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-B (NF-B) 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 DNAdamaging 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.

NF‐kB inhibition as a strategy to enhance etoposide‐induced apoptosis in K562 cell line

“…For example, it has been demonstrated that NF-kB inhibition with the proteasome PS-341 potentiates sensitivity of multiple myeloma cells to conventional cytotoxic drugs. In relation to these data, PS-341 has been administrated alone or in combination to other drugs in multiple myeloma patients, refractory to conventional therapies [19]. Similar results obtained with other NF-kB inhibitors have been described in ovarian cancer [20], in acute myeloid leukemia [8], and in other neoplasia.…”

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

“…Microarray experiments have demonstrated that the transcriptional profile of a potentially large number of genes is changed in response to proteasome inhibition [6,[47][48][49], however, only in a few instances transcriptional profiling was complemented with the analysis of changes instigated within the proteome of the treated cells [6,50]. In the present study we therefore compared the subproteome of cells induced to undergo apoptosis by treatment with the proteasome inhibitor PSI with the subproteome of control cells using a high throughput immunoblot screening procedure and attempted to define changes relevant for the regulation of apoptosis induction.…”

“…In contrast, other changes such as the upregulation of various kinases (Btk, C-Raf, CK1e, GSK3b, IKKγ, ILK, Lyn, MEK5, PI3K p110d, PKAc, PKB, PKCa, Yes, c-Cbl) and phosphatases (PP1, PP2C, PTP1C, CD45) had not been noted in previous proteomic studies [compare with 6,50], which could have been due to cell type-and reagent specific differences, since other cell types (multiple myeloma or megakaryoblastic leukemia cells) aand different proteasome inhibitors (bortezomib, MG-132-lactacystin) were investigated. In addition, the level of various proteins were modulated that are involved in cytoskeletal organization, potentially contributing to the morphological changes that are associated with apoptotic cell death (Annexin I, ABP280, AKAP149, CRP1, cdc42, DMPK, dystrobrevin, FLAP, MEK5a, PRK2/PAK2, Rac1, Rho, VASP).…”

“…Drexler, hannes.drexler@mpi-muenster.mpg.de. 3] and to sensitize tumor cells to radiotherapy [4] as well as to the cytotoxic action of various conventional chemotherapeutic compounds [5][6][7][8][9][10][11]. Following observations in preclinical tumor models, which revealed potent anti-neoplastic and anti-angiogenic properties of proteasome inhibitors also in vivo [5,[12][13][14], bortezomib (PS-341, Velcade®) has recently been approved as the first novel in class proteasome inhibitor for its use in patients suffering from refractory and relapsed multiple myeloma [15].…”

Augmenting Autologous Stem Cell Transplantation to Improve Outcomes in Myeloma

“…Synergistic myeloma cell kill in vitro has been noted with the combination of melphalan and bortezomib (Ma et al, 2003;Mitsiades et al, 2003). Bortezomib, by inhibiting the proteasome, interferes with DNA repair pathways and inhibitors of apoptosis, thus sensitising cells to DNAdamaging agents such as melphalan.…”