Metabolism of N-alkylated spermine analogues by polyamine and spermine oxidases |
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| Authors: | Merja R. Häkkinen Mervi T. Hyvönen Seppo Auriola Robert A. Casero Jr Jouko Vepsäläinen Alex R. Khomutov Leena Alhonen Tuomo A. Keinänen |
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| Affiliation: | (1) Laboratory of Chemistry, Department of Biosciences, Biocenter Kuopio, University of Kuopio, P.O.Box 1627, 70211 Kuopio, Finland;(2) Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Kuopio, P.O.Box 1627, 70211 Kuopio, Finland;(3) Department of Pharmaceutical Chemistry, Biocenter Kuopio, University of Kuopio, P.O.Box 1627, 70211 Kuopio, Finland;(4) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA;(5) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA;(6) Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia |
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| Abstract: | N-alkylated polyamine analogues have potential as anticancer and antiparasitic drugs. However, their metabolism in the host has remained incompletely defined thus potentially limiting their utility. Here, we have studied the degradation of three different spermine analogues N,N′-bis-(3-ethylaminopropyl)butane-1,4-diamine (DESPM), N-(3-benzyl-aminopropyl)-N′-(3-ethylaminopropyl)butane-1,4-diamine (BnEtSPM) and N,N′-bis-(3-benzylaminopropyl)butane-1,4-diamine (DBSPM) and related mono-alkylated derivatives as substrates of recombinant human polyamine oxidase (APAO) and spermine oxidase (SMO). APAO and SMO metabolized DESPM to EtSPD [K m(APAO) = 10 μM, k cat(APAO) = 1.1 s−1 and K m(SMO) = 28 μM, k cat(SMO) = 0.8 s−1, respectively], metabolized BnEtSPM to EtSPD [K m(APAO) = 0.9 μM, k cat(APAO) = 1.1 s−1 and K m(SMO) = 51 μM, k cat(SMO) = 0.4 s−1, respectively], and metabolized DBSPM to BnSPD [K m(APAO) = 5.4 μM, k cat(APAO) = 2.0 s−1 and K m(SMO) = 33 μM, k cat(SMO) = 0.3 s−1, respectively]. Interestingly, mono-alkylated spermine derivatives were metabolized by APAO and SMO to SPD [EtSPM K m(APAO) = 16 μM, k cat(APAO) = 1.5 s−1; K m(SMO) = 25 μM, k cat(SMO) = 8.2 s−1; BnSPM K m(APAO) = 6.0 μM, k cat(APAO) = 2.8 s−1; K m(SMO) = 19 μM, k cat(SMO) = 0.8 s−1, respectively]. Surprisingly, EtSPD [K m(APAO) = 37 μM, k cat(APAO) = 0.1 s−1; K m(SMO) = 48 μM, k cat(SMO) = 0.05 s−1] and BnSPD [K m(APAO) = 2.5 μM, k cat(APAO) = 3.5 s−1; K m(SMO) = 60 μM, k cat(SMO) = 0.54 s−1] were metabolized to SPD by both the oxidases. Furthermore, we studied the degradation of DESPM, BnEtSPM or DBSPM in the DU145 prostate carcinoma cell line. The same major metabolites EtSPD and/or BnSPD were detected both in the culture medium and intracellularly after 48 h of culture. Moreover, EtSPM and BnSPM were detected from cell samples. Present data shows that inducible SMO parallel with APAO could play an important role in polyamine based drug action, i.e. degradation of parent drug and its metabolites, having significant impact on efficiency of these drugs, and hence for the development of novel N-alkylated polyamine analogues. |
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