The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications.
Teru Hideshima,Dharminder Chauhan,Robert L. Schlossman,Paul G. Richardson,Kenneth C. Anderson +4 more
TLDR
Agents which act to inhibit TNFα may abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment.Abstract:
In this study we demonstrate that tumor necrosis factor alpha (TNFalpha) triggers only modest proliferation, as well as p44/p42 mitogen-activated protein kinase (MAPK) and NF-kappaB activation, in MM.1S multiple myeloma (MM) cells. TNFalpha also activates NF-kappaB and markedly upregulates (fivefold) secretion of interleukin-6 (IL-6), a myeloma growth and survival factor, in bone marrow stromal cells (BMSCs). TNFalpha in both a dose and time dependent fashion induced expression of CD11a (LFA-1), CD54 (intercellular adhesion molecule-1, ICAM-1), CD106 (vascular cell adhesion molecule-1, VCAM-1), CD49d (very late activating antigen-4, VLA-4), and/or MUC-1 on MM cell lines; as well as CD106 (VCAM-1) and CD54 (ICAM-1) expression on BMSCs. This resulted in increased (2-4-fold) per cent specific binding of MM cells to BMSCs, with related IL-6 secretion. Importantly, the proteasome inhibitor PS-341 abrogated TNFalpha-induced NF-kappaB activation, induction of ICAM-1 or VCAM-1, and increased adhesion of MM cells to BMSCs. Agents which act to inhibit TNFalpha may therefore abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment.read more
Citations
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A phase 2 study of bortezomib in relapsed, refractory myeloma.
Paul G. Richardson,Bart Barlogie,James R. Berenson,Seema Singhal,Sundar Jagannath,D. Irwin,S. Vincent Rajkumar,Gordan Srkalovic,Melissa Alsina,Raymond Alexanian,David S. Siegel,Robert Z. Orlowski,David J. Kuter,Steven Limentani,Stephanie J. Lee,Teru Hideshima,Dixie Lee Esseltine,Michael Kauffman,Julian Adams,David P. Schenkein,Kenneth C. Anderson +20 more
TL;DR: Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.
Journal ArticleDOI
Is NF-κB a good target for cancer therapy? Hopes and pitfalls
Véronique Baud,Michael Karin +1 more
TL;DR: Recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-κB in human cancer, particularly in multiple myeloma are discussed.
Journal ArticleDOI
NF-κB as a Therapeutic Target in Multiple Myeloma *
Teru Hideshima,Dharminder Chauhan,Paul G. Richardson,Constantine S. Mitsiades,Nicholas Mitsiades,Toshiaki Hayashi,Nikhil C. Munshi,Lenny Dang,Alfredo C. Castro,Vito Palombella,Julian Adams,Kenneth C. Anderson +11 more
TL;DR: These studies demonstrate that specific targeting of NF-κB can overcome the growth and survival advantage conferred both by tumor cell binding to BMSCs and cytokine secretion in the BM milieu.
Journal ArticleDOI
Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets
Teru Hideshima,Constantine S. Mitsiades,Giovanni Tonon,Paul G. Richardson,Kenneth C. Anderson +4 more
TL;DR: Recent oncogenomic studies have further advanced the understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.
Journal ArticleDOI
Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma
Paul G. Richardson,Robert L. Schlossman,Robert L. Schlossman,Edie Weller,Edie Weller,Teru Hideshima,Teru Hideshima,Constantine S. Mitsiades,Constantine S. Mitsiades,Faith E. Davies,Faith E. Davies,Richard Leblanc,Richard Leblanc,Laurence Catley,Laurence Catley,Deborah Doss,Deborah Doss,Kathleen Kelly,Kathleen Kelly,Mary McKenney,Mary McKenney,Julie Mechlowicz,Julie Mechlowicz,Andrea Freeman,Andrea Freeman,Reggie Deocampo,Reggie Deocampo,Rebecca Rich,Rebecca Rich,Joan J. Ryoo,Joan J. Ryoo,Dharminder Chauhan,Dharminder Chauhan,Kathe Balinski,Kathe Balinski,Jerome B. Zeldis,Jerome B. Zeldis,Kenneth C. Anderson,Kenneth C. Anderson +38 more
TL;DR: This study provides the basis for the evaluation of CC-5013, either alone or in combination, to treat patients with MM at earlier stages of disease and shows no significant somnolence, constipation, or neuropathy has been seen in any cohort.
References
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Constitutive Activation of Stat3 Signaling Confers Resistance to Apoptosis in Human U266 Myeloma Cells
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TL;DR: Findings provide evidence that constitutively activated Stat3 signaling contributes to the pathogenesis of multiple myeloma by preventing apoptosis.
Journal Article
The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells.
Teru Hideshima,Paul G. Richardson,Dharminder Chauhan,Vito J. Palombella,Peter J. Elliott,Julian Adams,Kenneth C. Anderson +6 more
TL;DR: It is demonstrated that the proteasome inhibitor PS-341 both acts directly on MM cells and alters cellular interactions and cytokine secretion in the BM millieu to inhibit tumor cell growth, induce apoptosis, and overcome drug resistance.
Journal ArticleDOI
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TL;DR: With IL 6 transgenic mice, deregulation of the IL 6 expression was suggested to be involved in the generation of plasmacytoma/myeloma and mesangium proliferative glomerulonephritis and the findings suggest the presence of a positive regulatory loop in acute‐phase reaction.
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