The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells.
Human multiple myeloma (MM) is a presently incurable hematological malignancy, and novel biologically based therapies are urgently needed. Proteasome inhibitors represent a novel potential anticancer therapy. In this study, we demonstrate that the proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis of human MM cell lines and freshly isolated patient MM cells; inhibits mitogen-activated protein kinase growth signaling in MM cells; induces apoptosis despite induction of p21 and p27 in both p53 wild-type and p53 mutant MM cells; overcomes drug resistance; adds to the anti-MM activity of dexamethasone; and overcomes the resistance to apoptosis in MM cells conferred by interleukin-6. PS-341 also inhibits the paracrine growth of human MM cells by decreasing their adherence to bone marrow stromal cells (BMSCs) and related nuclear factor kappaB-dependent induction of interleukin-6 secretion in BMSCs, as well as inhibiting proliferation and growth signaling of residual adherent MM cells. These data, therefore, demonstrate that 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. Given the acceptable animal and human toxicity profile of PS-341, these studies provide the framework for clinical evaluation of PS-341 to improve outcome for patients with this universally fatal hematological malignancy.
Hideshima
T
T
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Richardson
P
P
Chauhan
D
D
Palombella
V J
VJ
Elliott
P J
PJ
Adams
J
J
Anderson
K C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D011480:Protease Inhibitors; D011719:Pyrazines; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases