Skip to main content

Advertisement

SpringerLink
Log in

The phosphodiesterase 3 inhibitor cilostazol does not stimulate growth of colorectal liver metastases after major hepatectomy

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Liver failure after extended hepatectomy represents a major challenge in the surgery of hepatic colorectal metastasis. A previous study has indicated that inhibition of phosphodiesterase type 3 (PDE 3) stimulates liver regeneration. However, little is known whether PDE 3 inhibitors, such as cilostazol, also stimulate the growth of remnant metastases. Therefore, we herein studied the effect of cilostazol on engraftment, vascularization and growth of colorectal liver metastasis after major hepatectomy. WAG-rats underwent either major hepatectomy or sham operation. Metastases were induced by subcapsular implantation of 5 × 105 CC531-colorectal cancer cells. Animals were daily treated with cilostazol (5 mg/kg body weight) or glucose solution. Tumor growth was measured by high-resolution ultrasound at days 7 and 14. Tumor vascularization and tumor cell proliferation were determined by immunohistochemistry and western blotting. High-resolution ultrasound analysis in hepatectomized and non-hepatectomized animals showed that cilostazol does not stimulate tumor growth. Accordingly, the number of PCNA-positive tumor cells did not differ between cilostazol-treated animals and sham-treated controls. Interestingly, cilostazol reduced tumor vascularization in both hepatectomized and non-hepatectomized animals. This was indicated by a significantly lower number of platelet-endothelial cell adhesion molecule (PECAM-1)-positive cells in tumors of cilostazol-treated animals compared to sham-treated controls. The PDE 3 inhibitor cilostazol does not stimulate the growth of colorectal metastases during liver regeneration after major hepatectomy.

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

References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29

    Article  PubMed  Google Scholar 

  2. Taylor I (1996) Liver metastases from colorectal cancer: lessons from past and present clinical studies. Br J Surg 83:456–460

    Article  PubMed  CAS  Google Scholar 

  3. Morris EJA, Forman D, Thomas JD et al (2010) Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 97:1110–1118

    Article  PubMed  CAS  Google Scholar 

  4. Rees M, Tekkis PP, Welsh FKS, O’Rourke T, John TG (2008) Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 247:125–135

    Article  PubMed  Google Scholar 

  5. Nordlinger B, Sorbye H, Glimelius B et al (2008) Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 371:1007–1016

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Vauthey JN, Pawlik TM, Ribero D et al (2006) Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 24:2065–2072

    Article  PubMed  CAS  Google Scholar 

  7. Gomez D, Malik HZ, Bonney GK, Wong V, Toogood GJ, Lodge JPA, Prasad KR (2007) Steatosis predicts postoperative morbidity following hepatic resection for colorectal metastasis. Br J Surg 94:1395–1402

    Article  PubMed  CAS  Google Scholar 

  8. Hemming AW, Reed AI, Howard RJ et al (2003) Preoperative portal vein embolization for extended hepatectomy. Ann Surg 237:686–693

    PubMed  PubMed Central  Google Scholar 

  9. Wicherts DA, Miller R, de Haas RJ et al (2008) Long-term results of two-stage hepatectomy for irresectable colorectal cancer liver metastases. Ann Surg 248:994–1005

    Article  PubMed  Google Scholar 

  10. Primrose JN (2010) Surgery for colorectal liver metastases. Br J Cancer 102:1313–1318

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Nishino M, Iimuro Y, Ueki T, Hirano T, Fujimoto J (2008) Hepatocyte growth factor improves survival after partial hepatectomy in cirrhotic rats suppressing apoptosis of hepatocytes. Surgery 144:374–384

    Article  PubMed  Google Scholar 

  12. Schmeding M, Boas-Knoop S, Lippert S et al (2008) Erythropoietin promotes hepatic regeneration after extended liver resection in rats. J Gastroenterol Hepatol 23:1125–1131

    Article  PubMed  CAS  Google Scholar 

  13. Akcan A, Kucuk C, Ok E, Canoz O, Muhtaroglu S, Yilmaz N, Yilmaz Z (2006) The effect of amrinone on liver regeneration in experimental hepatic resection model. J Surg Res 130:66–72

    Article  PubMed  CAS  Google Scholar 

  14. Sunagawa M, Shimada S, Hanashiro K, Nakamura M, Kosugi T (2006) Elevation of intracellular cAMP up-regulated thrombomodulin mRNA in cultured vascular endothelial cells derived from spontaneous type-II diabetes mellitus model rat. Endothelium 13:325–333

    Article  PubMed  CAS  Google Scholar 

  15. Ikegami T, Nishizaki T, Hiroshige S, Ohta R, Yanaga K, Sugimachi K (2001) Experimental study of a type 3 phosphodiesterase inhibitor on liver graft function. Br J Surg 88:59–64

    Article  PubMed  CAS  Google Scholar 

  16. Saito S, Hata K, Iwaisako K, Yanagida A, Takeiri M, Tanaka H, Kageyama S, Hirao H, Ikeda K, Asagiri M, Uemoto S (2014) Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis. Hepatol Res 44:460–473

    Article  CAS  Google Scholar 

  17. Sill JC, Bertha B, Berger I, Uhl C, Nugent M, Folts J (1997) Human platelet Ca2+ mobilization, glycoprotein IIb/IIIa activation, and experimental coronary thrombosis in vivo in dogs are all inhibited by the inotropic agent amrinone. Circulation 96:1647–1653

    Article  PubMed  CAS  Google Scholar 

  18. Ogawa S, Koga S, Kuwabara K, Brett J, Morrow B, Morris SA, Bilezikian JP, Silverstein SC, Stern D (1992) Hypoxia-induced increased permeability of endothelial monolayers occurs through lowering of cellular cAMP levels. Am J Physiol 262:546–554

    Google Scholar 

  19. Dold S, von Heesen M, Müller S, Kollmar O, Schilling MK, Menger MD, Moussavian MR (2011) Effect of Cilostazol® on hepatic microcirculation and liver regeneration after partial hepatectomy in a rat model. Langenbecks Arch Surg 396:581 (abstract)

  20. Mizutani J, Hiraoka T, Yamashita R, Miyauchi Y (1992) Promotion of hepatic metastases by liver resection in the rat. Br J Cancer 65:794–797

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Slooter GD, Marquet RL, Jeekel J, Ijzermans JN (1995) Tumour growth stimulation after partial hepatectomy can be reduced by treatment with tumour necrosis factor alpha. Br J Surg 82:129–132

    Article  PubMed  CAS  Google Scholar 

  22. Drixler TA, Borel Rinkes IH, Ritchie ED, van Vroonhoven TJ, Gebbink MF, Voest EE (2000) Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy. Cancer Res 60:1761–1765

    PubMed  CAS  Google Scholar 

  23. Picardo A, Karpoff HM, Ng B, Lee J, Brennan MF, Fong Y (1998) Partial hepatectomy accelerates local tumor growth: potential roles of local cytokine activation. Surgery 124:57–64

    Article  PubMed  CAS  Google Scholar 

  24. Harun N, Nikfarjam M, Muralidharan V, Christophie C (2007) Liver regeneration stimulates tumor metastases. J Surg Res 138:284–290

    Article  PubMed  Google Scholar 

  25. Martins PNA, Theruvath TP, Neuhaus P (2008) Rodent models of partial hepatectomies. Liver Int 28:3–11

    Article  PubMed  Google Scholar 

  26. Kollmar O, Schilling MK, Menger MD (2004) Experimental liver metastasis: standards for local cell implantation to study isolated tumor growth in mice. Clin Exp Metastasis 21:453–460

    Article  PubMed  Google Scholar 

  27. Laschke MW, Körbel C, Rudzitis-Auth J et al (2010) High-resolution ultrasound imaging. Am J Pathol 176:585–593

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nguyen L, Fifis T, Malcontenti-Wilson C, Chan LS, Costa PN, Nikfarjam M, Muralidharan V, Christophi C (2012) Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments. BMC Cancer 12:522

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Sperling J, Brandhorst D, Schäfer T et al (2013) Liver-directed chemotherapy of cetuximab and bevacizumab in combination with oxaliplatin is more effective to inhibit tumor growth of CC531 colorectal rat liver metastases than systemic chemotherapy. Clin Exp Metastasis 30:447–455

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Nakamura T, Houchi H, Minami A et al (2001) Endothelium-dependent relaxation by cilostazol, a phosphodiesteras III inhibitor, on rat thoracic aorta. Life Sci 69:1709–1715

    Article  PubMed  CAS  Google Scholar 

  31. Weintraub WS (2006) The vascular effects of cilostazol. Can J Cardiol 22:56–60

    Article  Google Scholar 

  32. Lee TM, Su SF, Tsai CH, Lee YT, Wang SS (2001) Differential effects of cilostazol and pentoxifylline on vascular endothelial growth factor in patients with intermittent claudication. Clin Sci 101:305–311

    Article  PubMed  CAS  Google Scholar 

  33. Geng D, Deng J, Jin D, Wu W, Wang J (2012) Effect of cilostazol on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis 220:177–183

    Article  PubMed  CAS  Google Scholar 

  34. Friedland SN, Eisenberg MJ, Shimony A (2012) Meta-analysis of randomized controlled trials on effect of cilostazol on restenosis rates and outcomes after percutaneous coronary intervention. Am J Cardiol 109:1397–1404

    Article  PubMed  CAS  Google Scholar 

  35. Kim JE, Sung JY, Woo CH et al (2011) Cilostazol inhibits vascular smooth muscle cell proliferation and reactive oxygen species production through activation of AMP-activated protein kinase induced by heme oxygenase-1. Korean J Physiol Pharmacol 15:203–210

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Muñoz B, Huerta M, López-Bayghen E (2009) Cilostazol reduces proliferation through c-Myc down-regulation in MDCK cells. Eur J Pharmacol 616:22–30

    Article  PubMed  Google Scholar 

  37. Murata K, Kameyama M, Fukui F et al (1999) Phosphodiesterase type III inhibitor, cilostazol, inhibits colon cancer cell motility. Clin Exp Metastasis 17:525–530

    Article  PubMed  CAS  Google Scholar 

  38. Ikeda Y, Matsumata T, Takenaka K, Yamagata M, Sugimachi K (1998) Effects of doxorubicin and/or cilostazol on cancer cells during liver regeneration after two-thirds hepatectomy in rats. Oncology 55:354–356

    Article  PubMed  CAS  Google Scholar 

  39. Mendes JB, Campos PP, Rocha MA, Andrade SP (2009) Cilostazol and pentoxifylline decrease angiogenesis, inflammation, and fibrosis in sponge-induced intraperitoneal adhesion in mice. Life Sci 84:537–543

    Article  PubMed  CAS  Google Scholar 

  40. Wang F, Li M, Cheng L et al (2008) Intervention with cilostazol attenuates renal inflammation in streptozotocin-induced diabetic rats. Life Sci 83:828–835

    Article  PubMed  CAS  Google Scholar 

  41. Biscetti F, Pecorini G, Straface G et al (2013) Cilostazol promotes angiogenesis after peripheral ischemia through a VEGF-dependent mechanism. Int J Cardiol 167:910–916

    Article  PubMed  Google Scholar 

  42. Chao TH, Tseng SY, Li YH et al (2012) A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade. Clin Sci 123:147–159

    Article  PubMed  CAS  Google Scholar 

  43. Shin HK, Lee HR, Lee DH et al (2010) Cilostazol enhances neovascularization in the mouse hippocampus after transient forebrain ischemia. J Neurosci Res 88:2228–2238

    Article  PubMed  CAS  Google Scholar 

  44. Rajesh L, Joshi K, Bhalla V, Dey P, Radotra BD, Nijhawan R (2004) Correlation between VEGF expression and angiogenesis in breast carcinoma. Anal Quant Cytol Histol 26:105–108

    PubMed  Google Scholar 

  45. Wechsel HW, Feil G, Bichler KH, Beiter T, Gleichmann R (2000) Serologic angiogenesis factors and microvascular density in renal cell carcinoma: two independent parameters. Anticancer Res 20:5117–5120

    PubMed  CAS  Google Scholar 

  46. Amirkhosravi A, Meyer T, Warnes G et al (1998) Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor. Thromb Haemost 80:598–602

    PubMed  CAS  Google Scholar 

  47. Netherton SJ, Maurice DH (2005) Vascular endothelial cell cyclic nucleotide phosphodiesterases and regulated cell migration: implications in angiogenesis. Mol Pharmacol 67:263–272

    Article  PubMed  CAS  Google Scholar 

  48. Hayashi H, Sudo T (2009) Effects of the cAMP-elevating agents cilostamide, cilostazol and forskolin on the phosphorylation of Akt and GSK-3beta in platelets. Thromb Haemost 102:327–335

    PubMed  CAS  Google Scholar 

  49. D’Angelo G, Lee H, Weiner RI (1997) cAMP-dependent protein kinase inhibits the mitogenic action of vascular endothelial growth factor and fibroblast growth factor in capillary endothelial cells by blocking Raf activation. J Cell Biochem 67:353–366

    Article  PubMed  Google Scholar 

  50. Lee JH, Kim KY, Lee Y-K et al (2003) Cilostazol prevents focal cerebral ischemic injury by enhancing casein kinase 2 phosphorylation and suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation in rats. J Pharmacol Exp Ther 308:896–903

    Article  PubMed  Google Scholar 

  51. Santos M, Celotto AC, Capellini VK et al (2012) The protective effect of cilostazol on isolated rabbit femoral arteries under conditions of ischemia and reperfusion: the role of the nitric oxide pathway. Clinics 67:171–178

    Article  PubMed  PubMed Central  Google Scholar 

  52. Sprague RS, Bowles EA, Achilleus D, Stephenson AH, Ellis CG, Ellsworth ML (2011) A selective phosphodiesterase 3 inhibitor rescues low PO2-induced ATP release from erythrocytes of humans with type 2 diabetes: implication for vascular control. Am J Physiol Heart Circ Physiol 301:2466–2472

    Article  Google Scholar 

Download references

Acknowledgments

This study was supported by a HOMFOR 2010 grant (T201000614) of the Medical Faculty of the Saarland University. We appreciate the excellent technical assistance of Janine Becker and Christina Marx.

Conflict of interest

There is no conflict of interest of any of the authors.

Author information

Author notes

  1. Moritz J. Strowitzki

    Present address: Department of General, Visceral and Transplant Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

  2. Otto Kollmar

    Present address: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany

Authors and Affiliations

  1. Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany

    Moritz J. Strowitzki, Christina Körbel, Claudia Scheuer & Michael D. Menger

  2. Department of General, Vascular and Pediatric Surgery, Saarland University Hospital, Homburg/Saar, Germany

    Stefan Dold, Maximilian von Heesen, Mohammed R. Moussavian, Martin K. Schilling & Otto Kollmar

Authors
  1. Moritz J. Strowitzki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefan Dold
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maximilian von Heesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christina Körbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudia Scheuer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammed R. Moussavian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin K. Schilling
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Otto Kollmar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael D. Menger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Moritz J. Strowitzki.

Additional information

Moritz J. Strowitzki and Stefan Dold have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Strowitzki, M.J., Dold, S., von Heesen, M. et al. The phosphodiesterase 3 inhibitor cilostazol does not stimulate growth of colorectal liver metastases after major hepatectomy. Clin Exp Metastasis 31, 795–803 (2014). https://doi.org/10.1007/s10585-014-9669-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-014-9669-y

Keywords

Search

Navigation