Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells

Background It is well known that cancer cells have increased polyamine concentrations compared with normal cells. This relation is due to a combination of increased polyamine uptake via the polyamine transport system (PTS) as well as increased biosynthesis. Thus, we may be able to exploit the PTS...

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Main Authors:	Abdul Ghani, Radiah, Wallace, H.M., Phanstiel, O.V.
Format:	Article
Language:	English
Published:	Elsevier Inc. 2014
Subjects:	RM Therapeutics. Pharmacology
Online Access:	http://irep.iium.edu.my/38775/ http://irep.iium.edu.my/38775/ http://irep.iium.edu.my/38775/ http://irep.iium.edu.my/38775/2/use_of_polyamine.pdf

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spelling	iium-387752018-06-20T00:27:06Z http://irep.iium.edu.my/38775/ Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells Abdul Ghani, Radiah Wallace, H.M. Phanstiel, O.V. RM Therapeutics. Pharmacology Background It is well known that cancer cells have increased polyamine concentrations compared with normal cells. This relation is due to a combination of increased polyamine uptake via the polyamine transport system (PTS) as well as increased biosynthesis. Thus, we may be able to exploit the PTS for selective delivery of cytotoxic agents to cancer cells by attaching them to polyamine vectors. Such an approach should reduce non-specific toxicities and therefore decrease the side-effects associated with chemotherapy. This concept is also supported by the nature of PTS, which can accommodate a wide range of substrates. Three compounds combining the DNA intercalator, anthracene, with a polyamine side chain have been synthesised: Ant 4, Ant 44, and Ant 444.The aim of this study was to investigate the mode of cell death induced by anthracene conjugates in HL-60 cell lines. Methods We used a variety of techniques to study the response of HL-60 cells to Ant 4, Ant 44, and Ant 444. Findings Deconvolution microscopy analysis revealed that the conjugates entered the cells. Quantitative analysis using high-performance liquid chromatography showed that the amount of Ant 4 in cells increased 30% from 6 h to 12 h. Ant 44 showed the highest level in cells after 6 h of exposure. Ant 444 showed a gradual increase between 0 h to 48 h. The indirect evidence using pre-treated cells with 5 mmol difluromethylornithine (DFMO) showed a significant decrease of IC50 compared with no DFMO pretreatment for Ant 4, Ant 44, and Ant 444. The uptake study using radiolabelled polyamines showed there is a competition uptake between radiolabelled polyamines [14C] putrescine, spermidine, or spermine with Ant 4, Ant 44, and Ant 444. Interpretation Ant 4, Ant 44, and Ant 444 gain entry into HL-60 cells via the PTS. The idea of selectively targeting cancer cells via the PTS shows promise. In the future, the concept of selective targeting of cancer cells via the PTS could lead to the development of novel and effective anticancer therapies. Elsevier Inc. 2014-05 Article PeerReviewed application/pdf en http://irep.iium.edu.my/38775/2/use_of_polyamine.pdf Abdul Ghani, Radiah and Wallace, H.M. and Phanstiel, O.V. (2014) Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells. European Journal of Cancer, 50. e64-e65. ISSN 1879-0852 (O), 0959-8049 (P) http://dx.doi.org/10.1016/j.ejca.2014.03.244 10.1016/j.ejca.2014.03.244
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English
topic	RM Therapeutics. Pharmacology
spellingShingle	RM Therapeutics. Pharmacology Abdul Ghani, Radiah Wallace, H.M. Phanstiel, O.V. Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells
description	Background It is well known that cancer cells have increased polyamine concentrations compared with normal cells. This relation is due to a combination of increased polyamine uptake via the polyamine transport system (PTS) as well as increased biosynthesis. Thus, we may be able to exploit the PTS for selective delivery of cytotoxic agents to cancer cells by attaching them to polyamine vectors. Such an approach should reduce non-specific toxicities and therefore decrease the side-effects associated with chemotherapy. This concept is also supported by the nature of PTS, which can accommodate a wide range of substrates. Three compounds combining the DNA intercalator, anthracene, with a polyamine side chain have been synthesised: Ant 4, Ant 44, and Ant 444.The aim of this study was to investigate the mode of cell death induced by anthracene conjugates in HL-60 cell lines. Methods We used a variety of techniques to study the response of HL-60 cells to Ant 4, Ant 44, and Ant 444. Findings Deconvolution microscopy analysis revealed that the conjugates entered the cells. Quantitative analysis using high-performance liquid chromatography showed that the amount of Ant 4 in cells increased 30% from 6 h to 12 h. Ant 44 showed the highest level in cells after 6 h of exposure. Ant 444 showed a gradual increase between 0 h to 48 h. The indirect evidence using pre-treated cells with 5 mmol difluromethylornithine (DFMO) showed a significant decrease of IC50 compared with no DFMO pretreatment for Ant 4, Ant 44, and Ant 444. The uptake study using radiolabelled polyamines showed there is a competition uptake between radiolabelled polyamines [14C] putrescine, spermidine, or spermine with Ant 4, Ant 44, and Ant 444. Interpretation Ant 4, Ant 44, and Ant 444 gain entry into HL-60 cells via the PTS. The idea of selectively targeting cancer cells via the PTS shows promise. In the future, the concept of selective targeting of cancer cells via the PTS could lead to the development of novel and effective anticancer therapies.
format	Article
author	Abdul Ghani, Radiah Wallace, H.M. Phanstiel, O.V.
author_facet	Abdul Ghani, Radiah Wallace, H.M. Phanstiel, O.V.
author_sort	Abdul Ghani, Radiah
title	Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells
title_short	Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells
title_full	Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells
title_fullStr	Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells
title_full_unstemmed	Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells
title_sort	use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells
publisher	Elsevier Inc.
publishDate	2014
url	http://irep.iium.edu.my/38775/ http://irep.iium.edu.my/38775/ http://irep.iium.edu.my/38775/ http://irep.iium.edu.my/38775/2/use_of_polyamine.pdf
first_indexed	2023-09-18T20:55:44Z
last_indexed	2023-09-18T20:55:44Z
_version_	1777410291194134528

Use of polyamine transport system by polyamine anthracene conjugates in human leukaemic cells

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