Abstract
Modulating protein ubiquitination via pro-teasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-κB (NF-κB) activity and the expression of several NF-κB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.
| Original language | English |
|---|---|
| Pages (from-to) | 2765-2775 |
| Number of pages | 11 |
| Journal | Blood |
| Volume | 111 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Mar 1 2008 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
CEP-18770 : A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. / Piva, Roberto; Ruggeri, Bruce; Williams, Michael; Costa, Giulia; Tamagno, Maria; Ferrero, Dario; Giai, Valentina; Coscia, Marta; Peola, Silvia; Massaia, Massimo; Pezzoni, Gabriella; Allievi, Cecilia; Pescalli, Nicoletta; Cassin, Mara; Giovine, Stefano Di; Nicoli, Paola; De Feudis, Paola; Strepponi, Ivan; Roato, Maria; Ferracini, Riccardo; Bussolati, Benedetta; Camussi, Giovanni; Jones-Bolin, Susan; Hunter, Kathryn; Zhao, Hugh; Neri, Antonino; Palumbo, Antonio; Berkers, Celia; Ovaa, Huib; Bernareggi, Alberto; Inghirami, Giorgio.
In: Blood, Vol. 111, No. 5, 01.03.2008, p. 2765-2775.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CEP-18770
T2 - A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib
AU - Piva, Roberto
AU - Ruggeri, Bruce
AU - Williams, Michael
AU - Costa, Giulia
AU - Tamagno, Maria
AU - Ferrero, Dario
AU - Giai, Valentina
AU - Coscia, Marta
AU - Peola, Silvia
AU - Massaia, Massimo
AU - Pezzoni, Gabriella
AU - Allievi, Cecilia
AU - Pescalli, Nicoletta
AU - Cassin, Mara
AU - Giovine, Stefano Di
AU - Nicoli, Paola
AU - De Feudis, Paola
AU - Strepponi, Ivan
AU - Roato, Maria
AU - Ferracini, Riccardo
AU - Bussolati, Benedetta
AU - Camussi, Giovanni
AU - Jones-Bolin, Susan
AU - Hunter, Kathryn
AU - Zhao, Hugh
AU - Neri, Antonino
AU - Palumbo, Antonio
AU - Berkers, Celia
AU - Ovaa, Huib
AU - Bernareggi, Alberto
AU - Inghirami, Giorgio
PY - 2008/3/1
Y1 - 2008/3/1
N2 - Modulating protein ubiquitination via pro-teasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-κB (NF-κB) activity and the expression of several NF-κB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.
AB - Modulating protein ubiquitination via pro-teasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-κB (NF-κB) activity and the expression of several NF-κB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.
UR - http://www.scopus.com/inward/record.url?scp=41949110089&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41949110089&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-07-100651
DO - 10.1182/blood-2007-07-100651
M3 - Article
C2 - 18057228
AN - SCOPUS:41949110089
VL - 111
SP - 2765
EP - 2775
JO - Blood
JF - Blood
SN - 0006-4971
IS - 5
ER -