Cargando…
Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition
The angiogenesis inhibitor sunitinib is a tyrosine kinase inhibitor that acts mainly on the VEGF and PDGF pathways. We have previously shown that sunitinib is sequestered in the lysosomes of exposed tumor and endothelial cells. This phenomenon is part of the drug-induced resistance observed in the c...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669819/ https://www.ncbi.nlm.nih.gov/pubmed/25675301 http://dx.doi.org/10.1038/cddis.2015.4 |
_version_ | 1782404173755580416 |
---|---|
author | Nowak-Sliwinska, P Weiss, A van Beijnum, J R Wong, T J Kilarski, W W Szewczyk, G Verheul, H M W Sarna, T van den Bergh, H Griffioen, A W |
author_facet | Nowak-Sliwinska, P Weiss, A van Beijnum, J R Wong, T J Kilarski, W W Szewczyk, G Verheul, H M W Sarna, T van den Bergh, H Griffioen, A W |
author_sort | Nowak-Sliwinska, P |
collection | PubMed |
description | The angiogenesis inhibitor sunitinib is a tyrosine kinase inhibitor that acts mainly on the VEGF and PDGF pathways. We have previously shown that sunitinib is sequestered in the lysosomes of exposed tumor and endothelial cells. This phenomenon is part of the drug-induced resistance observed in the clinic. Here, we demonstrate that when exposed to light, sequestered sunitinib causes immediate destruction of the lysosomes, resulting in the release of sunitinib and cell death. We hypothesized that this photoactivation of sunitinib could be used as a vaso-occlusive vascular-targeting approach to treating cancer. Spectral properties of sunitinib and its lysosomal accumulation were measured in vitro. The human A2780 ovarian carcinoma transplanted onto the chicken chorioallantoic membrane (CAM) and the Colo-26 colorectal carcinoma model in Balb/c mice were used to test the effects of administrating sunitinib and subsequently exposing tumor tissue to light. Tumors were subsequently resected and subject to immunohistochemical analysis. In A2780 ovarian carcinoma tumors, treatment with sunitinib+light resulted in immediate specific angio-occlusion, leading to a necrotic tumor mass 24 h after treatment. Tumor growth was inhibited by 70% as compared with the control group (**P<0.0001). Similar observations were made in the Colo-26 colorectal carcinoma, where light exposure of the sunitinib-treated mice inhibited tumor growth by 50% as compared with the control and by 25% as compared with sunitinib-only-treated tumors (N≥4; P=0.0002). Histology revealed that photoactivation of sunitinib resulted in a change in tumor vessel architecture. The current results suggest that the spectral properties of sunitinib can be exploited for application against certain cancer indications. |
format | Online Article Text |
id | pubmed-4669819 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46698192015-12-08 Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition Nowak-Sliwinska, P Weiss, A van Beijnum, J R Wong, T J Kilarski, W W Szewczyk, G Verheul, H M W Sarna, T van den Bergh, H Griffioen, A W Cell Death Dis Original Article The angiogenesis inhibitor sunitinib is a tyrosine kinase inhibitor that acts mainly on the VEGF and PDGF pathways. We have previously shown that sunitinib is sequestered in the lysosomes of exposed tumor and endothelial cells. This phenomenon is part of the drug-induced resistance observed in the clinic. Here, we demonstrate that when exposed to light, sequestered sunitinib causes immediate destruction of the lysosomes, resulting in the release of sunitinib and cell death. We hypothesized that this photoactivation of sunitinib could be used as a vaso-occlusive vascular-targeting approach to treating cancer. Spectral properties of sunitinib and its lysosomal accumulation were measured in vitro. The human A2780 ovarian carcinoma transplanted onto the chicken chorioallantoic membrane (CAM) and the Colo-26 colorectal carcinoma model in Balb/c mice were used to test the effects of administrating sunitinib and subsequently exposing tumor tissue to light. Tumors were subsequently resected and subject to immunohistochemical analysis. In A2780 ovarian carcinoma tumors, treatment with sunitinib+light resulted in immediate specific angio-occlusion, leading to a necrotic tumor mass 24 h after treatment. Tumor growth was inhibited by 70% as compared with the control group (**P<0.0001). Similar observations were made in the Colo-26 colorectal carcinoma, where light exposure of the sunitinib-treated mice inhibited tumor growth by 50% as compared with the control and by 25% as compared with sunitinib-only-treated tumors (N≥4; P=0.0002). Histology revealed that photoactivation of sunitinib resulted in a change in tumor vessel architecture. The current results suggest that the spectral properties of sunitinib can be exploited for application against certain cancer indications. Nature Publishing Group 2015-02 2015-02-12 /pmc/articles/PMC4669819/ /pubmed/25675301 http://dx.doi.org/10.1038/cddis.2015.4 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0 |
spellingShingle | Original Article Nowak-Sliwinska, P Weiss, A van Beijnum, J R Wong, T J Kilarski, W W Szewczyk, G Verheul, H M W Sarna, T van den Bergh, H Griffioen, A W Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition |
title | Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition |
title_full | Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition |
title_fullStr | Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition |
title_full_unstemmed | Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition |
title_short | Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition |
title_sort | photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669819/ https://www.ncbi.nlm.nih.gov/pubmed/25675301 http://dx.doi.org/10.1038/cddis.2015.4 |
work_keys_str_mv | AT nowaksliwinskap photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT weissa photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT vanbeijnumjr photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT wongtj photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT kilarskiww photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT szewczykg photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT verheulhmw photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT sarnat photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT vandenberghh photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition AT griffioenaw photoactivationoflysosomallysequesteredsunitinibafterangiostatictreatmentcausesvascularocclusionandenhancestumorgrowthinhibition |