Disease relevance of Ps 341

• The FDA recently approved the first proteasome inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM) [1].
• Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL) [2].
• Finally, adherence of MM cells to bone marrow stromal cells confers growth and resistance to conventional treatments; in contrast, the combination of tubacin and bortezomib triggers toxicity even in adherent MM cells [3].
• Oral administration of PS-341 had anti-inflammatory effects in a model of Streptococcal cell wall-induced polyarthritis and liver inflammation in rats [4].
• Experience with bortezomib for the treatment of patients with relapsed classical Hodgkin lymphoma [5].

High impact information on Ps 341

• These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI-779 and RAD 001 [6].
• Treatment with the proteasome inhibitors MG132 and bortezomib increased WASP levels in T cells from WIP(-/-) mice and in T and B lymphocytes from two WAS patients with missense mutations (R86H and T45M) that disrupt WIP binding [7].
• The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined [8].
• To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively [3].
• We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells [9].

Chemical compound and disease context of Ps 341

• In this study we report that R-etodolac (SDX-101), at clinically relevant concentrations, induces potent cytotoxicity in drug-sensitive multiple myeloma (MM) cell lines, as well as in dexamethasone (MM.1R)-, doxorubicin (Dox40/RPMI8226)-, and bortezomib (DHL4)-resistant cell lines [10].
• Remarkable activity of novel agents bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell transplantation in multiple myeloma [11].
• Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study [12].
• Interactions between the tyrphostin adaphostin and proteasome inhibitors (eg, MG-132 and bortezomib) were examined in multiple human leukemia cell lines and primary acute myeloid leukemia (AML) specimens [13].
• To assess the effects of proteasome inhibition on chemotherapy response, human colorectal cancer cells were pretreated with the dipeptide boronic acid analogue PS-341 (1 microM) prior to exposure to SN-38, the active metabolite of the topoisomerase I inhibitor, CPT-11 [14].

Biological context of Ps 341

• The proteasome inhibitor PS-341 inhibits IkappaB degradation, prevents NF-kappaB activation, and induces apoptosis in several types of cancer cells, including chemoresistant multiple myeloma (MM) cells [15].
• By using gene expression profiling, we characterized the molecular sequelae of PS-341 treatment in MM cells and further focused on molecular pathways responsible for the anticancer actions of this promising agent [15].
• We conclude that initial 5F11-mediated NF-kappaB signaling sensitizes the tumor cells to bortezomib-induced cell death [16].
• In imatinib mesylate-resistant K562 cells displaying increased Bcr/Abl expression, bortezomib/flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and BclxL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt [17].
• Together, these findings provide the framework for clinical evaluation of CDDO-Im, either alone or in combination with bortezomib, to overcome drug resistance and improve patient outcome in MM [18].

Anatomical context of Ps 341

• Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival [9].
• Importantly, normal B lymphocytes were not sensitized to TRAIL by either Dox, SN50, or PS-341 [19].
• Using biochemical and microarray approaches, we found that proteasome inhibition by PS-341 induced endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in HNSCC cells [20].
• Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells [21].
• Here, we show that bortezomib, a proteasome inhibitor with anticancer activity, impairs several immune properties of human monocyte-derived dendritic cells (DCs) [22].

Associations of Ps 341 with other chemical compounds

• Addition of BDNF protects human MM cell lines (HMCLs) from apoptosis induced by dexamethasone or bortezomib and prolongs the survival of primary MM cells cultured alone or with human bone marrow (BM) stroma [23].
• Finally, combination studies of seliciclib with doxorubicin and bortezomib show in vitro synergism, providing the rationale for testing these drug combinations to improve patient outcome in MM [24].
• Transient transfection of cells with a constitutively active MEK construct significantly protected them from bortezomib/SAHA-mediated lethality [25].
• Finally, the bortezomib/flavopiridol regimen also potently induced apoptosis in Bcr/Abl(-) human leukemia cells [17].
• Namely, exposure of DCs to bortezomib reduces their phagocytic capacity, as shown by FITC-labeled dextran internalization and mannose-receptor CD206 down-regulation [22].

Gene context of Ps 341

• Coadministration of bortezomib and SAHA resulted in increased reactive oxygen species (ROS) generation and diminished nuclear factor kappa B (NF-kappa B) activation; moreover, the free radical scavenger L-N-acetylcyteine (LNAC) blocked bortezomib/SAHA-related ROS generation, induction of JNK and p21CIP1, and apoptosis [25].
• Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation [22].
• Consequently, bortezomib inhibited VEGF-induced multiple myeloma cell migration [26].
• These data strongly suggest that p21-mediated cdk inhibition promotes TRAIL sensitivity via caspase-8 activation and that TRAIL and bortezomib should be combined in appropriate in vivo models as a possible approach to solid tumor therapy [27].
• Collectively, our results suggest that proteasome inhibition using bortezomib affects cell adhesion and cell migration profoundly and provides a rationale for its clinical use in conjunction with an EGFR inhibitor [28].
• PS-341 and As/IFN-alpha treatment abrogated NF-kappaB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-X(L) [29].

Analytical, diagnostic and therapeutic context of Ps 341

• Using bioluminescence imaging after one dose of the chemo-therapeutic proteasome inhibitor bortezomib (PS-341), proteasome function in tumor xenografts was blocked within 30 min and returned to nearly baseline by 46 h [30].
• These data provide both insight into the molecular mechanisms of antitumor activity of PS-341 and the rationale for future clinical trials of PS-341, in combination with conventional and novel therapies, to improve patient outcome in MM [15].
• These results demonstrate the key role played by NF-kappaB in the resistance of CTCL to apoptosis and suggest that bortezomib might be useful for the treatment of patients with advanced stages of CTCL refractory to standard antineoplastic chemotherapy [31].
• In conclusion, in elderly patients ineligible for transplantation, the combination of bortezomib plus MP appears significantly superior to MP, producing very high CR rates, including immunophenotypic CRs, even in patients with poor prognostic features [12].
• Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy in an orthotopic model of multiple myeloma [32].

References