Novel Agents That Target Multiple Myeloma Cells
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.