title: The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications.
abstract: The proteasome inhibitor PS-341 inhibits nuclear factor-kappaB (NF-kappaB) activation, induces apoptosis in cancer cells, including multiple myeloma (MM) cells, and has marked clinical activity as a monotherapy for MM. In this study, we found that subtoxic concentrations of PS-341 potently sensitized MM cell lines and patient cells to DNA-damaging chemotherapeutic agents such as doxorubicin and melphalan, including cells resistant to these drugs and those isolated from a patient who had relapsed after PS-341 monotherapy. Moreover, PS-341 abolished cell adhesion-mediated drug resistance. Using gene expression profiling and proteomic analysis, we demonstrate that PS-341, among its other proapoptotic effects, down-regulates the expression of several effectors involved in the cellular response to genotoxic stress. These data suggest that, in addition to down-regulating the expression of apoptosis inhibitors, PS-341 inhibits genotoxic stress response pathways and thereby restores sensitivity to DNA-damaging chemotherapeutic agents. These studies, therefore, provide the framework for clinical use of this agent in combination with conventional chemotherapy.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Poulaki
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Galinos
authors.initials: G
authors.lastname: Fanourakis
authors.forename: Xuesong
authors.initials: X
authors.lastname: Gu
authors.forename: Charles
authors.initials: C
authors.lastname: Bailey
authors.forename: Marie
authors.initials: M
authors.lastname: Joseph
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Robert
authors.initials: R
authors.lastname: Schlossman
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002448:Cell Adhesion; D004249:DNA Damage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000008:administration & dosage*; D011719:Pyrazines / Q000008:administration & dosage*; D012008:Recurrence; D014407:Tumor Cells, Cultured
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D004317:Doxorubicin; D008558:Melphalan