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Induction of the PAOh1/SMO polyamine oxidase by polyamine analogues in human lung carcinoma cells

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Abstract

Purpose

The induction of polyamine catabolism has been directly associated with the cytotoxic response of various tumor types to the antitumor polyamine analogues. Initially, human polyamine catabolism was assumed to be under the control of a rate-limiting spermidine/spermine N1-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (PAO). We have recently cloned a new polyamine analogue-inducible human polyamine oxidase (PAOh1/SMO) that efficiently uses spermine as a substrate. The induction of PAOh1/SMO in response to multiple polyamine analogues was examined in representative lung tumor cell lines.

Methods

Representatives of three different classes of antitumor polyamine analogues were examined for their ability to induce PAOh1/SMO.

Results

The human adenocarcinoma line, NCI A549 was found to be the most responsive line with respect to induction of PAOh1/SMO in response to analogue exposure. Similar to previous observations with SSAT expression, PAOh1/SMO induction was found to occur primarily in non-small-cell lung cancers cell lines. Using a series of polyamine analogues, it was found that the most potent inducers of PAOh1/SMO possessed multiple three-carbon linkers between nitrogens, as typified by N1,N11-bis(ethyl)norspermine.

Conclusions

Since PAOh1/SMO is an analogue-inducible enzyme that produces H2O2 as a metabolic product, it may play a significant role in determining the sensitivity of various human tumors to specific polyamine analogues.

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Abbreviations

BENSpm:

N1,N11-bis(ethyl)norspermine

CHENSpm:

N1-ethyl-N11-(cycloheptyl)methyl-4,8,diazaundecane

CPENSpm:

N1-ethyl-N11-(cyclopropyl)methyl-4,8,diazaundecane

DAO:

Diamine oxidase

IPENSpm:

(S)-N1-(2-methyl-1-butyl)-N11-ethyl-4,8,diazaundecane

MAO:

Monoamine oxidase

MDL 72,527:

(N1,N4-bis(2,3-butadienyl)-1,4-butanediamine)

PAO:

Acetylpolyamine oxidase

PAOh1/SMO:

Human polyamine oxidase h1/spermine oxidase

SSAT:

Spermidine/spermine N1-acetyltransferase

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Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA

    Wendy Devereux, Yanlin Wang, Tracy Murray Stewart, Amy Hacker, Renee Smith & Robert A. Casero

  2. SLIL Biomedical Corporation, Madison, WI 53711, USA

    Benjamin Frydman, Aldonia L. Valasinas, Venodhar K. Reddy & Laurence J. Marton

  3. Department of Pharmaceutical Sciences, Wayne State University, 539 Shapero Hall, Detroit, MI 48202, USA

    Tracey D. Ward & Patrick M. Woster

Authors
  1. Wendy Devereux
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  2. Yanlin Wang
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  3. Tracy Murray Stewart
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  4. Amy Hacker
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  5. Renee Smith
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  6. Benjamin Frydman
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  7. Aldonia L. Valasinas
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  8. Venodhar K. Reddy
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  9. Laurence J. Marton
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  10. Tracey D. Ward
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  11. Patrick M. Woster
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  12. Robert A. Casero
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Corresponding author

Correspondence to Robert A. Casero.

Additional information

This work was supported by NIH grants CA51085, CA58184, CA85509, and CA88843.

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Devereux, W., Wang, Y., Stewart, T.M. et al. Induction of the PAOh1/SMO polyamine oxidase by polyamine analogues in human lung carcinoma cells. Cancer Chemother Pharmacol 52, 383–390 (2003). https://doi.org/10.1007/s00280-003-0662-4

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