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01.12.2012 | Primary research | Ausgabe 1/2012 Open Access

Cancer Cell International 1/2012

Increased toxicity of a trinuclear Pt-compound in a human squamous carcinoma cell line by polyamine depletion

Zeitschrift:
Cancer Cell International > Ausgabe 1/2012
Autoren:
Johan Kjellström, Stina M Oredsson, Johan Wennerberg
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2867-12-20) contains supplementary material, which is available to authorized users.
Presented by Johan Kjellström

Competing interests

The authors declare that they have no competing interests.

Authors’contributions

JK participated in the design of the study, performed most of the experiments, and drafted the manuscript. JW conceived of the study, and participated in its design and coordination and helped to draft the manuscript. SMO helped in polyamine analysis and final drafting of the manuscript. All authors read and approved the final manuscript.

Abstract

Background

Mononuclear platinum anticancer agents hold a pivotal place in the treatment of many forms of cancers, however, there is a potential to improve response to evade resistance development and toxic side effects. BBR3464 is a promising trinuclear platinum anticancer agent, which is a polyamine mimic. The aim was to investigate the influence of polyamine pool reduction on the cytotoxic effects of the trinuclear platinum complex BBR3464 and cisplatin. Polyamine pool reduction was achieved by treating cells with either the polyamine biosynthesis inhibitor α-difluoromethylornithine (DFMO) or the polyamine analogue N1,N11-diethylnorspermine (DENSPM).

Methods

A human squamous cell carcinoma cell line, LU-HNSCC-4, established from a primary head and neck tumour was used to evaluate cellular effects of each drug alone or combinations thereof. High-performance liquid-chromatography was used to quantify intracellular polyamine contents. Inductively coupled mass spectroscopy was used to quantify intracellular platinum uptake. Cells were exposed to DFMO or DENSPM during 48 h at concentrations ranging from 0 to 5 mM or 0 to 10 μM, respectively. Thereafter, non-treated and treated cells were exposed to cisplatin or BBR3464 during 1 h at concentrations ranging from 0 to 100 μM. A 96-well assay was used to determine cytotoxicity after five days after treatment.

Results

The cytotoxic effect of BBR3464 on LU-HNSCC-4 cells was increased after cells were pre-treated with DENSPM or DFMO, and the interaction was found to be synergistic. In contrast, the interaction between cisplatin and DFMO or DENSPM was near-additive to antagonistic. The intracellular levels of the polyamines putrescine and spermidine were decreased after treatment with DFMO, and treatment with DENSPM resulted in an increase in putrescine level and concomitant decrease in spermidine and spermine levels. The uptake of BBR3464 was significantly increased after pre-treatment of the cells with DFMO, and varied dependent on the concentration of DENSPM. The uptake of cisplatin was unchanged.

Conclusions

Taken together, these results demonstrate that combinations of polyamine synthesis inhibitors with BBR3464 appear to be a promising approach to enhance the anticancer activity against HSCC.
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
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Literatur
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