Abstract
At variance to solid tumors, which show percentage of p53 deletions and/ or mutations close to 50%, more than 80% of haematological malignancies,express wild-type p53 at diagnosis. Therefore, activation of the p53 pathway by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy for the great majority of haernatological malignancies. Recently, potent and selective small-molecule MDM2 inhibitors, the Nutlins, have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation might represent an alternative to the current cytotoxic chemotherapy. Interestingly, Nutlins not only are able to induce apoptotic cell death when added to primary leukemic cell cultures, but also show a synergistic effect when used in combination with the chemotherapeutic drugs commonly used for the treatment of haematological malignancies. Of interest, Nutlins also display non-cell autonomous biological activities, such as inhibition of vascular endothelial growth factor, stromal derived factor-1/CXCL12 and ostcprotegerin expression and/or release by primary fibroblasts and endothelial cells. Moreover, Nutlins have a direct anti-angiogenic and anti-osteoclastic activity. Thus, Nutlins, might have therapeutic effects by two distinct mechanisms: a direct cytotoxic effect on leukemic cells and an indirect non-cell autonomous effect on tumor stromal and vascular cells, and this latter effect might be therapeutically relevant also for treatment of haematological malignancies carrying p53 mutations.
| Original language | English |
|---|---|
| Pages (from-to) | 2100-2110 |
| Number of pages | 11 |
| Journal | Current Pharmaceutical Design |
| Volume | 14 |
| Issue number | 21 |
| DOIs | |
| Publication status | Published - Jul 2008 |
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Keywords
- Angiogenesis
- Apoptosis
- Cell-cycle
- Chemotherapeutic drugs
- Haematological malignancies
- Osteolysis
- P53 Pathway
- TRAIL/TRAIL receptor system
ASJC Scopus subject areas
- Drug Discovery
- Pharmacology
Cite this
The MDM2 inhibitor Nutlins as an innovative therapeutic tool for the treatment of haematological malignancies. / Secchiero, Paola; di Iasio, Maria Grazia; Gonelli, Arianna; Zauli, Giorgio.
In: Current Pharmaceutical Design, Vol. 14, No. 21, 07.2008, p. 2100-2110.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The MDM2 inhibitor Nutlins as an innovative therapeutic tool for the treatment of haematological malignancies
AU - Secchiero, Paola
AU - di Iasio, Maria Grazia
AU - Gonelli, Arianna
AU - Zauli, Giorgio
PY - 2008/7
Y1 - 2008/7
N2 - At variance to solid tumors, which show percentage of p53 deletions and/ or mutations close to 50%, more than 80% of haematological malignancies,express wild-type p53 at diagnosis. Therefore, activation of the p53 pathway by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy for the great majority of haernatological malignancies. Recently, potent and selective small-molecule MDM2 inhibitors, the Nutlins, have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation might represent an alternative to the current cytotoxic chemotherapy. Interestingly, Nutlins not only are able to induce apoptotic cell death when added to primary leukemic cell cultures, but also show a synergistic effect when used in combination with the chemotherapeutic drugs commonly used for the treatment of haematological malignancies. Of interest, Nutlins also display non-cell autonomous biological activities, such as inhibition of vascular endothelial growth factor, stromal derived factor-1/CXCL12 and ostcprotegerin expression and/or release by primary fibroblasts and endothelial cells. Moreover, Nutlins have a direct anti-angiogenic and anti-osteoclastic activity. Thus, Nutlins, might have therapeutic effects by two distinct mechanisms: a direct cytotoxic effect on leukemic cells and an indirect non-cell autonomous effect on tumor stromal and vascular cells, and this latter effect might be therapeutically relevant also for treatment of haematological malignancies carrying p53 mutations.
AB - At variance to solid tumors, which show percentage of p53 deletions and/ or mutations close to 50%, more than 80% of haematological malignancies,express wild-type p53 at diagnosis. Therefore, activation of the p53 pathway by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy for the great majority of haernatological malignancies. Recently, potent and selective small-molecule MDM2 inhibitors, the Nutlins, have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation might represent an alternative to the current cytotoxic chemotherapy. Interestingly, Nutlins not only are able to induce apoptotic cell death when added to primary leukemic cell cultures, but also show a synergistic effect when used in combination with the chemotherapeutic drugs commonly used for the treatment of haematological malignancies. Of interest, Nutlins also display non-cell autonomous biological activities, such as inhibition of vascular endothelial growth factor, stromal derived factor-1/CXCL12 and ostcprotegerin expression and/or release by primary fibroblasts and endothelial cells. Moreover, Nutlins have a direct anti-angiogenic and anti-osteoclastic activity. Thus, Nutlins, might have therapeutic effects by two distinct mechanisms: a direct cytotoxic effect on leukemic cells and an indirect non-cell autonomous effect on tumor stromal and vascular cells, and this latter effect might be therapeutically relevant also for treatment of haematological malignancies carrying p53 mutations.
KW - Angiogenesis
KW - Apoptosis
KW - Cell-cycle
KW - Chemotherapeutic drugs
KW - Haematological malignancies
KW - Osteolysis
KW - P53 Pathway
KW - TRAIL/TRAIL receptor system
UR - http://www.scopus.com/inward/record.url?scp=52949124436&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=52949124436&partnerID=8YFLogxK
U2 - 10.2174/138161208785294663
DO - 10.2174/138161208785294663
M3 - Article
VL - 14
SP - 2100
EP - 2110
JO - Current Pharmaceutical Design
JF - Current Pharmaceutical Design
SN - 1381-6128
IS - 21
ER -