10-03-2013, 10:40 PM
Proteasomal inhibition and myeloma
The original article in this thread addresses the ubiquitin-protease system in cancer therapy. The article describes the proteasome, the cellular structure responsible for ATP-dependent degradation of ubiquitin-tagged damaged proteins. The article also alludes to the effectiveness of proteasome inhibition on the treatment of the multiple myeloma. In fact, a proteasome inhibitor called bortezomib has already been approved for treatment of both multiple myeloma and mantle cell lymphoma. However, the situation is not straightforward, despite the acceptance of bortezomib as an important weapon in the armoury of myeloma therapy. Matters are complicated by various problems associated with bortezomib, including emerging drug resistance issues, some normal cell toxicity and inconvenience to patients due to administration by intravenous injection. Thus, research continues on other potential proteasome inhibitors that may be safer and more conveniently taken.
A review from the University of Michigan, for example, has summarised current research on enzymes upstream of the proteasome, namely the Cullin-RING Ligases (CRLs) as attractive targets for multiple myeloma therapy. These are the largest family of E3 ubiquitin ligases, the enzymes that tag damaged proteins with ubiquitin to identify them for proteasomal degradation. Activity of CRLs is dynamically regulated, requiring both the RING component and cullin neddylation. A small molecule indirect inhibitor of CRL named MLN4924, which blocks cullin neddylation, is currently in phase I clinical trials and other inhibitors are under investigation.
Other studies are focusing more on alternative proteasome inhibitors. A group from The Netherlands Cancer Institute in Amsterdam investigated the possibilities of the novel proteasome inhibitor delanzomib and compared its activity to bortezomib both in vitro and in a preclinical multiple myeloma model. Using fluorogenic substrates and a recently developed fluorescent proteasome activity probe as indicators of inhibition of proteasome activity, the group found that both inhibitors inhibited proteasome activity to a similar extent in cell lines in vitro. In the pre-clinical model, while both inhibitors exhibited similar inhibition of the proteasome in normal tissues, delanzomib was twice as potent as bortezomib in terms of tumour proteasome activity. Further clinical testing of delanzomib was indicated.
Meanwhile a study from Jichi Medical University was concerned with the inconvenience of the necessity of administering Bortezomib by intravenous injection as well as drug resistance. This study focused on the necessity of developing orally active proteasome inhibitors. K-7174 is a member of the homopiperazine derivatives, a class of proteasome inhibitors with a different mode of action than bortezomib. K-7174 acts by repressing transcription of class I histone deacetylases (HDAC1, -2, and -3) via caspase-8-dependent degradation of Sp1. In a mouse myeloma model, K-7174 had a therapeutic effect, which was stronger when administered orally than intravenously. No obvious cytotoxic side-effects were observed. In terms of drug resistance to bortezomib, K-7174 was also able to kill bortezomib-resistant myeloma cells carrying a β5-subunit mutation in vivo and primary cells from a patient resistant to bortezomib. HDAC inhibitors enhanced K-7174 activity with an increase in histone acetylation. Thus K-7174 has potential as a proteasome inhibitor that can be taken orally and which may overcome drug resistance issues associated with bortezomib resistance. Clinical testing may yield promising results.
Sources
BERKERS, C.R. et al., 2012. Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib. Molecular Pharmaceutics, 9(5), pp. 1126-1135
KIKUCHI, J. et al., 2013. The Novel Orally Active Proteasome Inhibitor K-7174 Exerts Anti-myeloma Activity in Vitro and in Vivo by Down-regulating the Expression of Class I Histone Deacetylases. The Journal Of Biological Chemistry, 288(35), pp. 25593-25602
ZHAO, Y. and SUN, Y., 2013. Cullin-RING Ligases as attractive anti-cancer targets. Current pharmaceutical design, 19(18), pp. 3215-3225
The original article in this thread addresses the ubiquitin-protease system in cancer therapy. The article describes the proteasome, the cellular structure responsible for ATP-dependent degradation of ubiquitin-tagged damaged proteins. The article also alludes to the effectiveness of proteasome inhibition on the treatment of the multiple myeloma. In fact, a proteasome inhibitor called bortezomib has already been approved for treatment of both multiple myeloma and mantle cell lymphoma. However, the situation is not straightforward, despite the acceptance of bortezomib as an important weapon in the armoury of myeloma therapy. Matters are complicated by various problems associated with bortezomib, including emerging drug resistance issues, some normal cell toxicity and inconvenience to patients due to administration by intravenous injection. Thus, research continues on other potential proteasome inhibitors that may be safer and more conveniently taken.
A review from the University of Michigan, for example, has summarised current research on enzymes upstream of the proteasome, namely the Cullin-RING Ligases (CRLs) as attractive targets for multiple myeloma therapy. These are the largest family of E3 ubiquitin ligases, the enzymes that tag damaged proteins with ubiquitin to identify them for proteasomal degradation. Activity of CRLs is dynamically regulated, requiring both the RING component and cullin neddylation. A small molecule indirect inhibitor of CRL named MLN4924, which blocks cullin neddylation, is currently in phase I clinical trials and other inhibitors are under investigation.
Other studies are focusing more on alternative proteasome inhibitors. A group from The Netherlands Cancer Institute in Amsterdam investigated the possibilities of the novel proteasome inhibitor delanzomib and compared its activity to bortezomib both in vitro and in a preclinical multiple myeloma model. Using fluorogenic substrates and a recently developed fluorescent proteasome activity probe as indicators of inhibition of proteasome activity, the group found that both inhibitors inhibited proteasome activity to a similar extent in cell lines in vitro. In the pre-clinical model, while both inhibitors exhibited similar inhibition of the proteasome in normal tissues, delanzomib was twice as potent as bortezomib in terms of tumour proteasome activity. Further clinical testing of delanzomib was indicated.
Meanwhile a study from Jichi Medical University was concerned with the inconvenience of the necessity of administering Bortezomib by intravenous injection as well as drug resistance. This study focused on the necessity of developing orally active proteasome inhibitors. K-7174 is a member of the homopiperazine derivatives, a class of proteasome inhibitors with a different mode of action than bortezomib. K-7174 acts by repressing transcription of class I histone deacetylases (HDAC1, -2, and -3) via caspase-8-dependent degradation of Sp1. In a mouse myeloma model, K-7174 had a therapeutic effect, which was stronger when administered orally than intravenously. No obvious cytotoxic side-effects were observed. In terms of drug resistance to bortezomib, K-7174 was also able to kill bortezomib-resistant myeloma cells carrying a β5-subunit mutation in vivo and primary cells from a patient resistant to bortezomib. HDAC inhibitors enhanced K-7174 activity with an increase in histone acetylation. Thus K-7174 has potential as a proteasome inhibitor that can be taken orally and which may overcome drug resistance issues associated with bortezomib resistance. Clinical testing may yield promising results.
Sources
BERKERS, C.R. et al., 2012. Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib. Molecular Pharmaceutics, 9(5), pp. 1126-1135
KIKUCHI, J. et al., 2013. The Novel Orally Active Proteasome Inhibitor K-7174 Exerts Anti-myeloma Activity in Vitro and in Vivo by Down-regulating the Expression of Class I Histone Deacetylases. The Journal Of Biological Chemistry, 288(35), pp. 25593-25602
ZHAO, Y. and SUN, Y., 2013. Cullin-RING Ligases as attractive anti-cancer targets. Current pharmaceutical design, 19(18), pp. 3215-3225
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