The Radiosensitizing Effect of AZD0530 in Glioblastoma and Glioblastoma Stem-Like Cells
©2021 American Association for Cancer Research..
AZD0530, a potent small-molecule inhibitor of the Src kinase family, is an anticancer drug used in the treatment of various cancers. In the case of glioblastoma (GBM), where resistance to radiotherapy frequently occurs, Src kinase is known as one of the molecules responsible for imparting radioresistance to GBM. Thus, we evaluated the effect of AZD0530 on the radiosensitivity of human GBM cells and human glioblastoma stem-like cells (GSCs). We show that Src activity of GBM and GSC is increased by radiation and inhibited by AZD0530, and using clonogenic assays, AZD0530 enhances the radiosensitivity of GBM and GSCs. Also, AZD0530 induced a prolongation of radiation-induced γH2AX without specific cell cycle and mitotic index changes, suggesting that AZD0530-induced radiosensitization in GBM cells and GSCs results from the inhibition of DNA repair. In addition, AZD0530 was shown to inhibit the radiation-induced EGFR/PI3K/AKT pathway, which is known to promote and regulate radioresistance and survival of GBM cells by radiation. Finally, mice bearing orthotopic xenografts initiated from GBM cells were then used to evaluate the in vivo response to AZD0530 and radiation. The combination of AZD0530 and radiation showed the longest median survival compared with any single modality. Thus, these results show that AZD0530 enhances the radiosensitivity of GBM cells and GSCs and suggest the possibility of AZD0530 as a clinical radiosensitizer for treatment of GBM.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
|---|---|
| Enthalten in: |
Molecular cancer therapeutics - 20(2021), 9 vom: 01. Sept., Seite 1672-1679 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Yun, Hong Shik [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
9KD24QGH76 |
|---|
| Anmerkungen: |
Date Completed 10.02.2022 Date Revised 14.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/1535-7163.MCT-20-0883 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM327056819 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM327056819 | ||
| 003 | DE-627 | ||
| 005 | 20240214232322.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/1535-7163.MCT-20-0883 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1292.xml |
| 035 | |a (DE-627)NLM327056819 | ||
| 035 | |a (NLM)34158343 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Yun, Hong Shik |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Radiosensitizing Effect of AZD0530 in Glioblastoma and Glioblastoma Stem-Like Cells |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 10.02.2022 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2021 American Association for Cancer Research. | ||
| 520 | |a AZD0530, a potent small-molecule inhibitor of the Src kinase family, is an anticancer drug used in the treatment of various cancers. In the case of glioblastoma (GBM), where resistance to radiotherapy frequently occurs, Src kinase is known as one of the molecules responsible for imparting radioresistance to GBM. Thus, we evaluated the effect of AZD0530 on the radiosensitivity of human GBM cells and human glioblastoma stem-like cells (GSCs). We show that Src activity of GBM and GSC is increased by radiation and inhibited by AZD0530, and using clonogenic assays, AZD0530 enhances the radiosensitivity of GBM and GSCs. Also, AZD0530 induced a prolongation of radiation-induced γH2AX without specific cell cycle and mitotic index changes, suggesting that AZD0530-induced radiosensitization in GBM cells and GSCs results from the inhibition of DNA repair. In addition, AZD0530 was shown to inhibit the radiation-induced EGFR/PI3K/AKT pathway, which is known to promote and regulate radioresistance and survival of GBM cells by radiation. Finally, mice bearing orthotopic xenografts initiated from GBM cells were then used to evaluate the in vivo response to AZD0530 and radiation. The combination of AZD0530 and radiation showed the longest median survival compared with any single modality. Thus, these results show that AZD0530 enhances the radiosensitivity of GBM cells and GSCs and suggest the possibility of AZD0530 as a clinical radiosensitizer for treatment of GBM | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Benzodioxoles |2 NLM | |
| 650 | 7 | |a Quinazolines |2 NLM | |
| 650 | 7 | |a Radiation-Sensitizing Agents |2 NLM | |
| 650 | 7 | |a saracatinib |2 NLM | |
| 650 | 7 | |a 9KD24QGH76 |2 NLM | |
| 700 | 1 | |a Lee, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Kil, Whoon Jong |e verfasserin |4 aut | |
| 700 | 1 | |a Kramp, Tamalee R |e verfasserin |4 aut | |
| 700 | 1 | |a Tofilon, Philip J |e verfasserin |4 aut | |
| 700 | 1 | |a Camphausen, Kevin |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular cancer therapeutics |d 2001 |g 20(2021), 9 vom: 01. Sept., Seite 1672-1679 |w (DE-627)NLM122520580 |x 1538-8514 |7 nnns |
| 773 | 1 | 8 | |g volume:20 |g year:2021 |g number:9 |g day:01 |g month:09 |g pages:1672-1679 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/1535-7163.MCT-20-0883 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 20 |j 2021 |e 9 |b 01 |c 09 |h 1672-1679 | ||