Skip to main content

Advertisement

SpringerLink
Log in

Unravelling the antimetastatic potential of pentoxifylline, a methylxanthine derivative in human MDA-MB-231 breast cancer cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Pentoxifylline (PTX), a methylxanthine derivative is a non-steroidal immunomodulating agent with unique hemorheologic properties. It is used in the treatment of intermittent claudication as it increases the amount of oxygen reaching tissues by increasing the flexibility of red blood cells. Recently, it has also shown to exhibit anti-metastatic and anti-angiogenic activities in B16F10 melanoma cells both in vitro as well as in vivo. As per the reports, the choice of drug in the treatment of breast cancer is paclitaxel, but the major limitation is its toxicity. However, the effects of PTX on metastatic processes in breast cancer are not currently known. Therefore, in this study, we have examined the effect of PTX in MDA-MB-231 human breast cancer cells. The MTT assay showed dose- and time-dependent decreases in cellular proliferation. The non-toxic concentration of PTX selected were 1, 2.5 and 5 mM for 24 h. PTX induced a G0-G1 cell-cycle arrest leading to apoptosis. Further, it affected adhesion to both the matrigel and collagen type-IV in a time- and dose-dependent manner. The PTX impeded the migration of MDA-MB-231 cells and also decreased the activities of both MMP-2 and MMP-9. Thus, PTX at non-toxic doses affected cellular proliferation, adhesion, migration and invasion. These results demonstrate its anti-metastatic effect on MDA-MB-231 cells, and further studies need to be carried out to understand the mechanism of action.

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917

    Article  PubMed  CAS  Google Scholar 

  2. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  PubMed  Google Scholar 

  3. Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284

    Article  PubMed  CAS  Google Scholar 

  4. Guarneri V, Conte P (2009) Metastatic breast cancer: therapeutic options according to molecular subtypes and prior adjuvant therapy. Oncologist 14:645–656

    Article  PubMed  CAS  Google Scholar 

  5. Dettelbach HR, Aviado DM (1985) Clinical pharmacology of pentoxifylline with special reference to its hemorrheologic effect for the treatment of intermittent claudication. J Clin Pharmacol 25:8–26

    PubMed  CAS  Google Scholar 

  6. Jacoby D, Mohler ER 3rd (2004) Drug treatment of intermittent claudication. Drugs 64:1657–1670

    Article  PubMed  CAS  Google Scholar 

  7. Gastpar H (1974) The inhibition of cancer cell stickness by the methylxanthine derivative pentoxifylline (BL 191). Thromb Res 5:277–289

    Article  PubMed  CAS  Google Scholar 

  8. Zhang M, Xu YJ, Mengi SA, Arneja AS, Dhalla NS (2004) Therapeutic potentials of pentoxifylline for treatment of cardiovascular diseases. Exp Clin Cardiol 9:103–111

    PubMed  CAS  Google Scholar 

  9. D’Hellencourt CL, Diaw L, Cornillet P, Guenounou M (1996) Differential regulation of TNF alpha, IL-1 beta, IL-6, IL-8, TNF beta, and IL-10 by pentoxifylline. Int J Immunopharmacol 18:739–748

    Article  PubMed  Google Scholar 

  10. Zhang M, Xu YJ, Saini HK, Turan B, Liu PP, Dhalla NS (2005) Pentoxifylline attenuates cardiac dysfunction and reduces TNF-alpha level in ischemic-reperfused heart. Am J Physiol Heart Circ Physiol 289:H832–H839

    Article  PubMed  CAS  Google Scholar 

  11. Collingridge DR, Rockwell S (2000) Pentoxifylline improves the oxygenation and radiation response of BA1112 rat rhabdomyosarcomas and EMT6 mouse mammary carcinomas. Int J Cancer 90:256–264

    Article  PubMed  CAS  Google Scholar 

  12. Bohm L, Roos WP, Serafin AM (2003) Inhibition of DNA repair by pentoxifylline and related methylxanthine derivatives. Toxicology 193:153–160

    Article  PubMed  CAS  Google Scholar 

  13. Stork PJ, Schmitt JM (2002) Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 12:258–266

    Article  PubMed  CAS  Google Scholar 

  14. Shmueli A, Oren M (2004) Regulation of p53 by Mdm2: fate is in the numbers. Mol Cell 13:4–5

    Article  PubMed  CAS  Google Scholar 

  15. Glenn HL, Jacobson BS (2003) Cyclooxygenase and cAMP-dependent protein kinase reorganize the actin cytoskeleton for motility in HeLa cells. Cell Motil Cytoskeleton 55:265–277

    Article  PubMed  CAS  Google Scholar 

  16. Dua P, Gude RP (2008) Pentoxifylline impedes migration in B16F10 melanoma by modulating Rho GTPase activity and actin organisation. Eur J Cancer 44:1587–1595

    Article  PubMed  CAS  Google Scholar 

  17. Ratheesh A, Ingle A, Gude RP (2007) Pentoxifylline modulates cell surface integrin expression and integrin mediated adhesion of B16F10 cells to extracellular matrix components. Cancer Biol Ther 6:1743–1752

    Article  PubMed  CAS  Google Scholar 

  18. Dua P, Gude RP (2006) Antiproliferative and antiproteolytic activity of pentoxifylline in cultures of B16F10 melanoma cells. Cancer Chemother Pharmacol 58:195–202

    Article  PubMed  CAS  Google Scholar 

  19. Di Lullo GA, Sweeney SM, Korkko J, Ala-Kokko L, San Antonio JD (2002) Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen. J Biol Chem 277:4223–4231

    Article  PubMed  CAS  Google Scholar 

  20. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C (2006) Clonogenic assay of cells in vitro. Nat Protoc 1:2315–2319

    Article  PubMed  CAS  Google Scholar 

  21. Ribble D, Goldstein NB, Norris DA, Shellman YG (2005) A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnol 5:12

    Article  PubMed  Google Scholar 

  22. Pichot CS, Hartig SM, Xia L, Arvanitis C, Monisvais D, Lee FY, Frost JA, Corey SJ (2009) Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer 101:38–47

    Article  PubMed  CAS  Google Scholar 

  23. Lee HS, Seo EY, Kang NE, Kim WK (2008) [6]-Gingerol inhibits metastasis of MDA-MB-231 human breast cancer cells. J Nutr Biochem 19:313–319

    Article  PubMed  CAS  Google Scholar 

  24. Wang S, Liu Q, Zhang Y, Liu K, Yu P, Liu K, Luan J, Duan H, Lu Z, Wang F, Wu E, Yagasaki K, Zhang G (2009) Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action. Mol Cancer 8:81

    Article  PubMed  Google Scholar 

  25. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  26. Hirsh L, Dantes A, Suh BS, Yoshida Y, Hosokawa K, Tajima K, Kotsuji F, Merimsky O, Amsterdam A (2004) Phosphodiesterase inhibitors as anti-cancer drugs. Biochem Pharmacol 68:981–988

    Article  PubMed  CAS  Google Scholar 

  27. Weigelt B, Peterse JL, van‘t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602

    Article  PubMed  CAS  Google Scholar 

  28. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695

    Article  PubMed  CAS  Google Scholar 

  29. DiMasi JA, Hansen RW, Grabowski HG (2003) The price of innovation: new estimates of drug development costs. J Health Econ 22:151–185

    Article  PubMed  Google Scholar 

  30. Chen TC, Wadsten P, Su S, Rawlinson N, Hofman FM, Hill CK, Schonthal AH (2002) The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. Cancer Biol Ther 1:268–276

    PubMed  CAS  Google Scholar 

  31. Gallagher HC, Bacon CL, Odumeru OA, Gallagher KF, Fitzpatrick T, Regan CM (2004) Valproate activates phosphodiesterase-mediated cAMP degradation: relevance to C6 glioma G1 phase progression. Neurotoxicol Teratol 26:73–81

    Article  PubMed  CAS  Google Scholar 

  32. Lin SL, Chen RH, Chen YM, Chiang WC, Tsai TJ, Hsieh BS (2003) Pentoxifylline inhibits platelet-derived growth factor-stimulated cyclin D1 expression in mesangial cells by blocking Akt membrane translocation. Mol Pharmacol 64:811–822

    Article  PubMed  CAS  Google Scholar 

  33. Polo ML, Arnoni MV, Riggio M, Wargon V, Lanari C, Novaro V (2010) Responsiveness to PI3K and MEK inhibitors in breast cancer. Use of a 3D culture system to study pathways related to hormone independence in mice. PLoS One 5:e10786

    Article  PubMed  Google Scholar 

  34. Renvoize C, Biola A, Pallardy M, Breard J (1998) Apoptosis: identification of dying cells. Cell Biol Toxicol 14:111–120

    Article  PubMed  CAS  Google Scholar 

  35. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174

    Article  PubMed  CAS  Google Scholar 

  36. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67

    Article  PubMed  CAS  Google Scholar 

  37. Farina HG, Pomies M, Alonso DF, Gomez DE (2006) Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer. Oncol Rep 16:885–891

    PubMed  CAS  Google Scholar 

  38. Scorilas A, Karameris A, Arnogiannaki N, Ardavanis A, Bassilopoulos P, Trangas T, Talieri M (2001) Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br J Cancer 84:1488–1496

    Article  PubMed  CAS  Google Scholar 

  39. Shellman YG, Makela M, Norris DA (2006) Induction of secreted matrix metalloproteinase-9 activity in human melanoma cells by extracellular matrix proteins and cytokines. Melanoma Res 16:207–211

    Article  PubMed  CAS  Google Scholar 

  40. Okada Y, Tsuchiya H, Shimizu H, Tomita K, Nakanishi I, Sato H, Seiki M, Yamashita K, Hayakawa T (1990) Induction and stimulation of 92-kDa gelatinase/type IV collagenase production in osteosarcoma and fibrosarcoma cell lines by tumor necrosis factor alpha. Biochem Biophys Res Commun 171:610–617

    Article  PubMed  CAS  Google Scholar 

  41. Ries C, Kolb H, Petrides PE (1994) Regulation of 92 kD gelatinase release in HL-60 leukemia cells: tumor necrosis factor-alpha as an autocrine stimulus for basal- and phorbol ester-induced secretion. Blood 83:3638–3646

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors acknowledge the support of grant from the ACTREC, Tata Memorial Centre. Mr. Peeyush N. Goel is supported by CSIR-Junior Research Fellowship. The authors would also like to thank Shimul Salot for providing technical assistance.

Conflict of Interest

None.

Author information

Authors and Affiliations

  1. Gude Lab, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, India

    Peeyush N. Goel & R. P. Gude

Authors
  1. Peeyush N. Goel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. P. Gude
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. P. Gude.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goel, P.N., Gude, R.P. Unravelling the antimetastatic potential of pentoxifylline, a methylxanthine derivative in human MDA-MB-231 breast cancer cells. Mol Cell Biochem 358, 141–151 (2011). https://doi.org/10.1007/s11010-011-0929-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0929-8

Keywords

Search

Navigation