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

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

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Abstract

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.

Item Type:	Article (Journal)
Additional Information:	4458/36999
Uncontrolled Keywords:	polyamine transport system, potentially toxic agents, cancer cells?
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Allied Health Sciences > Department of Biomedical Science (Effective:1st July 2011)
Depositing User:	Dr. Radiah Abdul Ghani
Date Deposited:	20 Jun 2014 09:27
Last Modified:	20 Jun 2014 09:27
URI:	http://irep.iium.edu.my/id/eprint/36999

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