Find a Researcher

The ubiquitin-proteasome pathway is a major proteolytic system in both the cytosol and nucleus that regulates a broad spectrum of proteins - including cyclin and cyclin-dependent kinase inhibitors as well as anti-apoptotic proteins - thereby regulating cell cycle progression and apoptosis. Bortezomib (PS-341 or Velcade) represents a class of peptide boronate proteasome inhibitors that inhibits the chymotryptic activity of the 26S proteasome. Our studies have confirmed that bortezomib induces apoptosis, mediated by phosphorylation of c-Jun NH2-terminal kinase (JNK) followed by activation of caspase-8, -9, -3 and poly (ADP-ribose) polymerase cleavage. This is true even in multiple myeloma (MM) cell lines resistant to conventional drugs (dexamethasone, melphalan, doxorubicin), as well as in MM cells from patients. Bortezomib also downregulates expression of adhesion molecules on MM cells and bone marrow stromal cells (BMSCs) and related binding, blocks constitutive and MM cell adhesion-induced NF-kappaB dependent cytokine secretion in BMSCs, and inhibits angiogenesis. Moreover, bortezomib inhibits DNA repair by cleavage of the DNA-dependent protein kinase catalytic subunit; importantly, treatment of MM cell lines resistant to DNA damaging agents (melphalan, doxorubicin) with agents to which they are resistant, followed by bortezomib, can inhibit repair of DNA damage and restore drug sensitivity. In the bone marrow of MM cells, IL-6 mediates the following: (1) downstream extracellular signal-regulated kinases and mitogen-activated protein kinase, which mediate growth; (2) Janus kinase 2/signal transducers and activators of transcription 3, which mediate survival; and (3) phosphatidylinositol-3 kinase/Akt signaling pathways, which mediate drug resistance. We have demonstrated that bortezomib triggers caspase-dependent cleavage of gp130, thereby abrogating these signaling cascades induced by IL-6. Our preclinical studies have already translated to the bedside and FDA approval of bortezomib for treatment of relapsed or refractory MM. In spite of this remarkable progress, two-thirds of patients with relapsed/refractory MM do not respond to bortezomib, and those with initially responsive disease acquire resistance. Therefore, we are trying to define the role of the alternative aggresome pathway for protein catabolism in MM cells, and have already confirmed that blockade of proteasome and aggresome pathways with bortezomib and tubacin (a specific inhibitor of histone deacetylase 6), induces synergistic antitumor activity even in bortezomib-resistant MM cells.

Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, Treon SP, Lin B, Schlossman RL, Richardson P, Muller G, Stirling DI, Anderson KC. Thalidomide and its analogues overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000, 96: 2943-2950.{line break}Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001, 61:3071-3076.{line break}Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson KC. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: Therapeutic Applications. Oncogene 2001, 20: 4519-4527.{line break}Hideshima T, Nakamura N, Chauhan D, Anderson KC. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 2001,20: 5991-6000.{line break}Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dong L, Castro A, Palombella V, Adams J, Anderson KC. NF-kappaB as a therapeutic target in multiple myeloma. J Biol Chem 2002, 277:16639-16647.{line break}Hideshima T and Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002, 2:927-937.{line break}Hideshima T, Akiyama M, Hayashi T, Richardson P, Schlossman R, Chauhan D, Anderson KC. Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood 2003, 101:703-705.{line break}Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, Schlossman R, Poda K, Munshi NC, Mitsiades N, Anderson KC. Molecular mechanisms mediating anti-myeloma activity of proteasome inhibitor PS-341. Blood 2003, 101:1530-1534.{line break}Hideshima T, Hayashi T, Chauhan D, Akiyama M, Richardson PG, Anderson KC. Biologic Sequelae of c-Jun NH2-Terminal Kinase (JNK) Activation in Multiple Myeloma Cell Lines. Oncogene 2003, 22:8797-8801{line break}Hideshima T, Chauhan D, Hayashi T, Akiyama M, Mitsiades N, Mitsiades C, Podar K, Munshi NC, Richardson PG, Anderson KC. Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogen 2003, 22:8386-839l.{line break}Hideshima T, Chauhan D, Hayashi T, Podar K, Akiyama M, Mitsiades C, Mitsiades N, Gong B, Bonham L, de Vries L, Richardson PG, Singer JW, Anderson KC. Anti-Tumor Activity of Lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors, a novel class of agents, in multiple myeloma. Cancer Res 2003, 63:8428-8436.{line break}Hideshima T, Podar K, Chauhan D, Ishitsuka K, Mitsiades C, Tai Y-T, Hamasaki M, Raje N, Hideshima H, Schreiner G, Nguyen AN, Navas T, Munshi NC, Richardson PG, Higgins LS, Anderson KC. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 2004, 23:8766-8776.{line break}Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004, 104:607-618.{line break}Hideshima T, Chauhan D, Ishitsuka K, Yasui H, Raje N, Kumar S, Podar K, Mitsiades C, Hideshima H, Bonham L, Munshi NC, Richardson PG, Singer JW, Anderson KC. Molecular characterization of PS-341 (bortezomib) resistance: Implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors. Oncogene, 2005, 24:3121-3129.{line break}Hideshima T, Bradner J, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC. Small molecule inhibition of proteasome and aggresome function induces synergistic anti-tumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005, 102: 8567-8572.{line break}Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, Podar K, Munshi NC, Chauhan D, Richardson PG, Anderson KC. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006, 107:4053-4062.{line break}Hideshima T, Neri P, Tassone P, Yasui H, Ishitsuka K, Raje N, Chauhan D, Podar K, Mitsiades C, Dang L, Munshi N, Richardson P, Schenkein D, Anderson KC. MLN120B, a novel IKKbeta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res, 2006,12:5887-5894.{line break}Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis and the role of bone marrow microenvironment to identify new therapeutic targets. Nat Rev Cancer 2007, 8:585-98.{line break}Hideshima T, Chauhan D, Kiziltepe T, Ikeda H, Okawa Y, Podar K, Raje N, Protopopov A, Munshi NC, Richardson PG, Carrasco RD, Anderson KC. Biologic Sequelae of IkappaB Kinase (IKK) Inhibition in Multiple Myeloma: Therapeutic Implications. Blood, 2009, 113:5228-5236{line break}Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K, Mitsiades C, Munshi NC, Richardson PG, Carrasco RD, Anderson KC. Bortezomib induces canonical NF-kappaB activation in multiple myeloma cells. Blood, 2009, 114:1046-1052.{line break}