p53-Mediated Radiosensitization of 177Lu-DOTATATE in Neuroblastoma Tumor Spheroids
p53 is involved in DNA damage response and is an exciting target for radiosensitization in cancer. Targeted radionuclide therapy against somatostatin receptors with 177Lu-DOTATATE is currently being explored as a treatment for neuroblastoma. The aim of this study was to investigate the novel p53-stabilizing peptide VIP116 in neuroblastoma, both as monotherapy and together with 177Lu-DOTATATE. Five neuroblastoma cell lines, including two patient-derived xenograft (PDX) lines, were characterized in monolayer cultures. Four out of five were positive for 177Lu-DOTATATE uptake. IC50 values after VIP116 treatments correlated with p53 status, ranging between 2.8-238.2 μM. IMR-32 and PDX lines LU-NB-1 and LU-NB-2 were then cultured as multicellular tumor spheroids and treated with 177Lu-DOTATATE and/or VIP116. Spheroid growth was inhibited in all spheroid models for all treatment modalities. The most pronounced effects were observed for combination treatments, mediating synergistic effects in the IMR-32 model. VIP116 and combination treatment increased p53 levels with subsequent induction of p21, Bax and cleaved caspase 3. Combination treatment resulted in a 14-fold and 1.6-fold induction of MDM2 in LU-NB-2 and IMR-32 spheroids, respectively. This, together with differential MYCN signaling, may explain the varying degree of synergy. In conclusion, VIP116 inhibited neuroblastoma cell growth, potentiated 177Lu-DOTATATE treatment and could, therefore, be a feasible treatment option for neuroblastoma.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2021 |
---|---|
Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
---|---|
Enthalten in: |
Biomolecules - 11(2021), 11 vom: 15. Nov. |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Lundsten, Sara [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 12.01.2022 Date Revised 12.01.2022 published: Electronic Citation Status MEDLINE |
---|
doi: |
10.3390/biom11111695 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM333648161 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM333648161 | ||
003 | DE-627 | ||
005 | 20231225222100.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2021 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.3390/biom11111695 |2 doi | |
028 | 5 | 2 | |a pubmed24n1112.xml |
035 | |a (DE-627)NLM333648161 | ||
035 | |a (NLM)34827693 | ||
035 | |a (PII)1695 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Lundsten, Sara |e verfasserin |4 aut | |
245 | 1 | 0 | |a p53-Mediated Radiosensitization of 177Lu-DOTATATE in Neuroblastoma Tumor Spheroids |
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 12.01.2022 | ||
500 | |a Date Revised 12.01.2022 | ||
500 | |a published: Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a p53 is involved in DNA damage response and is an exciting target for radiosensitization in cancer. Targeted radionuclide therapy against somatostatin receptors with 177Lu-DOTATATE is currently being explored as a treatment for neuroblastoma. The aim of this study was to investigate the novel p53-stabilizing peptide VIP116 in neuroblastoma, both as monotherapy and together with 177Lu-DOTATATE. Five neuroblastoma cell lines, including two patient-derived xenograft (PDX) lines, were characterized in monolayer cultures. Four out of five were positive for 177Lu-DOTATATE uptake. IC50 values after VIP116 treatments correlated with p53 status, ranging between 2.8-238.2 μM. IMR-32 and PDX lines LU-NB-1 and LU-NB-2 were then cultured as multicellular tumor spheroids and treated with 177Lu-DOTATATE and/or VIP116. Spheroid growth was inhibited in all spheroid models for all treatment modalities. The most pronounced effects were observed for combination treatments, mediating synergistic effects in the IMR-32 model. VIP116 and combination treatment increased p53 levels with subsequent induction of p21, Bax and cleaved caspase 3. Combination treatment resulted in a 14-fold and 1.6-fold induction of MDM2 in LU-NB-2 and IMR-32 spheroids, respectively. This, together with differential MYCN signaling, may explain the varying degree of synergy. In conclusion, VIP116 inhibited neuroblastoma cell growth, potentiated 177Lu-DOTATATE treatment and could, therefore, be a feasible treatment option for neuroblastoma | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a 177Lu-DOTATATE | |
650 | 4 | |a neuroblastoma | |
650 | 4 | |a p53 | |
650 | 4 | |a radionuclide therapy | |
650 | 4 | |a radiosensitization | |
650 | 4 | |a stapled peptides | |
650 | 7 | |a Receptors, Somatostatin |2 NLM | |
650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
650 | 7 | |a copper dotatate CU-64 |2 NLM | |
700 | 1 | |a Berglund, Hanna |e verfasserin |4 aut | |
700 | 1 | |a Jha, Preeti |e verfasserin |4 aut | |
700 | 1 | |a Krona, Cecilia |e verfasserin |4 aut | |
700 | 1 | |a Hariri, Mehran |e verfasserin |4 aut | |
700 | 1 | |a Nelander, Sven |e verfasserin |4 aut | |
700 | 1 | |a Lane, David P |e verfasserin |4 aut | |
700 | 1 | |a Nestor, Marika |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Biomolecules |d 2011 |g 11(2021), 11 vom: 15. Nov. |w (DE-627)NLM228347106 |x 2218-273X |7 nnns |
773 | 1 | 8 | |g volume:11 |g year:2021 |g number:11 |g day:15 |g month:11 |
856 | 4 | 0 | |u http://dx.doi.org/10.3390/biom11111695 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 11 |j 2021 |e 11 |b 15 |c 11 |