JBIC Journal of Biological Inorganic Chemistry

, Volume 17, Issue 1, pp 123–132 | Cite as

Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells

  • Peyman Kabolizadeh
  • Brigitte J. Engelmann
  • Nicholas Pullen
  • Jennifer K. Stewart
  • John J. Ryan
  • Nicholas P. Farrell
Original Paper

Abstract

A unique synergistic effect on platinum drug cytotoxicity is noted in the presence of the tricyclic antidepressant desipramine. Desipramine is used for treating neuropathic pain, particularly in prostate cancer patients. The clinically used drugs cisplatin (cis-[PtCl2(NH3)2]), oxaliplatin [1,2-diaminocyclohexaneoxalatoplatinum(II)], and the cationic trinuclear agent BBR3464 [{trans-PtCl(NH3)2}2-μ-(trans-Pt(NH3)2(H2N(CH2)6NH2)2)]4+, which has undergone evaluation in phase II clinical trials for activity in lung and ovarian cancers, were evaluated. Surprisingly, desipramine greatly augments the cytotoxicity of all the platinum-based chemotherapeutics in HCT116 colorectal carcinoma cell lines. Desipramine enhanced cellular accumulation of cisplatin, but had no effect on the accumulation of oxaliplatin or BBR3464, suggesting that enhanced accumulation could not be a consistent means by which desipramine altered the platinum-drug-mediated cytotoxicity. The desipramine/cisplatin combination resulted in increased levels of p53 as well as mitochondrial damage, caspase activation, and poly(ADP ribose) polymerase cleavage, suggesting that desipramine may synergize with cisplatin more than with other platinum chemotherapeutics partly by activating distinct apoptotic pathways. The study argues that desipramine may be a means of enhancing chemoresponsiveness of platinum drugs and the results warrant further investigation. The results emphasize the importance of understanding the differential pharmacological action of adjuvants employed in combinations with cancer chemotherapeutics.

Keywords

Anticancer drug Albumin DNA damage Toxicity 

Abbreviations

c-DDP

Cisplatin

CI

Combination index

HSA

Human serum albumin

PARP

Poly(ADP ribose) polymerase

PBS

Phosphate-buffered saline

PI

Propidium iodide

Notes

Acknowledgments

We thank Fréderic Frezard and Paul Dent for helpful discussions. This work was supported by grants from the National Institutes of Health, R01-CA78754 (N.P.F.) and R01-AI59638 (J.R.).

Supplementary material

775_2011_836_MOESM1_ESM.pdf (208 kb)
Fig. 1S (PDF 208 kb)

References

  1. 1.
    Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM (2008) Annu Rev Pharmacol Toxicol 48:495–535PubMedCrossRefGoogle Scholar
  2. 2.
    Howell SB, Safaei R, Larson CA, Sailor MJ (2010) Mol Pharmacol 77:887–894PubMedCrossRefGoogle Scholar
  3. 3.
    Heim M, Scharifi M, Zisowsky J, Jaehde U, Voliotis D, Seeber S, Strumberg D (2005) Anticancer Drugs 16:129–136PubMedCrossRefGoogle Scholar
  4. 4.
    Jandial DD, Farshchi-Heydari S, Larson CA, Elliott GI, Wrasidlo WJ, Howell SB (2009) Clin Cancer Res 15:553–560PubMedCrossRefGoogle Scholar
  5. 5.
    Tanihara Y, Masuda S, Katsura T, Inui K (2009) Biochem Pharmacol 78:1263–1271PubMedCrossRefGoogle Scholar
  6. 6.
    Pirl WF, Roth AJ (1999) Oncology (Williston Park) 13:1293–1301 (discussion 1301-1292, 1305-1296)Google Scholar
  7. 7.
    Massie MJ (2004) J Natl Cancer Inst Monogr 57–71Google Scholar
  8. 8.
    Desmarais JE, Looper KJ (2009) J Clin Psychiatry 70:1688–1697PubMedCrossRefGoogle Scholar
  9. 9.
    Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF (2010) BMJ 340:c693PubMedCrossRefGoogle Scholar
  10. 10.
    Kishore-Kumar R, Max MB, Schafer SC, Gaughan AM, Smoller B, Gracely RH, Dubner R (1990) Clin Pharmacol Ther 47:305–312PubMedCrossRefGoogle Scholar
  11. 11.
    Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R (1992) N Engl J Med 326:1250–1256PubMedCrossRefGoogle Scholar
  12. 12.
    Koepsell H, Lips K, Volk C (2007) Pharm Res 24:1227–1251PubMedCrossRefGoogle Scholar
  13. 13.
    O’Dwyer PJ, Stevenson JP, Johnson SW (1999) Clinical status of cisplatin, carboplatin, and other platinum-based antitumor drugs. In: Lippert B (ed) Cisplatin: chemistry and biochemistry of a leading anticancer drug. Helvetica Chimica Acta, Zurich, pp 26–69. doi: 10.1002/9783906390420.ch2
  14. 14.
    Manzotti C, Pratesi G, Menta E, Di Domenico R, Cavalletti E, Fiebig HH, Kelland LR, Farrell N, Polizzi D, Supino R, Pezzoni G, Zunino F (2000) Clin Cancer Res 6:2626–2634PubMedGoogle Scholar
  15. 15.
    Harris AL, Ryan JJ, Farrell N (2006) Mol Pharmacol 69:666–672PubMedCrossRefGoogle Scholar
  16. 16.
    Chou T, Talalay P (1983) Trends Pharmacol Sci 4:450–454CrossRefGoogle Scholar
  17. 17.
    Hiemke C, Hartter S (2000) Pharmacol Ther 85:11–28PubMedCrossRefGoogle Scholar
  18. 18.
    Colmenarejo G, Alvarez-Pedraglio A, Lavandera JL (2001) J Med Chem 44:4370–4378PubMedCrossRefGoogle Scholar
  19. 19.
    Moller C, Tastesen HS, Gammelgaard B, Lambert IH, Sturup S (2010) Metallomics 2:811–818PubMedCrossRefGoogle Scholar
  20. 20.
    Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK (2006) Chem Rev 106:2224–2248PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A, Chen Y, Komori T, Gray JW, Chen X, Lippard SJ, Giacomini KM (2006) Cancer Res 66:8847–8857PubMedCrossRefGoogle Scholar
  22. 22.
    Kabolizadeh P, Ryan J, Farrell N (2007) Biochem Pharmacol 73:1270–1279PubMedCrossRefGoogle Scholar
  23. 23.
    Haupt S, Berger M, Goldberg Z, Haupt Y (2003) J Cell Sci 116:4077–4085PubMedCrossRefGoogle Scholar
  24. 24.
    Siddik ZH (2003) Oncogene 22:7265–7279PubMedCrossRefGoogle Scholar
  25. 25.
    O’Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace AJ Jr, Kohn KW (1997) Cancer Res 57:4285–4300PubMedGoogle Scholar
  26. 26.
    Arimochi H, Morita K (2008) Pharmacology 81:164–172PubMedCrossRefGoogle Scholar
  27. 27.
    No authors (2010) Harv Ment Health Lett 26:6–7Google Scholar
  28. 28.
    Burgi S, Baltensperger K, Honegger UE (2003) J Biol Chem 278:1044–1052PubMedCrossRefGoogle Scholar
  29. 29.
    Deupree JD, Reed AL, Bylund DB (2007) J Pharmacol Exp Ther 321:770–776PubMedCrossRefGoogle Scholar
  30. 30.
    Yau JL, Noble J, Thomas S, Kerwin R, Morgan PE, Lightman S, Seckl JR, Pariante CM (2007) Neuropsychopharmacology 32:2520–2529PubMedCrossRefGoogle Scholar
  31. 31.
    Mangrum JB, Farrell NP (2010) Chem Commun 46:6640–6650CrossRefGoogle Scholar
  32. 32.
    Farrell N (2004) Met Ions Biol Syst 42:251–296PubMedGoogle Scholar
  33. 33.
    Arimochi H, Morita K (2006) Eur J Pharmacol 541:17–23PubMedCrossRefGoogle Scholar
  34. 34.
    Hursting MJ, Clark GD, Raisys VA, Miller SJ, Opheim KE (1992) Clin Chem 38:2468–2471PubMedGoogle Scholar
  35. 35.
    Gillman PK (2007) Br J Pharmacol 151:737–748PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2011

Authors and Affiliations

  • Peyman Kabolizadeh
    • 1
  • Brigitte J. Engelmann
    • 1
  • Nicholas Pullen
    • 2
  • Jennifer K. Stewart
    • 2
  • John J. Ryan
    • 2
  • Nicholas P. Farrell
    • 1
  1. 1.Department of ChemistryVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of BiologyVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations