scholarly journals Targeted Inhibition of Multiple Proinflammatory Signalling Pathways for the Prevention and Treatment of Multiple Myeloma

10.5772/30444 ◽  
2012 ◽  
Author(s):  
Radhamani Kannaiyan ◽  
Rohit Surana ◽  
Eun Myoung ◽  
Lalitha Ramachandran ◽  
Gautam Sethi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signalling Pathways ◽  
Prevention And Treatment ◽  
Targeted Inhibition

Down-Regulation of NF-κB and STAT3 Signaling Pathways Upon Protein Kinase CK2 Inhibition Empowers Bortezomib-Induced Multiple Myeloma Cell-Death

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1849-1849
Author(s):  
Sabrina Manni ◽  
Alessandra Brancalion ◽  
Quotti Tubi Laura ◽  
Anna Cabrelle ◽  
Livio Trentin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Membrane Potential ◽  
Protein Kinase ◽  
Cell Apoptosis ◽  
Mitochondrial Membrane ◽  
Protein Kinase Ck2 ◽  
Plasma Cells ◽  
Signalling Pathways ◽  
Kinase Ck2 ◽  
Ck2 Inhibitors

Abstract Abstract 1849 Multiple Myeloma (MM) malignant plasma cells can be induced to die by blocking the proteasome. Bortezomib (BZ), a first-in class proteasome inhibitor of wide clinical use in MM patients, causes MM cell apoptosis through different mechanisms; however, the means of resistance to its effects are poorly recognized. Our group identified protein kinase CK2 as a critical survival molecule for MM cells (Piazza FA et al., 2006, Blood, 108(5):1698–707). This kinase regulates pivotal apoptosis-related pathways in cancer cells; however, it is currently unknown whether CK2 could be involved downstream proteasome inhibition. Intriguingly, phase I clinical trials are currently ongoing with an oral ATP-competitive CK2 inhibitor in MM and other tumors. We have here sought to investigate whether CK2 takes part in BZ-induced MM cell apoptosis and we studied whether blocking CK2 could influence pro-survival signalling pathways, which could account for MM cell resistance to BZ and chemotherapy. MM cell lines U-266, RPMI-8226 and INA-6, human bone marrow stromal cells and freshly isolated plasma cells from patients were cultured and exposed to BZ and CK2 inhibitors K27 and CX4945 for different time points. Annexin V and propidium iodide staining, evaluation of mitochondrial membrane potential depolarization and western blot (WB) analysis of PARP cleavage and apoptosis-related proteins expression were the assays employed to assess cell growth and viability upon the different treatments. We found that the rate of BZ-induced MM cell apoptosis was significantly increased by the simultaneous inhibition of CK2 and the proteasome in all the MM models tested and mitochondrial membrane potential measurements revealed that CK2 inhibition enhanced BZ-triggered intrinsic apoptotic cascade. Importantly, the combination of CK2 inhibitors and BZ resulted in a synergic growth-suppressive action. WB and RT-PCR analysis revealed that survival-signalling pathways associated with STAT3 and NF-κB were activated by BZ, which also caused a rise in the levels of the unfolded protein response-associated kinase/endoribonuclease IRE1α. These effects could represent unwanted side consequences of BZ treatment and could lend MM cells the ability to escape the cytotoxic effects of this drug. CK2 inhibition produced a strong reduction of phospho Ser 536 and phospho Ser 529 p65 NF-κB subunit, phospho Ser 727 STAT3 and IRE1α levels in MM cells. Remarkably, the simultaneous treatment with BZ and CK2 inhibitors was accompanied by a significant reduction of BZ-triggered p65 NF-κB and STAT3 activation and IRE1α protein levels. These results indicate that protein kinase CK2 protects from BZ-induced apoptosis and modulates pivotal signaling pathways in MM cells, such as the NF-κB and STAT3 cascades, which could otherwise be exploited in the selection of BZ-resistant MM cell clones. Our findings suggest that CK2 inhibition could offer a rational therapeutic option when designing novel BZ-based anti-MM combination therapies. Disclosures: No relevant conflicts of interest to declare.

Depression Rises the Risk of Hypertension Incidence: Discussing the Link through the Ca2+/cAMP Signalling

2020 ◽  
Vol 16 (1) ◽  
pp. 73-78
Author(s):  
Leandro B. Bergantin
Keyword(s):  
Signalling Pathways ◽  
Cellular Mechanisms ◽  
Medical Problems ◽  
Camp Signalling ◽  
Data Support ◽  
High Prevalence ◽  
The World ◽  
Prevention And Treatment ◽  
Treatment Of Hypertension ◽  
Risk Issue

Background: Depression and hypertension are medical problems both with clearly restricted pharmacotherapies, along with a high prevalence around the world. In fact, an intensive discussion in the field is that a dysregulation of the intracellular Ca2+ homeostasis (e.g. excess of intracellular Ca2+) contributes to the pathogenesis of both hypertension and depression. Furthermore, depression rises the risk of hypertension incidence. Indeed, several data support the concept that depression is an independent risk issue for hypertension. Conclusion: Then, which are the possible cellular mechanisms involved in this link between depression and hypertension? Considering our previous reports about the Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling), in this review I have discussed the virtual involvement of the Ca2+/cAMP signalling in this link (between depression and hypertension). Then, it is important to consider depression into account during the process of prevention, and treatment, of hypertension.

Fc Receptor Targeting Reduces Bone Disease in a Pre-Clinical Model of Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3011-3011
Author(s):  
Mark T Williams ◽  
Katya Thümmler ◽  
Susan Kitson ◽  
Richard Soutar ◽  
Carl S Goodyear
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Signalling Pathways ◽  
Micro Ct ◽  
Cell Injection ◽  
Clinical Model ◽  
Rank Gene

Abstract Background: Multiple Myeloma (MM) is currently incurable, with a median survival of 5-7 years post diagnosis. MM-associated bone disease (MM-OBD), represents a major cause of morbidity and mortality in MM patients. Despite current therapies for MM-OBD exhibiting significant potential (e.g. Zoledronate), their clinical use has been restricted due to severe treatment associated toxicities. Safe novel therapies for MM-OBD are therefore crucially required. Molecular crosstalk between receptor activator of nuclear factor Kappa B ligand (RANKL), present on and secreted by MM plasma cells, and its corresponding receptor (RANK) on osteoclast precursors (OCPs), represents a key mechanism driving osteoclastogenesis and subsequent bone pathology in MM. Our previous studies have demonstrated that Fc receptor (FcR)-mediated signals can inhibit RANKL induced osteoclastogenesis in vitro1. In addition, findings from preliminary studies show that FcR-mediated signalling in pre-osteoclasts can reduce MM plasma cell driven osteoclastogenesis in vitro. Further interrogation of the underlying molecular mechanisms show that FcR-mediated signals profoundly reduce RANK transcript, and subsequent protein expression, in pre-osteoclasts. However, the effects of FcR engagement on MM-OBD in vivo, and the FcR elicited signalling pathways responsible for inhibition of RANK expression have still to be elucidated. Aims: This study aimed to determine the in vivo potential of FcR engagement to treat bone disease in a pre-clinical model of MM. Additionally, the mechanisms underlyingFcR-mediated down-regulation of RANK expression in OCPs were interrogated. Methods: The well-characterised 5TGM1 murine model of MM, together with micro-computed topography (micro-CT), were used to evaluate the effect of FcR engagement on MM-OBD. FcR stimulation was achieved by I.P. injecting mice (every other day, following 5TGM1 I.V. cell injection), with 100 μg/ml of Protein A derived from Staphylococcus aureus (SpA). SpA has been shown to form small immune complexes (SICs) through its affinity for endogenous IgG, which in turn binds to FcγR1 receptors on monocytes and pre-OCs1. Additionally, the potential involvement of FcR signalling pathways in the down-regulation of RANK in healthy and MM-derived human OCPs was determined via immunoblotting and the use of signalling pathway inhibitors. Results: Twenty six days post-myeloma cell injection, micro-CT analysis of femurs revealed that mice receiving PBS (vehicle control, n=5) exhibited a significant decrease in bone morphmetric parameters consistent with bone erosion compared to non-myeloma bearing mice (n=3); trabecullar bone volume [BV/TV] = 2.673 vs. 3.449, p=0.034; trabecullar number [Tb.N] = 0.0035 vs. 0.0042, p=0.0041; trabecullar pattern factor [Tb.Pf] = 0.2329 vs. 0.2033, p=0.0393. Importantly, myeloma bearing mice (n=5) receiving SpA, were protected from MM-OBD. In human OCPs (sourced from healthy individuals and MM patients), FcR engagement substantially activated SyK, MEK-ERK1/2, and PI3K signaling cascades. However, inhibition of these pathways failed to restore RANK transcript levels. Discussion: These findings demonstrate novel mechanisms of RANK gene expression regulation in healthy and MM OCPs, with Fc receptors representing a potential therapeutic strategy for MM-OBD. Further studies will aim to elucidate the molecular mechanisms responsible for FcR-mediated regulation of RANK gene expression. 1. MacLellan, L. M. et al. Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice. Arthritis Rheum.63, 3897-3907 (2011). Disclosures No relevant conflicts of interest to declare.

Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment

2009 ◽  
Vol 39 (5) ◽  
pp. 304-316 ◽  
Author(s):  
M. Dickinson ◽  
H. M. Prince ◽  
S. Kirsa ◽  
A. Zannettino ◽  
S. D. J. Gibbs ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Osteonecrosis Of The Jaw ◽  
Bisphosphonate Treatment ◽  
Prevention And Treatment

scholarly journals Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death

2009 ◽  
Vol 145 (4) ◽  
pp. 481-490 ◽  
Author(s):  
Peter M. Voorhees ◽  
Qing Chen ◽  
George W. Small ◽  
Deborah J. Kuhn ◽  
Sally A. Hunsucker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Interleukin 6 ◽  
Clinical Models ◽  
Targeted Inhibition

Targeting signalling pathways for the treatment of multiple myeloma

2005 ◽  
Vol 9 (2) ◽  
pp. 359-381 ◽  
Author(s):  
Klaus Podar ◽  
Teru Hideshima ◽  
Dharminder Chauhan ◽  
Kenneth C Anderson
Keyword(s):  
Multiple Myeloma ◽  
Signalling Pathways

The Wiskott Aldrich Syndrome Protein (WASP) Is Involved in Dexamethasone-Signalling Pathways Leading to Apoptosis of Multiple Myeloma Cells and in Cell Adhesion Mediated Drug Resistance Against Dexamethasone

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1809-1809
Author(s):  
Hazera Khatun ◽  
Amna Anwar ◽  
Majid A. Kazmi ◽  
Stephen Schey ◽  
Yolanda Calle
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Death ◽  
Cell Adhesion ◽  
Cell Line ◽  
Stromal Cells ◽  
Signalling Pathway ◽  
Actin Dynamics ◽  
Signalling Pathways ◽  
Syndrome Protein

Abstract Abstract 1809 Direct contact of multiple myeloma (MM) cells with the bone marrow (BM) stroma promotes cell survival leading to cell adhesion mediated drug resistance (CAM-DR). Dexamethasone is a conventional anti-MM drug that effectively induces MM cell death at presentation and in relapsed patients but the signalling pathways involved in its mechanisms of action are not completely understood. Resistance of MM to Dexamethasone may result from genetic changes in MM cells or through the contact of MM cells with the BM microenvironment. It has been shown that CAM-DR blocks the effect of Dexamethasone by the binding of MM cells to the BM stroma. Our data indicate a key role of the binding of MM CXCR4 receptor on stromal cell derived SDF1-a in CAM-DR against Dexamethasone. Dexamethasone induced upregulation of CXCR4 in the MM1.S cell line (sensitive to Dexamethasone) whilst, as expected, having no effect on the MM1.R cell line (resistant to Dexamethasone by expression of a mutated form of the glucocorticoid receptor). Bortezomib induced down regulation of CXCR4 in both MM1.S and MM1.R cell lines in a dose dependent manner that correlated with decreased adhesion on BM stromal cells and increased sensitisation of MM cells in the presence of the BM stroma. The Wiskott Aldrich Syndrome Protein (WASP) is an adaptor protein that regulates actin polymerization and organization of cell adhesion molecules of the integrin family in haematopoietic cells. WASP is involved in the signalling pathway downstream of CXCR4 in various leukocytes and we hypothesised that blocking this pathway would prevent MM cell adhesion on stromal cells and sensitise them to treatment with Dexamethasone. We found that downregulation of WASP in the Dexamethasone-sensitive cell line MM1.S using shRNA reduced the adhesion to the BM stroma. However, it also rendered MM1.S cells resistant to treatment with Dexamethasone but not with Bortezomib, Doxorubicin or Melphalan independently of the presence of BM stromal cells. Similarly, downregulation of WASP in MM1.R cells did not affect their sensitivity to Bortezomib, Doxorubicin or Melphalan. Dexamethasone has been shown to induce changes in actin dynamics or in levels or activity of actin and/or adhesion related proteins. Western blot analysis showed both Dexamethasone and Bortezomib to cause modulation of WASP expression, inducing partial downregulation and upregulation, respectively. Downregulation of WASP expression in MM1.S cells using shRNA or treatment with Dexamethasone or Bortezomib did not affect the expression of other proteins involved in WASP-mediated F-actin remodelling or cell adhesion such as WIP, Arp 2/3 or vinculin. We conclude that WASP is involved in the signalling pathways that promote cell-adhesion of MM cells on BM stroma but it is also a vital component of the signalling pathway of Dexamethasone's mechanism of action. These data indicate that while blocking WASP signalling could theoretically have potential therapeutic benefits to prevent CAM-DR to Dexamethasone, it would inhibit the action of Dexamethasone rendering cells resistant to treatment with this drug. Our study suggest a possible paradox of a dual pro-apoptotic and pro-survival effect of certain therapies targeting pathways involved in the interaction of MM cells with the microenvironment. Detailed studies of the intricate connexion between the intracellular pathways involved in the process of adhesion and drug induced cell death through modulation of actin dynamics may lead to improved therapeutic strategies to overcome drug resistance against Dexamethasone and perhaps other drugs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 5095-5102 ◽  
Author(s):  
Erik A. Nelson ◽  
Sarah R. Walker ◽  
Alicia Kepich ◽  
Laurie B. Gashin ◽  
Teru Hideshima ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mononuclear Cells ◽  
Mek Inhibitor ◽  
Myeloma Cell ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Myeloma Cells ◽  
Deacetylase Inhibitor ◽  
Targeted Inhibition ◽  
Constitutive Phosphorylation

Abstract Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival.

scholarly journals Matrix metalloproteinase-1 induction by diethyldithiocarbamate is regulated via Akt and ERK/miR222/ETS-1 pathways in hepatic stellate cells

2016 ◽  
Vol 36 (4) ◽  
Author(s):  
Tianhui Liu ◽  
Ping Wang ◽  
Min Cong ◽  
Dong Zhang ◽  
Lin Liu ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Transcriptional Factor ◽  
Signalling Pathways ◽  
Akt Inhibitor ◽  
Matrix Metalloproteinase 1 ◽  
Prevention And Treatment ◽  
Important Regulator

Matrix metalloproteinase-1 (MMP-1) plays an important role in fibrolysis by degrading excessively deposited collagen I and III. We previously demonstrated that diethyldithiocarbamate (DDC) up-regulates MMP-1 in hepatic stellate cells via the ERK1/2 and Akt signalling pathways. In the current study, we attempted to further explore the molecular mechanisms involved in the regulation of MMP-1. We treated a co-cultured system that included hepatocytes (C3A) and hepatic stellate cells (LX-2) with DDC. The data revealed that the transcriptional factor ETS-1, which is an important regulator of MMP-1, was up-regulated in LX-2 cells following DDC treatment. Furthermore, the up-regulation of MMP-1 by DDC has been abrogated through employing si-ETS-1 to block expression of ETS-1. We found that DDC significantly inhibited the expression of miR-222 in LX-2 cells. We transfected miR-222 mimic into LX-2 cells and then co-cultured the cells with C3A. The up-regulation of ETS-1 and MMP-1 in LX-2 cells treated with DDC were inhibited after miR-222 mimic transfection. These data indicate that DDC up-regulated MMP-1 in LX-2 cells through the miR-222/ETS-1 pathway. Finally, we treated the co-cultured system with an Akt inhibitor (T3830) and an ERK1/2 inhibitor (U0126). Both T3830 and U0126 blocked the suppression of miR-222 by DDC in LX-2. Collectively, these data indicate that DDC up-regulated MMP-1 in LX-2 cells through the Akt and ERK/miR-222/ETS-1 pathways. Our study provides experimental data that will aid the control of the process of fibrolysis in liver fibrosis prevention and treatment.

scholarly journals MMSET: Role and Therapeutic Opportunities in Multiple Myeloma

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Zhigang Xie ◽  
Wee Joo Chng
Keyword(s):  
Multiple Myeloma ◽  
Poor Prognosis ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Hematologic Malignancies ◽  
Chromosomal Translocations ◽  
Signalling Pathways ◽  
Set Domain ◽  
Diagnosis And Prognosis ◽  
Potential Therapeutics

Recurrent chromosomal translocations are central to the pathogenesis, diagnosis, and prognosis of hematologic malignancies. The translocation t(4; 14)(p16; q32) is one of the most common translocations in multiple myeloma (MM) and is associated with very poor prognosis. The t(4; 14) translocation leads to the simultaneous overexpression of two genes,FGFR3(fibroblast growth factor receptor 3) andMMSET(multiple myeloma SET domain), both of which have potential oncogenic activity. However, approximately 30% of t(4; 14) MM patients do not express FGFR3 and have poor prognosis irrespective of FGFR3 expression, whereas MMSET overexpression is universal in t(4; 14) cases. In this review, we provide an overview of recent findings regarding the oncogenic roles of MMSET in MM and its functions on histone methylation. We also highlight some of MMSET partners and its downstream signalling pathways and discuss the potential therapeutics targeting MMSET.

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