Proteasome inhibitors bortezomib

Antineoplastic agents that cannot be grouped under subheadings 1-9 include miltefosine which is an alkylphosphocholine that is used to treat skin metastasis of breast cancer, and crispantase which breaks down asparagine to aspartic acid and ammonia. It is active against tumor cells that lack the enzyme asparaginase, such as acute lymphoblastic leukemia cells. Side effects include irritation of the skin in the case of miltefosine and anaphylactic reactions in the case of crispantase. Another recent development is the proteasome inhibitor bortezomib which is used to treat multiple myeloma. 

Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/AblJ) cells sensitive and resistant to STI571. Blood 102 3765-3774... 

Tassone, P., Atadja, P., Chauhan, D., Munshi, N.C. and Anderson, KC. (2006) Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood, 108, 3441-3449. 

These mechanistic findings supported the exploration of the therapeutic potential of proteasome inhibitors in oncology, with the first clinical trials involving a proteasome inhibitor (bortezomib) commencing about ten years ago. Lessons learned from bench to bedside during this time period have recently been reviewed.19... 

The pharmacodynamic profile of NPI-0052 is different from other proteasome inhibitors (bortezomib and carfilzomib) in that upon a single IV administration to mice, a sustained inhibition ( > 72 hours) of the main three 20.S proteolytic activities is observed in packed whole blood lysates (Figure 12.2A). Bortezomib has been reported to either have no effect on or to enhance the T-L activity, while carfilzomib specifically inhibits the CT-L 20V proteasome activity.14,31 Repeated NPI-0052 administration to rodents and monkeys leads to sustained dose-dependent inhibition of whole blood 20V proteasome activity, with higher inhibition observed after subsequent administrations and with partial recovery between consecutive NPI-0052 treatments. 

Uttamsingh V, Lu C, Miwa G, et al. Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Disp. 2005 33 1723-1728. 

IkB-q (inhibitor of transcription factor NF-kB)), proteins that regulate cellular adaptation to hypoxic stress (i.e., HIF-lct), and proteins related to aberrant gene expression in tumors (e.g., c-Jun, /3-catenin, IttB-a, E2F1). Proteasome inhibitors are under development as new antitumor chemotherapeutic agents and the proteasome inhibitor bortezomib (PS-341, Velcade) has been approved by the U.S. Food and Drug Administration (FDA). 

O Connor OA, Wright J, Moskowitz C et al. (2005) Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin s lymphoma and mantle cell lymphoma. J Clin Oncol... 

Pei XY, Dai Y, Grant S (2003) The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells. Leukemia 17 2036-2045... 

Pei XY, Dai Y, Grant S (2004a) Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 10 3839-3852... 

Yu C, Rahmani M, Dent P et al. (2004) The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res 295 555-566... 

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