The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells?

The development of a means of delivering drugs selectively to cancer cells is a huge challenge in cancer research today. The development of such methods would decrease the non-specific toxicities which limit the use of most anti-cancer drugs. One way to achieve this is to utilise a specific transpor...

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Main Authors:	Abdul Ghani, Radiah, Palmer, Andrew J., Kaur, Navneet, Phanstiel, Otto, Wallace, Heather M.
Format:	Article
Language:	English
Published:	ELSEVIER 2009
Subjects:	RM Therapeutics. Pharmacology
Online Access:	http://irep.iium.edu.my/36999/ http://irep.iium.edu.my/36999/ http://irep.iium.edu.my/36999/ http://irep.iium.edu.my/36999/1/Mypaper3.pdf

id	iium-36999
recordtype	eprints
spelling	iium-369992014-06-20T01:27:14Z http://irep.iium.edu.my/36999/ The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells? Abdul Ghani, Radiah Palmer, Andrew J. Kaur, Navneet Phanstiel, Otto Wallace, Heather M. RM Therapeutics. Pharmacology The development of a means of delivering drugs selectively to cancer cells is a huge challenge in cancer research today. The development of such methods would decrease the non-specific toxicities which limit the use of most anti-cancer drugs. One way to achieve this is to utilise a specific transport mechanism such as polyamine transport system (PTS). Polyamine transport system is an energy-dependent process that is upregulated in cancer cells which have a high requirement for polyamines (Gardner et al., 2004). Exogenous polyamines are taken up into the cells via PTS. In addition, there have been a number of studies indicating that the PTS is not restricted to natural polyamines but can accommodate a wide range of substrates (Phanstiel et al., 2004). With this knowledge, a strategy was devised to use the polyamines as a means of vectoral transport into cells to introduce potentially toxic agents which would not normally enter cancer cells. The aim is to increase the selectivity of anti-cancer agents and minimise the side effects in normal cells (Phanstiel et al., 2004). To this end, a series of compounds combining the DNA intercalator, anthracene, with a polyamine side chain were synthesized (Phanstiel et al., 2000). The aim of our study was to determine the effect of two of these compounds, namely 9-anthracenylmethyl-butanediamine (Ant 4), N1-anthracenylmethyl-4,4-triamine (Ant 4,4) as a paradigm for the delivery of cytotoxic agents via PTS using human leukaemic cells (HL-60) as in vitro model. Both Ant 4 and Ant 44 demonstrated dose-dependent cytotoxicity with IC50 of 9 μM and 20 μM, respectively. Morphological staining with DAPI was used to identify the cell death as apoptosis ( Table 1). An interesting finding was the significant polyamine depletion caused by treatment with both compounds after 48 h exposure ( Table 1). Polyamine depletion results in a compensatory increase in activity of PTS. This was used to show indirectly that Ant 4 and Ant 44 use the PTS. When polyamine depletion occurred, the toxicity of both compounds increased indicating increased uptake via PTS (results not shown). No polyamine was detected in the medium used. ELSEVIER 2009-07-28 Article PeerReviewed application/pdf en http://irep.iium.edu.my/36999/1/Mypaper3.pdf Abdul Ghani, Radiah and Palmer, Andrew J. and Kaur, Navneet and Phanstiel, Otto and Wallace, Heather M. (2009) The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells? Toxicology, 262 (1). p. 13. ISSN 0300-483X http://www.sciencedirect.com/science/article/pii/S0300483X09001899# 10.1016/j.tox.2009.04.012
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 Palmer, Andrew J. Kaur, Navneet Phanstiel, Otto Wallace, Heather M. The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells?
description	The development of a means of delivering drugs selectively to cancer cells is a huge challenge in cancer research today. The development of such methods would decrease the non-specific toxicities which limit the use of most anti-cancer drugs. One way to achieve this is to utilise a specific transport mechanism such as polyamine transport system (PTS). Polyamine transport system is an energy-dependent process that is upregulated in cancer cells which have a high requirement for polyamines (Gardner et al., 2004). Exogenous polyamines are taken up into the cells via PTS. In addition, there have been a number of studies indicating that the PTS is not restricted to natural polyamines but can accommodate a wide range of substrates (Phanstiel et al., 2004). With this knowledge, a strategy was devised to use the polyamines as a means of vectoral transport into cells to introduce potentially toxic agents which would not normally enter cancer cells. The aim is to increase the selectivity of anti-cancer agents and minimise the side effects in normal cells (Phanstiel et al., 2004). To this end, a series of compounds combining the DNA intercalator, anthracene, with a polyamine side chain were synthesized (Phanstiel et al., 2000). The aim of our study was to determine the effect of two of these compounds, namely 9-anthracenylmethyl-butanediamine (Ant 4), N1-anthracenylmethyl-4,4-triamine (Ant 4,4) as a paradigm for the delivery of cytotoxic agents via PTS using human leukaemic cells (HL-60) as in vitro model. Both Ant 4 and Ant 44 demonstrated dose-dependent cytotoxicity with IC50 of 9 μM and 20 μM, respectively. Morphological staining with DAPI was used to identify the cell death as apoptosis ( Table 1). An interesting finding was the significant polyamine depletion caused by treatment with both compounds after 48 h exposure ( Table 1). Polyamine depletion results in a compensatory increase in activity of PTS. This was used to show indirectly that Ant 4 and Ant 44 use the PTS. When polyamine depletion occurred, the toxicity of both compounds increased indicating increased uptake via PTS (results not shown). No polyamine was detected in the medium used.
format	Article
author	Abdul Ghani, Radiah Palmer, Andrew J. Kaur, Navneet Phanstiel, Otto Wallace, Heather M.
author_facet	Abdul Ghani, Radiah Palmer, Andrew J. Kaur, Navneet Phanstiel, Otto Wallace, Heather M.
author_sort	Abdul Ghani, Radiah
title	The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells?
title_short	The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells?
title_full	The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells?
title_fullStr	The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells?
title_full_unstemmed	The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells?
title_sort	polyamine transport system: a means of selective delivery of potentially toxic agents to cancer cells?
publisher	ELSEVIER
publishDate	2009
url	http://irep.iium.edu.my/36999/ http://irep.iium.edu.my/36999/ http://irep.iium.edu.my/36999/ http://irep.iium.edu.my/36999/1/Mypaper3.pdf
first_indexed	2023-09-18T20:53:04Z
last_indexed	2023-09-18T20:53:04Z
_version_	1777410123428265984

The polyamine transport system: A means of selective delivery of potentially toxic agents to cancer cells?

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