p53-Mediated Radiosensitization of <sup>177</sup>Lu-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 <sup>177</sup>Lu-DOTATATE is currently being explored as a treatment for neuroblastoma. The aim of this study was to invest...

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Autores principales:	Sara Lundsten, Hanna Berglund, Preeti Jha, Cecilia Krona, Mehran Hariri, Sven Nelander, David P. Lane, Marika Nestor
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neuroblastoma radionuclide therapy p53 <sup>177</sup>Lu-DOTATATE radiosensitization stapled peptides Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4d7ad4c2ba884c0ea627c2e375ac1c7a
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spelling	oai:doaj.org-article:4d7ad4c2ba884c0ea627c2e375ac1c7a2021-11-25T16:53:54Zp53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids10.3390/biom111116952218-273Xhttps://doaj.org/article/4d7ad4c2ba884c0ea627c2e375ac1c7a2021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1695https://doaj.org/toc/2218-273Xp53 is involved in DNA damage response and is an exciting target for radiosensitization in cancer. Targeted radionuclide therapy against somatostatin receptors with <sup>177</sup>Lu-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 <sup>177</sup>Lu-DOTATATE. Five neuroblastoma cell lines, including two patient-derived xenograft (PDX) lines, were characterized in monolayer cultures. Four out of five were positive for <sup>177</sup>Lu-DOTATATE uptake. IC<sub>50</sub> 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 <sup>177</sup>Lu-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 <sup>177</sup>Lu-DOTATATE treatment and could, therefore, be a feasible treatment option for neuroblastoma.Sara LundstenHanna BerglundPreeti JhaCecilia KronaMehran HaririSven NelanderDavid P. LaneMarika NestorMDPI AGarticleneuroblastomaradionuclide therapyp53<sup>177</sup>Lu-DOTATATEradiosensitizationstapled peptidesMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1695, p 1695 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neuroblastoma radionuclide therapy p53 <sup>177</sup>Lu-DOTATATE radiosensitization stapled peptides Microbiology QR1-502
spellingShingle	neuroblastoma radionuclide therapy p53 <sup>177</sup>Lu-DOTATATE radiosensitization stapled peptides Microbiology QR1-502 Sara Lundsten Hanna Berglund Preeti Jha Cecilia Krona Mehran Hariri Sven Nelander David P. Lane Marika Nestor p53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids
description	p53 is involved in DNA damage response and is an exciting target for radiosensitization in cancer. Targeted radionuclide therapy against somatostatin receptors with <sup>177</sup>Lu-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 <sup>177</sup>Lu-DOTATATE. Five neuroblastoma cell lines, including two patient-derived xenograft (PDX) lines, were characterized in monolayer cultures. Four out of five were positive for <sup>177</sup>Lu-DOTATATE uptake. IC<sub>50</sub> 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 <sup>177</sup>Lu-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 <sup>177</sup>Lu-DOTATATE treatment and could, therefore, be a feasible treatment option for neuroblastoma.
format	article
author	Sara Lundsten Hanna Berglund Preeti Jha Cecilia Krona Mehran Hariri Sven Nelander David P. Lane Marika Nestor
author_facet	Sara Lundsten Hanna Berglund Preeti Jha Cecilia Krona Mehran Hariri Sven Nelander David P. Lane Marika Nestor
author_sort	Sara Lundsten
title	p53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids
title_short	p53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids
title_full	p53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids
title_fullStr	p53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids
title_full_unstemmed	p53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids
title_sort	p53-mediated radiosensitization of <sup>177</sup>lu-dotatate in neuroblastoma tumor spheroids
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4d7ad4c2ba884c0ea627c2e375ac1c7a
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p53-Mediated Radiosensitization of <sup>177</sup>Lu-DOTATATE in Neuroblastoma Tumor Spheroids

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