014.4722 ◽

2020 ◽

Vol 56 (2) ◽

pp. 1-6

Author(s):

Magdalena Zduńska ◽

Sylwia Ziółkowska ◽

Danuta Rość

Keyword(s):

Multiple Myeloma ◽

Clinical Research ◽

Plasma Cells ◽

Bone Lesions ◽

Direct Production ◽

Incurable Disease ◽

Health And Disease ◽

Tumor Growth And Metastasis

Angiogenesis is an important biological process of the formation of new blood vessels from pre-existing ones. It occurs throughout life in health and disease, beginning in the prenatal stage and continuing through old age. Angiogenesis is regulated, by both activator and inhibitor molecules. Physiological angiogenesis is under the control of angioinhibitory molecules. Unregulated angiogenesis may lead to several angiogenic diseases and is thought to be indispensable for solid tumor growth and metastasis. Multiple myeloma is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections. Angiogenesis plays an important role in the biology of multiple myeloma and has a prognostic value in this disease. The pathophysiology of multiple myeloma-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment cells. Multiple myeloma has been the most intractable hematological disease for many years. Recently, basic and clinical research has advanced remarkably and a new therapeutic strategy has been established. Despite unusual progress in the therapy of multiple myeloma none of the available drugs are curative. Present clinical research focuses on the balance between treatment efficacy and quality of life. In this review, we summarize recent data about myeloma-induces angiogenesis, the mechanism involved in this process, and the treatment of multiple myeloma.

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Boosting Immunity against Multiple Myeloma

Cancers ◽

10.3390/cancers13061221 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1221

Author(s):

Raquel Lopes ◽

Bruna Velosa Ferreira ◽

Joana Caetano ◽

Filipa Barahona ◽

Emilie Arnault Carneiro ◽

...

Keyword(s):

Multiple Myeloma ◽

Residual Disease ◽

Proteasome Inhibitors ◽

Treatment Strategies ◽

Complete Response ◽

Drug Conjugates ◽

Incurable Disease ◽

Car T ◽

Patient’S Outcome ◽

The Impact

Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug conjugates or bispecific antibodies broadened the possibility of improving patients’ survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome.

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Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma

Cells ◽

10.3390/cells10061490 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1490

Author(s):

Osama M. Elzamzamy ◽

Brandon E. Johnson ◽

Wei-Chih Chen ◽

Gangqing Hu ◽

Reinhold Penner ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Transient Receptor Potential ◽

Cyclic Peptide ◽

Calcium Influx ◽

Acquired Resistance ◽

Treatment Strategies ◽

Prognostic Indicators ◽

Causative Role

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca2+ entry (SOCE): PLCβ, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca2+ and Na+ influx. However, replacing extracellular Na+ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca2+ reduced both MTI-101-induced Ca2+ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca2+ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca2+ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM.

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B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders

Pharmaceuticals ◽

10.3390/ph14010037 ◽

2021 ◽

Vol 14 (1) ◽

pp. 37

Author(s):

Jan Traub ◽

Leila Husseini ◽

Martin S. Weber

Keyword(s):

B Cells ◽

Neuromyelitis Optica ◽

Plasma Cells ◽

Treatment Options ◽

Treatment Strategies ◽

Therapeutic Interventions ◽

Complement Factor ◽

Major Subset ◽

Spectrum Disorders

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

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Silencing of MEG3 attenuated the role of lipopolysaccharides by modulating the miR-93-5p/PTEN pathway in Leydig cells

Reproductive Biology and Endocrinology ◽

10.1186/s12958-021-00712-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Xu Zhou ◽

Jingliang He ◽

Jinbo Chen ◽

Yu Cui ◽

Zhenyu Ou ◽

...

Keyword(s):

Cell Viability ◽

Cell Apoptosis ◽

Leydig Cells ◽

Treatment Strategies ◽

Pten Expression ◽

Luciferase Reporter ◽

Western Blots ◽

New Treatment ◽

Lps Treatment

Abstract Background Leydig cells reflect the activation of inflammation, decrease of androgen production, inhibition of cell growth and promotion of cell apoptosis under orchitis. Maternally expressed gene 3 (MEG3) exerts a crucial role in various human diseases, but under orchitis, the role and underlying molecular mechanism of MEG3 in Leydig cells remain unclear. Methods Lipofectamine 2000 was used for the cell transfections. qPCR and western blots assay were applied to assess the gene expression. ELISA assay was used to measure the TNFα, IL6 and testosterone secretion. CCK8 and EdU assay was employ to test the cell viability and proliferation respectively. Luciferase reporter and RIP assay were introduced to detect the binding of miR-93-5p with MEG3 and PTEN. Results Lipopolysaccharides (LPS) induced TNFα and IL6 secretion, lowered testosterone production, inhibited cell viability and proliferation, and induced cell apoptosis in Leydig cells. MEG3 was upregulated in Leydig cells treated with LPS and that knockdown of MEG3 inhibited the role of LPS in Leydig cells. MEG3 absorbed miR-93-5p and that suppression of miR-93-5p restored the role of silenced MEG3 in Leydig cells under LPS treatment. miR-93-5p inhibited PTEN expression and that over-expressed PTEN alleviated the effect of miR-93-5p in Leydig cells treated with LPS. LPS activated the MEG3/miR-93-5p/PTEN signalling pathway in Leydig cells. Conclusions This study revealed that MEG3 serves as a molecular sponge to absorb miR-93-5p, thus leading to elevation of PTEN expression in Leydig cells under LPS treatment, offering a theoretical basis on which to establish potential new treatment strategies for orchitis.

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Role of Aiolos and Ikaros in the Antitumor and Immunomodulatory Activity of IMiDs in Multiple Myeloma: Better to Lose Than to Find Them

International Journal of Molecular Sciences ◽

10.3390/ijms22031103 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1103

Author(s):

Marco Cippitelli ◽

Helena Stabile ◽

Andrea Kosta ◽

Sara Petillo ◽

Angela Gismondi ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Immunomodulatory Activity ◽

Cancer Cell Growth ◽

Cytotoxic Effects ◽

Growth And Survival ◽

Therapeutic Implications ◽

Development And Differentiation ◽

Innate Lymphocytes

The Ikaros zing-finger family transcription factors (IKZF TFs) are important regulators of lymphocyte development and differentiation and are also highly expressed in B cell malignancies, including Multiple Myeloma (MM), where they are required for cancer cell growth and survival. Moreover, IKZF TFs negatively control the functional properties of many immune cells. Thus, the targeting of these proteins has relevant therapeutic implications in cancer. Indeed, accumulating evidence demonstrated that downregulation of Ikaros and Aiolos, two members of the IKZF family, in malignant plasma cells as well as in adaptative and innate lymphocytes, is key for the anti-myeloma activity of Immunomodulatory drugs (IMiDs). This review is focused on IKZF TF-related pathways in MM. In particular, we will address how the depletion of IKZF TFs exerts cytotoxic effects on MM cells, by reducing their survival and proliferation, and concomitantly potentiates the antitumor immune response, thus contributing to therapeutic efficacy of IMiDs, a cornerstone in the treatment of this neoplasia.

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SUCCESSFUL MANAGEMENT OF SPHENOID RELAPSE OF MULTIPLE MYELOMA WITH RADIATION THERAPY: A CASE REPORT

10.36106/ijar/1213145 ◽

2021 ◽

pp. 1-2

Author(s):

A. Bazine ◽

M. Torreis ◽

M. Elmarjany ◽

M. Benlemlih ◽

A. Maghous ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Radiation Therapy ◽

Case Report ◽

Skull Base ◽

Plasma Cells ◽

Complete Disappearance ◽

Successful Management ◽

Shed Light

Multiple myeloma (MM) is typically characterized by neoplastic proliferation of plasma cells in the bone marrow and can result in extensive skeletal destruction. Involvement of skull base is extremely rare, especially sphenoid bone. We report in this work the case of a 62-year-old woman, who presented with a sphenoid relapse of multiple myeloma treated with radiation therapy, with signicant clinical improvement and almost complete disappearance of the sphenoid metastasis. We shed light, through this case, on the rarity of sphenoid metastases in multiple myeloma and on the role of radiotherapy in the management of this type of location.

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Deep Phenotyping Reveals Distinct Immune Signatures Correlating with Prognostication, Treatment Responses, and MRD Status in Multiple Myeloma

Cancers ◽

10.3390/cancers12113245 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3245 ◽

Cited By ~ 1

Author(s):

Konstantinos Papadimitriou ◽

Nikolaos Tsakirakis ◽

Panagiotis Malandrakis ◽

Panagiotis Vitsos ◽

Andreas Metousis ◽

...

Keyword(s):

Multiple Myeloma ◽

Immune Cell ◽

Residual Disease ◽

Critical Role ◽

Induction Treatment ◽

Molecular Characteristics ◽

Limited Information ◽

Incurable Disease ◽

Deep Phenotyping

Despite recent advances, Multiple Myeloma (MM) remains an incurable disease with apparent heterogeneity that may explain patients’ variable clinical outcomes. While the phenotypic, (epi)genetic, and molecular characteristics of myeloma cells have been thoroughly examined, there is limited information regarding the role of the bone marrow (BM) microenvironment in the natural history of the disease. In the present study, we performed deep phenotyping of 32 distinct immune cell subsets in a cohort of 94 MM patients to reveal unique immune profiles in both BM and peripheral blood (PB) that characterize distinct prognostic groups, responses to induction treatment, and minimal residual disease (MRD) status. Our data show that PB cells do not reflect the BM microenvironment and that the two sites should be studied independently. Adverse ISS stage and high-risk cytogenetics were correlated with distinct immune profiles; most importantly, BM signatures comprised decreased tumor-associated macrophages (TAMs) and erythroblasts, whereas the unique Treg signatures in PB could discriminate those patients achieving complete remission after VRd induction therapy. Moreover, MRD negative status was correlated with a more experienced CD4- and CD8-mediated immunity phenotype in both BM and PB, thus highlighting a critical role of by-stander cells linked to MRD biology.

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