Skip to main content

Advertisement

SpringerLink
Log in

The role of the polyamine catabolic enzymes SSAT and SMO in the synergistic effects of standard chemotherapeutic agents with a polyamine analogue in human breast cancer cell lines

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Introduction

Polyamine analogues have demonstrated significant activity against human breast cancer cell lines as single agents as well as in combination with other cytotoxic drugs. This study evaluates the ability of a polyamine analogue N 1,N 11-bis(ethyl)norspermine (BENSpm) to synergize with six standard chemotherapeutic agents, 5-fluorouracil (FU), fluorodeoxyuridine, cis-diaminechloroplatinum(II) (C-DDP), paclitaxel, docetaxel, and vinorelbine.

Materials and methods

Four human breast cancer cell lines (MDA-MB-231, MCF-7, Hs578t, and T47D) and one immortalized, non-tumorigenic mammary epithelial cell line (MCF-10A) were used for in vitro combination studies with BENSpm and cytotoxic drugs. Xenograft mice models generated with MDA-MB-231 cells were used for in vivo studies with BENSpm and paclitaxel.

Results and conclusion

BENSpm exhibited synergistic inhibitory effect on cell proliferation in combination with 5-FU or paclitaxel in human breast cancer cell lines (MDA-MB-231 and MCF-7) and was either antagonistic or less effective in the non-tumorigenic MCF-10A cell line. Synergism was highest with 120 h concomitant treatment or pre-treatment with BENSpm for 24 h followed by concomitant treatment for 96 additional hours. Since the cytotoxic effects of many polyamine analogues and cytotoxic agents are believed to act, in part, through induction of the polyamine catabolic enzymes SSAT and SMO, the role of these enzymes on synergistic response was evaluated in MDA-MB-231 and MCF-7 treated with BENSpm and 5-FU or paclitaxel. Combination treatments of BENSpm with 5-FU or paclitaxel resulted in induction of SSAT mRNA and activity in both cell lines compared to either drug alone, while SMO mRNA and activity were increased only in MDA-MB-231 cells. Induction was greater with BENSpm/paclitaxel combination than BENSpm/5-FU. Further, RNAi studies demonstrated that both SSAT and SMO play a significant role in the response of MDA-MB-231 cells to treatment with BENSpm and 5-FU or paclitaxel. In MCF-7 cells, only SSAT appears to be involved in the response to these treatments. In an effort to translate combination studies from in vitro to in vivo, and to form a basis for clinical setting, the in vivo therapeutic efficacy of BENSpm alone and in combination with paclitaxel on tumor regression was evaluated in xenograft mice models generated with MDA-MB-231 cells. Intraperitoneal exposure to BENSpm or taxol singly and in combination for 4 weeks resulted in significant inhibition in tumor growth. These findings help elucidate the mechanisms involved in synergistic drug response and support combinations of polyamine analogues with chemotherapeutic agents which could potentially be used in the treatment of breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ODC:

Ornithine decarboxylase

AdoMetDC:

S-adenosylmethionine decarboxylase

SSAT:

Spermidine/spermine N 1-acetyltransferase

APAO:

N1-acetylpolyamine oxidase

SMO:

Spermine oxidase

BENSpm:

N1,N11-Bis(ethyl)norspermine (also known as DENSpm, N1,N11-Diethylnorspermine)

ER:

Estrogen receptor alpha

TS:

Thymidylate synthase

FdURd:

Fluorodeoxyuridine

5-FU:

5-Fluorouracil

C-DDP:

cis-Diaminechloroplatinum(II)

CPENSpm:

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

CHENSpm:

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

References

  1. Allen WL, McLean EG, Boyer J, McCulla A, Wilson PM, Coyle V, Longley DB, Casero RA Jr, Johnston PG (2007) The role of spermidine/spermine N1-acetyltransferase in determining response to chemotherapeutic agents in colorectal cancer cells. Mol Cancer Ther 6:128–137

    Article  CAS  PubMed  Google Scholar 

  2. Balasundaram D, Tyagi AK (1991) Polyamine–DNA nexus: structural ramifications and biological implications. Mol Cell Biochem 100:129–140

    Article  CAS  PubMed  Google Scholar 

  3. Basu HS, Pellarin M, Feuerstein BG, Shirahata A, Samejima K, Deen DF, Marton LJ (1993) Interaction of a polyamine analogue, 1, 19-bis-(ethylamino)-5, 10, 15-triazanonadecane (BE-4–4-4–4), with DNA and effect on growth, survival, and polyamine levels in seven human brain tumor cell lines. Cancer Res 53:3948–3955

    CAS  PubMed  Google Scholar 

  4. Bergeron RJ, Neims AH, McManis JS, Hawthorne TR, Vinson JR, Bortell R, Ingeno MJ (1988) Synthetic polyamine analogues as antineoplastics. J Med Chem 31:1183–1190

    Article  CAS  PubMed  Google Scholar 

  5. Bernacki RJ, Bergeron RJ, Porter CW (1992) Antitumor activity of N,N′-bis(ethyl)spermine homologues against human MALME-3 melanoma xenografts. Cancer Res 52:2424–2430

    CAS  PubMed  Google Scholar 

  6. Bernacki RJ, Oberman EJ, Seweryniak KE, Atwood A, Bergeron RJ, Porter CW (1995) Preclinical antitumor efficacy of the polyamine analogue N1, N11-diethylnorspermine administered by multiple injection or continuous infusion. Clin Cancer Res 1:847–857

    CAS  PubMed  Google Scholar 

  7. Boyer J, Allen WL, McLean EG, Wilson PM, McCulla A, Moore S, Longley DB, Caldas C, Johnston PG (2006) Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res 66:2765–2777

    Article  CAS  PubMed  Google Scholar 

  8. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  9. Budman DR (1997) Vinorelbine (Navelbine): a third-generation vinca alkaloid. Cancer Invest 15:475–490

    Article  CAS  PubMed  Google Scholar 

  10. Camargo SM, Francescato HD, Lavrador MA, Bianchi ML (2001) Oral administration of sodium selenite minimizes cisplatin toxicity on proximal tubules of rats. Biol Trace Elem Res 83:251–262

    Article  CAS  PubMed  Google Scholar 

  11. Casero RA Jr, Celano P, Ervin SJ, Porter CW, Bergeron RJ, Libby PR (1989) Differential induction of spermidine/spermine N1-acetyltransferase in human lung cancer cells by the bis(ethyl)polyamine analogues. Cancer Res 49:3829–3833

    CAS  PubMed  Google Scholar 

  12. Casero RA Jr, Celano P, Ervin SJ, Wiest L, Pegg AE (1990) High specific induction of spermidine/spermine N1-acetyltransferase in a human large cell lung carcinoma. Biochem J 270:615–620

    CAS  PubMed  Google Scholar 

  13. Casero RA Jr, Wang Y, Stewart TM, Devereux W, Hacker A, Smith R, Woster PM (2003) The role of polyamine catabolism in anti-tumour drug response. Biochem Soc Trans 31:361–365

    Article  CAS  PubMed  Google Scholar 

  14. Casero RA Jr, Woster PM (2001) Terminally alkylated polyamine analogues as chemotherapeutic agents. J Med Chem 44:1–26

    Article  CAS  PubMed  Google Scholar 

  15. Chang BK, Bergeron RJ, Porter CW, Vinson JR, Liang Y, Libby PR (1992) Regulatory and antiproliferative effects of N-alkylated polyamine analogues in human and hamster pancreatic adenocarcinoma cell lines. Cancer Chemother Pharmacol 30:183–188

    Article  CAS  PubMed  Google Scholar 

  16. Chang BK, Gutman R, Black O Jr (1986) Combined effects of alpha-difluoromethylornithine and doxorubicin against pancreatic cancer cell lines in culture. Pancreas 1:49–54

    Article  CAS  PubMed  Google Scholar 

  17. Choi W, Gerner EW, Ramdas L, Dupart J, Carew J, Proctor L, Huang P, Zhang W, Hamilton SR (2005) Combination of 5-fluorouracil and N1, N11-diethylnorspermine markedly activates spermidine/spermine N1-acetyltransferase expression, depletes polyamines, and synergistically induces apoptosis in colon carcinoma cells. J Biol Chem 280:3295–3304

    Article  CAS  PubMed  Google Scholar 

  18. Choi W, Proctor L, Xia Q, Feng Y, Gerner EW, Chiao PJ, Hamilton SR, Zhang W (2006) Inactivation of IkappaB contributes to transcriptional activation of spermidine/spermine N(1)-acetyltransferase. Mol Carcinog 45:685–693

    Article  CAS  PubMed  Google Scholar 

  19. Chou TC, Talalay P (1984) Quantitative analysis of dose–effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  CAS  PubMed  Google Scholar 

  20. Coleman CS, Pegg AE, Megosh LC, Guo Y, Sawicki JA, O’Brien TG (2002) Targeted expression of spermidine/spermine N1-acetyltransferase increases susceptibility to chemically induced skin carcinogenesis. Carcinogenesis 23:359–364

    Article  CAS  PubMed  Google Scholar 

  21. Culine S, Roch I, Pinguet F, Romieu G, Bressolle F (1999) Combination paclitaxel and vinorelbine therapy: in vitro cytotoxic interactions and dose-escalation study in breast cancer patients previously exposed to anthracyclines. Int J Oncol 14:999–1006

    CAS  PubMed  Google Scholar 

  22. Das B, Rao AR, Madhubala R (1997) Difluoromethylornithine antagonizes taxol cytotoxicity in MCF-7 human breast cancer cells. Oncol Res 9:565–572

    CAS  PubMed  Google Scholar 

  23. Davidson NE, Hahm HA, McCloskey DE, Woster PM, Casero RA Jr (1999) Clinical aspects of cell death in breast cancer: the polyamine pathway as a new target for treatment. Endocr Relat Cancer 6:69–73

    Article  CAS  PubMed  Google Scholar 

  24. Davidson NE, Mank AR, Prestigiacomo LJ, Bergeron RJ, Casero RA Jr (1993) Growth inhibition of hormone-responsive and -resistant human breast cancer cells in culture by N1, N12-bis(ethyl)spermine. Cancer Res 53:2071–2075

    CAS  PubMed  Google Scholar 

  25. Desiderio MA, Bergamaschi D, Mascellani E, De Feudis P, Erba E, D’Incalci M (1997) Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors. Br J Cancer 75:1028–1034

    CAS  PubMed  Google Scholar 

  26. Devereux W, Wang Y, Stewart TM, Hacker A, Smith R, Frydman B, Valasinas AL, Reddy VK, Marton LJ, Ward TD, Woster PM, Casero RA (2003) Induction of the PAOh1/SMO polyamine oxidase by polyamine analogues in human lung carcinoma cells. Cancer Chemother Pharmacol 52:383–390

    Article  CAS  PubMed  Google Scholar 

  27. Feuerstein BG, Pattabiraman N, Marton LJ (1990) Molecular mechanics of the interactions of spermine with DNA: DNA bending as a result of ligand binding. Nucl Acids Res 18:1271–1282

    Article  CAS  PubMed  Google Scholar 

  28. Fine JP, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496–509

    Article  Google Scholar 

  29. Fitzpatrick FA, Wheeler R (2003) The immunopharmacology of paclitaxel (Taxol), docetaxel (Taxotere), and related agents. Int Immunopharmacol 3:1699–1714

    Article  CAS  PubMed  Google Scholar 

  30. Gray RJ (1988) A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141–1154

    Article  Google Scholar 

  31. Ha HC, Woster PM, Yager JD, Casero RA Jr (1997) The role of polyamine catabolism in polyamine analogue-induced programmed cell death. Proc Natl Acad Sci USA 94:11557–11562

    Article  CAS  PubMed  Google Scholar 

  32. Hacker A, Marton LJ, Sobolewski M, Casero RA Jr (2008) In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells. Cancer Chemother Pharmacol 63:45–53

    Article  CAS  PubMed  Google Scholar 

  33. Hahm HA, Dunn VR, Butash KA, Deveraux WL, Woster PM, Casero RA Jr, Davidson NE (2001) Combination of standard cytotoxic agents with polyamine analogues in the treatment of breast cancer cell lines. Clin Cancer Res 7:391–399

    CAS  PubMed  Google Scholar 

  34. Hahm HA, Ettinger DS, Bowling K, Hoker B, Chen TL, Zabelina Y, Casero RA Jr (2002) Phase I study of N(1), N(11)-diethylnorspermine in patients with non-small cell lung cancer. Clin Cancer Res 8:684–690

    CAS  PubMed  Google Scholar 

  35. Hawthorne TR, Austin JK Jr (1996) Synergism of the polyamine analogue, N1, N11-bisethylnorspermine with cis-diaminedichloroplatinum (II) against murine neoplastic cell lines in vitro and in vivo. Cancer Lett 99:99–107

    Article  CAS  PubMed  Google Scholar 

  36. Hector S, Hawthorn L, Greco W, Pendyala L (2002) Gene expression profiles after oxaliplatin treatment in A2780 ovarian carcinoma cells. Proc Am Assoc Cancer Res 43:62

    Google Scholar 

  37. Hector S, Porter CW, Kramer DL, Clark K, Prey J, Kisiel N, Diegelman P, Chen Y, Pendyala L (2004) Polyamine catabolism in platinum drug action: Interactions between oxaliplatin and the polyamine analogue N1, N11-diethylnorspermine at the level of spermidine/spermine N1-acetyltransferase. Mol Cancer Ther 3:813–822

    CAS  PubMed  Google Scholar 

  38. Hector S, Tummala R, Kisiel ND, Diegelman P, Vujcic S, Clark K, Fakih M, Kramer DL, Porter CW, Pendyala L (2008) Polyamine catabolism in colorectal cancer cells following treatment with oxaliplatin, 5-fluorouracil and N1, N11 diethylnorspermine. Cancer Chemother Pharmacol 62:517–527

    Article  CAS  PubMed  Google Scholar 

  39. Holst CM, Johansson VM, Alm K, Oredsson SM (2008) Novel anti-apoptotic effect of Bcl-2: prevention of polyamine depletion-induced cell death. Cell Biol Int 32:66–74

    Article  CAS  PubMed  Google Scholar 

  40. Huang Y, Hager ER, Phillips DL, Dunn VR, Hacker A, Frydman B, Kink JA, Valasinas AL, Reddy VK, Marton LJ, Casero RA Jr, Davidson NE (2003) A novel polyamine analog inhibits growth and induces apoptosis in human breast cancer cells. Clin Cancer Res 9:2769–2777

    CAS  PubMed  Google Scholar 

  41. Huang Y, Pledgie A, Casero RA Jr, Davidson NE (2005) Molecular mechanisms of polyamine analogs in cancer cells. Anticancer Drugs 16:229–241

    Article  CAS  PubMed  Google Scholar 

  42. Johansson VM, Oredsson SM, Alm K (2008) Polyamine depletion with two different polyamine analogues causes DNA damage in human breast cancer cell lines. DNA Cell Biol 27:511–516

    Article  CAS  PubMed  Google Scholar 

  43. Johnson M, Shaw M, Rubenstein M, Guinan P (1990) Effect of early and delayed difluoromethylornithine pretreatment upon cyclophosphamide chemotherapy. Clin Physiol Biochem 8:11–15

    CAS  PubMed  Google Scholar 

  44. Kano Y, Akutsu M, Tsunoda S, Izumi T, Mori K, Fujii H, Yazawa Y, Mano H, Furukawa Y (2004) Schedule-dependent synergism and antagonism between pemetrexed and paclitaxel in human carcinoma cell lines in vitro. Cancer Chemother Pharmacol 54:505–513

    Article  CAS  PubMed  Google Scholar 

  45. Kano Y, Akutsu M, Tsunoda S, Mori K, Suzuki K, Adachi KI (1998) In vitro schedule-dependent interaction between paclitaxel and SN-38 (the active metabolite of irinotecan) in human carcinoma cell lines. Cancer Chemother Pharmacol 42:91–98

    Article  CAS  PubMed  Google Scholar 

  46. Keen JC, Davidson NE (2003) The biology of breast carcinoma. Cancer 97:825–833

    Article  PubMed  Google Scholar 

  47. Kingsnorth AN, Russell WE, McCann PP, Diekema KA, Malt RA (1983) Effects of alpha-difluoromethylornithine and 5-fluorouracil on the proliferation of a human colon adenocarcinoma cell line. Cancer Res 43:4035–4038

    CAS  PubMed  Google Scholar 

  48. Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338

    Article  CAS  PubMed  Google Scholar 

  49. Marton LJ, Pegg AE (1995) Polyamines as targets for therapeutic intervention. Annu Rev Pharmacol Toxicol 35:55–91

    Article  CAS  PubMed  Google Scholar 

  50. Marverti G, Piccinini G, Ghiaroni S, Barbieri D, Quaglino D, Moruzzi MS (1998) N1, N12-bis(ethyl)spermine effect on growth of cis-diamminedichloroplatinum(II)-sensitive and -resistant human ovarian-carcinoma cell lines. Int J Cancer 78:33–40

    Article  CAS  PubMed  Google Scholar 

  51. Maxwell PJ, Longley DB, Latif T, Boyer J, Allen W, Lynch M, McDermott U, Harkin DP, Allegra CJ, Johnston PG (2003) Identification of 5-fluorouracil-inducible target genes using cDNA microarray profiling. Cancer Res 63:4602–4606

    CAS  PubMed  Google Scholar 

  52. McCloskey DE, Casero RA Jr, Woster PM, Davidson NE (1995) Induction of programmed cell death in human breast cancer cells by an unsymmetrically alkylated polyamine analogue. Cancer Res 55:3233–3236

    CAS  PubMed  Google Scholar 

  53. McCloskey DE, Yang J, Woster PM, Davidson NE, Casero RA Jr (1996) Polyamine analogue induction of programmed cell death in human lung tumor cells. Clin Cancer Res 2:441–446

    CAS  PubMed  Google Scholar 

  54. Nakagawa H, Yamada M, Fukushima M, Ikenaka K (1999) Intrathecal 5-fluoro-2′-deoxyuridine (FdUrd) for the treatment of solid tumor neoplastic meningitis: an in vivo study. Cancer Chemother Pharmacol 43:247–256

    Article  CAS  PubMed  Google Scholar 

  55. Oredsson SM, Alm K, Dahlberg E, Holst CM, Johansson VM, Myhre L, Soderstjerna E (2007) Inhibition of cell proliferation and induction of apoptosis by N(1), N(11)-diethylnorspermine-induced polyamine pool reduction. Biochem Soc Trans 35:405–409

    Article  CAS  PubMed  Google Scholar 

  56. Pegg AE (2008) Spermidine/spermine-N(1)-acetyltransferase: a key metabolic regulator. Am J Physiol Endocrinol Metab 294:E995–E1010

    Article  CAS  PubMed  Google Scholar 

  57. Pledgie A, Huang Y, Hacker A, Zhang Z, Woster PM, Davidson NE, Casero RA Jr (2005) 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 280:39843–39851

    Article  CAS  PubMed  Google Scholar 

  58. Porter CW, Ganis B, Libby PR, Bergeron RJ (1991) Correlations between polyamine analogue-induced increases in spermidine/spermine N1-acetyltransferase activity, polyamine pool depletion, and growth inhibition in human melanoma cell lines. Cancer Res 51:3715–3720

    CAS  PubMed  Google Scholar 

  59. Porter CW, McManis J, Casero RA, Bergeron RJ (1987) Relative abilities of bis(ethyl) derivatives of putrescine, spermidine, and spermine to regulate polyamine biosynthesis and inhibit L1210 leukemia cell growth. Cancer Res 47:2821–2825

    CAS  PubMed  Google Scholar 

  60. Schipper RG, Deli G, Deloyer P, Lange WP, Schalken JA, Verhofstad AA (2000) Antitumor activity of the polyamine analog N(1), N(11)-diethylnorspermine against human prostate carcinoma cells. Prostate 44:313–321

    Article  CAS  PubMed  Google Scholar 

  61. Seidenfeld J, Barnes D, Block AL, Erickson LC (1987) Comparison of DNA interstrand cross-linking and strand breakage by 1, 3-bis(2-chloroethyl)-1-nitrosourea in polyamine-depleted and control human adenocarcinoma cells. Cancer Res 47:4538–4543

    CAS  PubMed  Google Scholar 

  62. Sharma A, Glaves D, Porter CW, Raghavan D, Bernacki RJ (1997) Antitumor efficacy of N1, N11-diethylnorspermine on a human bladder tumor xenograft in nude athymic mice. Clin Cancer Res 3:1239–1244

    CAS  PubMed  Google Scholar 

  63. Shaw MW, Guinan PD, McKiel CF, Dubin A, Rubenstein M (1987) Combination therapy using polyamine synthesis inhibitor alpha-difluoromethylornithine and adriamycin in treatment of rats carrying the Dunning R3327 MAT-LyLu prostatic adenocarcinoma. Prostate 11:87–93

    Article  CAS  PubMed  Google Scholar 

  64. Shrestha RD, Fujimoto S, Okui K (1987) Contradictory antitumor efficacies produced by the combination of DNA attacking drugs and polyamine antimetabolites. Jpn J Surg 17:263–268

    Article  CAS  PubMed  Google Scholar 

  65. Snyder RD (1989) Polyamine depletion is associated with altered chromatin structure in HeLa cells. Biochem J 260:697–704

    CAS  PubMed  Google Scholar 

  66. Stanic I, Cetrullo S, Facchini A, Stefanelli C, Borzi RM, Tantini B, Guarnieri C, Caldarera CM, Flamigni F (2008) Effect of the polyamine analogue N1, N11-diethylnorspermine on cell survival and susceptibility to apoptosis of human chondrocytes. J Cell Physiol 216:153–161

    Article  CAS  PubMed  Google Scholar 

  67. Stearns V, Davidson NE, Flockhart DA (2004) Pharmacogenetics in the treatment of breast cancer. Pharmacogenom J 4:143–153

    Article  CAS  Google Scholar 

  68. Thomas T, Kiang DT (1987) Additive growth-inhibitory effects of DL-alpha-difluoromethylornithine and antiestrogens on MCF-7 breast cancer cell line. Biochem Biophys Res Commun 148:1338–1345

    Article  CAS  PubMed  Google Scholar 

  69. Thomas T, Thomas TJ (2001) Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications. Cell Mol Life Sci 58:244–258

    Article  CAS  PubMed  Google Scholar 

  70. Varma R, Hector S, Greco WR, Clark K, Hawthorn L, Porter C, Pendyala L (2007) Platinum drug effects on the expression of genes in the polyamine pathway: time-course and concentration-effect analysis based on Affymetrix gene expression profiling of A2780 ovarian carcinoma cells. Cancer Chemother Pharmacol 59:711–723

    Article  CAS  PubMed  Google Scholar 

  71. Wallace HM, Fraser AV, Hughes A (2003) A perspective of polyamine metabolism. Biochem J 376:1–14

    Article  CAS  PubMed  Google Scholar 

  72. Wang Y, Hacker A, Murray-Stewart T, Fleischer JG, Woster PM, Casero RA Jr (2005) Induction of human spermine oxidase SMO(PAOh1) is regulated at the levels of new mRNA synthesis, mRNA stabilization and newly synthesized protein. Biochem J 386:543–547

    Article  CAS  PubMed  Google Scholar 

  73. Webb HK, Wu Z, Sirisoma N, Ha HC, Casero RA Jr, Woster PM (1999) 1-(N-alkylamino)-11-(N-ethylamino)-4, 8-diazaundecanes: simple synthetic polyamine analogues that differentially alter tubulin polymerization. J Med Chem 42:1415–1421

    Article  CAS  PubMed  Google Scholar 

  74. Wolff AC, Armstrong DK, Fetting JH, Carducci MK, Riley CD, Bender JF, Casero RA Jr, Davidson NE (2003) 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 9:5922–5928

    CAS  PubMed  Google Scholar 

  75. Zagaja GP, Shrivastav M, Fleig MJ, Marton LJ, Rinker-Schaeffer CW, Dolan ME (1998) Effects of polyamine analogues on prostatic adenocarcinoma cells in vitro and in vivo. Cancer Chemother Pharmacol 41:505–512

    Article  CAS  PubMed  Google Scholar 

  76. Zhang W, Ramdas L, Shen W, Song SW, Hu L, Hamilton SR (2003) Apoptotic response to 5-fluorouracil treatment is mediated by reduced polyamines, non-autocrine Fas ligand and induced tumor necrosis factor receptor 2. Cancer Biol Ther 2:572–578

    CAS  PubMed  Google Scholar 

  77. Zirvi KA, Atabek U (1991) In vitro response of a human colon tumor xenograft and a lung adenocarcinoma cell line to alpha-difluoromethylornithine alone and in combination with 5-fluorouracil and doxorubicin. J Surg Oncol 48:34–38

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, MD, 21250, USA

    Allison Pledgie-Tracy

  2. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, 21231, USA

    Madhavi Billam, Amy Hacker, Zhe Zhang & Robert A. Casero

  3. Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Michele D. Sobolewski

  4. The Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, MI, 48202, USA

    Patrick M. Woster

  5. University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Suite 500, UPMC Cancer Pavilion, Pittsburgh, PA, 15232, USA

    Nancy E. Davidson

Authors
  1. Allison Pledgie-Tracy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Madhavi Billam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amy Hacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michele D. Sobolewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrick M. Woster
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhe Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert A. Casero
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nancy E. Davidson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy E. Davidson.

Additional information

A. Pledgie-Tracy, M. Billam contributed equally to this work.

This work was supported by grants from the NIH, the Department of Defense and the Breast Cancer Research Foundation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pledgie-Tracy, A., Billam, M., Hacker, A. et al. The role of the polyamine catabolic enzymes SSAT and SMO in the synergistic effects of standard chemotherapeutic agents with a polyamine analogue in human breast cancer cell lines. Cancer Chemother Pharmacol 65, 1067–1081 (2010). https://doi.org/10.1007/s00280-009-1112-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-009-1112-8

Keywords

Search

Navigation