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

• 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/38775/2/use_of_polyamine.pdf; http://irep.iium.edu.my/38775/; http://dx.doi.org/10.1016/j.ejca.2014.03.244

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.