KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.

KML001 is sodium metaarsenite, and has shown cytotoxic activity in human tumor cell lines. The anti-cancer mechanism of KML001 involves cancer cell destruction due to DNA damage at the telomeres of cancer cell chromosomes. In this study, we assessed the vascular disrupting properties of KML001 and i...

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Autores principales:	Chang Hoon Moon, Seung Ju Lee, Ho Yong Lee, Jong Cheol Lee, Heejeong Cha, Wha Ja Cho, Jeong Woo Park, Hyun Jin Park, Jin Seo, Young Han Lee, Ho-Taek Song, Young Joo Min
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f4e650dbf6c243d3801265b9a36ecb77
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spelling	oai:doaj.org-article:f4e650dbf6c243d3801265b9a36ecb772021-11-18T08:01:47ZKML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.1932-620310.1371/journal.pone.0053900https://doaj.org/article/f4e650dbf6c243d3801265b9a36ecb772013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23326531/?tool=EBIhttps://doaj.org/toc/1932-6203KML001 is sodium metaarsenite, and has shown cytotoxic activity in human tumor cell lines. The anti-cancer mechanism of KML001 involves cancer cell destruction due to DNA damage at the telomeres of cancer cell chromosomes. In this study, we assessed the vascular disrupting properties of KML001 and investigated whether KML001 as VDA is able to increase anti-tumor activity in irinotecan combined treatment. We used a murine model of the CT26 colon carcinoma cell line. CT26 isograft mice treated intraperitoneally with 10 mg/kg KML001 displayed extensive central necrosis of tumor by 24 h. The vascular disrupting effects of KML001 were assessed by dynamic contrast enhanced magnetic resonance imaging. Gadopentetic acid-diethylene triaminepentaacetic acid contrast enhancement was markedly decreased in KML001-treated mice one day after treatment, whereas persistently high signal enhancement was observed in mice injected with saline. Rate constant K(ep) value representing capillary permeability was significantly decreased (p<0.05) in mice treated with KML001. Cytoskeletal changes of human umbilical vein endothelial cells (HUVECs) treated with 10 uM KML001 were assessed by immune blotting and confocal imaging. KML001 degraded tubulin protein in HUVECs, which may be related to vascular disrupting properties of KML001. Finally, in the mouse CT26 isograft model, KML001 combined with irinotecan significantly delayed tumor growth as compared to control and irinotecan alone. These results suggest that KML001 is a novel vascular disrupting agent, which exhibits significant vascular shut-down activity and enhances anti-tumor activity in combination with chemotherapy. These data further suggest an avenue for effective combination therapy in treating solid tumors.Chang Hoon MoonSeung Ju LeeHo Yong LeeJong Cheol LeeHeejeong ChaWha Ja ChoJeong Woo ParkHyun Jin ParkJin SeoYoung Han LeeHo-Taek SongYoung Joo MinPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e53900 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chang Hoon Moon Seung Ju Lee Ho Yong Lee Jong Cheol Lee Heejeong Cha Wha Ja Cho Jeong Woo Park Hyun Jin Park Jin Seo Young Han Lee Ho-Taek Song Young Joo Min KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.
description	KML001 is sodium metaarsenite, and has shown cytotoxic activity in human tumor cell lines. The anti-cancer mechanism of KML001 involves cancer cell destruction due to DNA damage at the telomeres of cancer cell chromosomes. In this study, we assessed the vascular disrupting properties of KML001 and investigated whether KML001 as VDA is able to increase anti-tumor activity in irinotecan combined treatment. We used a murine model of the CT26 colon carcinoma cell line. CT26 isograft mice treated intraperitoneally with 10 mg/kg KML001 displayed extensive central necrosis of tumor by 24 h. The vascular disrupting effects of KML001 were assessed by dynamic contrast enhanced magnetic resonance imaging. Gadopentetic acid-diethylene triaminepentaacetic acid contrast enhancement was markedly decreased in KML001-treated mice one day after treatment, whereas persistently high signal enhancement was observed in mice injected with saline. Rate constant K(ep) value representing capillary permeability was significantly decreased (p<0.05) in mice treated with KML001. Cytoskeletal changes of human umbilical vein endothelial cells (HUVECs) treated with 10 uM KML001 were assessed by immune blotting and confocal imaging. KML001 degraded tubulin protein in HUVECs, which may be related to vascular disrupting properties of KML001. Finally, in the mouse CT26 isograft model, KML001 combined with irinotecan significantly delayed tumor growth as compared to control and irinotecan alone. These results suggest that KML001 is a novel vascular disrupting agent, which exhibits significant vascular shut-down activity and enhances anti-tumor activity in combination with chemotherapy. These data further suggest an avenue for effective combination therapy in treating solid tumors.
format	article
author	Chang Hoon Moon Seung Ju Lee Ho Yong Lee Jong Cheol Lee Heejeong Cha Wha Ja Cho Jeong Woo Park Hyun Jin Park Jin Seo Young Han Lee Ho-Taek Song Young Joo Min
author_facet	Chang Hoon Moon Seung Ju Lee Ho Yong Lee Jong Cheol Lee Heejeong Cha Wha Ja Cho Jeong Woo Park Hyun Jin Park Jin Seo Young Han Lee Ho-Taek Song Young Joo Min
author_sort	Chang Hoon Moon
title	KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.
title_short	KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.
title_full	KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.
title_fullStr	KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.
title_full_unstemmed	KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.
title_sort	kml001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/f4e650dbf6c243d3801265b9a36ecb77
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KML001 displays vascular disrupting properties and irinotecan combined antitumor activities in a murine tumor model.

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