Spermine Oxidase (SMO) Activity in Breast Tumor Tissues and Biochemical Analysis of the Anticancer Spermine Analogues BENSpm and CPENSpm

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2010 Oct 16

PMID 20946629

Citations 23

Authors

Manuela Cervelli

Gabriella Bellavia

Emiliano Fratini

Roberto Amendola

Fabio Polticelli

Marco Barba

Rodolfo Federico

Fabrizio Signore

Giacomo Gucciardo

Rosalba Grillo

Patrick M Woster

Robert A Casero Jr

Paolo Mariottini

Affiliations

Soon will be listed here.

Abstract

Background: Polyamine metabolism has a critical role in cell death and proliferation representing a potential target for intervention in breast cancer (BC). This study investigates the expression of spermine oxidase (SMO) and its prognostic significance in BC. Biochemical analysis of Spm analogues BENSpm and CPENSpm, utilized in anticancer therapy, was also carried out to test their property in silico and in vitro on the recombinant SMO enzyme.

Methods: BC tissue samples were analyzed for SMO transcript level and SMO activity. Student's t test was applied to evaluate the significance of the differences in value observed in T and NT samples. The structure modeling analysis of BENSpm and CPENSpm complexes formed with the SMO enzyme and their inhibitory activity, assayed by in vitro experiments, were examined.

Results: Both the expression level of SMO mRNA and SMO enzyme activity were significantly lower in BC samples compared to NT samples. The modeling of BENSpm and CPENSpm complexes formed with SMO and their inhibition properties showed that both were good inhibitors.

Conclusions: This study shows that underexpression of SMO is a negative marker in BC. The SMO induction is a remarkable chemotherapeutical target. The BENSpm and CPENSpm are efficient SMO inhibitors. The inhibition properties shown by these analogues could explain their poor positive outcomes in Phases I and II of clinical trials.

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References

Streiff R, BENDER J . Phase 1 study of N1-N11-diethylnorspermine (DENSPM) administered TID for 6 days in patients with advanced malignancies. Invest New Drugs. 2001; 19(1):29-39. DOI: 10.1023/a:1006448516938. View

Sali A, Blundell T . Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993; 234(3):779-815. DOI: 10.1006/jmbi.1993.1626. View

Cervelli M, Bellini A, Bianchi M, Marcocci L, Nocera S, Polticelli F . Mouse spermine oxidase gene splice variants. Nuclear subcellular localization of a novel active isoform. Eur J Biochem. 2004; 271(4):760-70. DOI: 10.1111/j.1432-1033.2004.03979.x. View

Pledgie A, Huang Y, Hacker A, Zhang Z, Woster P, Davidson N . Spermine oxidase SMO(PAOh1), Not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated human breast cancer cell lines. J Biol Chem. 2005; 280(48):39843-51. DOI: 10.1074/jbc.M508177200. View

Huang Q, Liu Q, Hao Q . Crystal structures of Fms1 and its complex with spermine reveal substrate specificity. J Mol Biol. 2005; 348(4):951-9. DOI: 10.1016/j.jmb.2005.03.008. View

Deng W, Jiang X, Mei Y, Sun J, Ma R, Liu X . Role of ornithine decarboxylase in breast cancer. Acta Biochim Biophys Sin (Shanghai). 2008; 40(3):235-43. DOI: 10.1111/j.1745-7270.2008.00397.x. View

Manni A, Mauger D, Gimotty P, Badger B . Prognostic influence on survival of increased ornithine decarboxylase activity in human breast cancer. Clin Cancer Res. 1996; 2(11):1901-6. View

Bianchi M, Polticelli F, Ascenzi P, Botta M, Federico R, Mariottini P . Inhibition of polyamine and spermine oxidases by polyamine analogues. FEBS J. 2006; 273(6):1115-23. DOI: 10.1111/j.1742-4658.2006.05137.x. View

Wolff A, Armstrong D, Fetting J, Carducci M, Riley C, Bender J . A Phase II study of the polyamine analog N1,N11-diethylnorspermine (DENSpm) daily for five days every 21 days in patients with previously treated metastatic breast cancer. Clin Cancer Res. 2003; 9(16 Pt 1):5922-8. View

10.

Thomas T, Thomas T . Estradiol control of ornithine decarboxylase mRNA, enzyme activity, and polyamine levels in MCF-7 breast cancer cells: therapeutic implications. Breast Cancer Res Treat. 1994; 29(2):189-201. DOI: 10.1007/BF00665680. View

11.

Faaland C, Thomas T, Balabhadrapathruni S, Langer T, Mian S, Shirahata A . Molecular correlates of the action of bis(ethyl)polyamines in breast cancer cell growth inhibition and apoptosis. Biochem Cell Biol. 2000; 78(4):415-26. View

12.

Goodwin A, Jadallah S, Toubaji A, Lecksell K, Hicks J, Kowalski J . Increased spermine oxidase expression in human prostate cancer and prostatic intraepithelial neoplasia tissues. Prostate. 2008; 68(7):766-72. PMC: 3065872. DOI: 10.1002/pros.20735. View

13.

Creaven P, Perez R, Pendyala L, Meropol N, Loewen G, Levine E . Unusual central nervous system toxicity in a phase I study of N1N11 diethylnorspermine in patients with advanced malignancy. Invest New Drugs. 1997; 15(3):227-34. DOI: 10.1023/a:1005827231849. View

14.

Wallace H, Duthie J, Evans D, Lamond S, Nicoll K, Heys S . Alterations in polyamine catabolic enzymes in human breast cancer tissue. Clin Cancer Res. 2000; 6(9):3657-61. View

15.

Xu H, Chaturvedi R, Cheng Y, Bussiere F, Asim M, Yao M . Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implications for gastric carcinogenesis. Cancer Res. 2004; 64(23):8521-5. DOI: 10.1158/0008-5472.CAN-04-3511. View

16.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

17.

Wang Y, Murray-Stewart T, Devereux W, Hacker A, Frydman B, Woster P . Properties of purified recombinant human polyamine oxidase, PAOh1/SMO. Biochem Biophys Res Commun. 2003; 304(4):605-11. DOI: 10.1016/s0006-291x(03)00636-3. View

18.

Cervelli M, Polticelli F, Federico R, Mariottini P . Heterologous expression and characterization of mouse spermine oxidase. J Biol Chem. 2002; 278(7):5271-6. DOI: 10.1074/jbc.M207888200. View

19.

Davidson N, Hahm H, McCloskey D, Woster P, Casero Jr R . Clinical aspects of cell death in breast cancer: the polyamine pathway as a new target for treatment. Endocr Relat Cancer. 2000; 6(1):69-73. DOI: 10.1677/erc.0.0060069. View

20.

Amendola R, Cervelli M, Fratini E, Polticelli F, Sallustio D, Mariottini P . Spermine metabolism and anticancer therapy. Curr Cancer Drug Targets. 2009; 9(2):118-30. DOI: 10.2174/156800909787580935. View