Abstract
Glioblastomas are grade IV brain tumors characterized by high aggressiveness and invasiveness, giving patients a poor prognosis. We investigated the effects of the multi-kinase inhibitor sorafenib on six cultures isolated from human glioblastomas and maintained in tumor initiating cells-enriching conditions. These cell subpopulations are thought to be responsible for tumor recurrence and radio- and chemo-resistance, representing the perfect target for glioblastoma therapy. Sorafenib reduces proliferation of glioblastoma cultures, and this effect depends, at least in part, on the inhibition of PI3K/Akt and MAPK pathways, both involved in gliomagenesis. Sorafenib significantly induces apoptosis/cell death via downregulation of the survival factor Mcl-1. We provide evidence that sorafenib has a selective action on glioblastoma stem cells, causing enrichment of cultures in differentiated cells, downregulation of the expression of stemness markers required to maintain malignancy (nestin, Olig2 and Sox2) and reducing cell clonogenic ability in vitro and tumorigenic potential in vivo. The selectivity of sorafenib effects on glioblastoma stem cells is confirmed by the lower sensitivity of glioblastoma cultures after differentiation as compared with the undifferentiated counterpart. Since current GBM therapy enriches the tumor in cancer stem cells, the evidence of a selective action of sorafenib on these cells is therapeutically relevant, even if, so far, results from first phase II clinical trials did not demonstrate its efficacy.
| Original language | English |
|---|---|
| Pages (from-to) | 491-500 |
| Number of pages | 10 |
| Journal | Cell Cycle |
| Volume | 12 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Feb 1 2013 |
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Keywords
- Glioblastoma
- Mcl-1
- Sorafenib
- Stemness
- Therapy
- Tumor initiating cells
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
- Developmental Biology
Cite this
Sorafenib selectively depletes human glioblastoma tumor-initiating cells from primary cultures. / Carra, Elisa; Barbieri, Federica; Marubbi, Daniela; Pattarozzi, Alessandra; Favoni, Roberto E.; Florio, Tullio; Daga, Antonio.
In: Cell Cycle, Vol. 12, No. 3, 01.02.2013, p. 491-500.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Sorafenib selectively depletes human glioblastoma tumor-initiating cells from primary cultures
AU - Carra, Elisa
AU - Barbieri, Federica
AU - Marubbi, Daniela
AU - Pattarozzi, Alessandra
AU - Favoni, Roberto E.
AU - Florio, Tullio
AU - Daga, Antonio
PY - 2013/2/1
Y1 - 2013/2/1
N2 - Glioblastomas are grade IV brain tumors characterized by high aggressiveness and invasiveness, giving patients a poor prognosis. We investigated the effects of the multi-kinase inhibitor sorafenib on six cultures isolated from human glioblastomas and maintained in tumor initiating cells-enriching conditions. These cell subpopulations are thought to be responsible for tumor recurrence and radio- and chemo-resistance, representing the perfect target for glioblastoma therapy. Sorafenib reduces proliferation of glioblastoma cultures, and this effect depends, at least in part, on the inhibition of PI3K/Akt and MAPK pathways, both involved in gliomagenesis. Sorafenib significantly induces apoptosis/cell death via downregulation of the survival factor Mcl-1. We provide evidence that sorafenib has a selective action on glioblastoma stem cells, causing enrichment of cultures in differentiated cells, downregulation of the expression of stemness markers required to maintain malignancy (nestin, Olig2 and Sox2) and reducing cell clonogenic ability in vitro and tumorigenic potential in vivo. The selectivity of sorafenib effects on glioblastoma stem cells is confirmed by the lower sensitivity of glioblastoma cultures after differentiation as compared with the undifferentiated counterpart. Since current GBM therapy enriches the tumor in cancer stem cells, the evidence of a selective action of sorafenib on these cells is therapeutically relevant, even if, so far, results from first phase II clinical trials did not demonstrate its efficacy.
AB - Glioblastomas are grade IV brain tumors characterized by high aggressiveness and invasiveness, giving patients a poor prognosis. We investigated the effects of the multi-kinase inhibitor sorafenib on six cultures isolated from human glioblastomas and maintained in tumor initiating cells-enriching conditions. These cell subpopulations are thought to be responsible for tumor recurrence and radio- and chemo-resistance, representing the perfect target for glioblastoma therapy. Sorafenib reduces proliferation of glioblastoma cultures, and this effect depends, at least in part, on the inhibition of PI3K/Akt and MAPK pathways, both involved in gliomagenesis. Sorafenib significantly induces apoptosis/cell death via downregulation of the survival factor Mcl-1. We provide evidence that sorafenib has a selective action on glioblastoma stem cells, causing enrichment of cultures in differentiated cells, downregulation of the expression of stemness markers required to maintain malignancy (nestin, Olig2 and Sox2) and reducing cell clonogenic ability in vitro and tumorigenic potential in vivo. The selectivity of sorafenib effects on glioblastoma stem cells is confirmed by the lower sensitivity of glioblastoma cultures after differentiation as compared with the undifferentiated counterpart. Since current GBM therapy enriches the tumor in cancer stem cells, the evidence of a selective action of sorafenib on these cells is therapeutically relevant, even if, so far, results from first phase II clinical trials did not demonstrate its efficacy.
KW - Glioblastoma
KW - Mcl-1
KW - Sorafenib
KW - Stemness
KW - Therapy
KW - Tumor initiating cells
UR - http://www.scopus.com/inward/record.url?scp=84875522870&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875522870&partnerID=8YFLogxK
U2 - 10.4161/cc.23372
DO - 10.4161/cc.23372
M3 - Article
C2 - 23324350
AN - SCOPUS:84875522870
VL - 12
SP - 491
EP - 500
JO - Cell Cycle
JF - Cell Cycle
SN - 1538-4101
IS - 3
ER -