Skip to main content

Advertisement

SpringerLink
Log in

Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Inhibition of angiogenesis is an important new treatment modality for malignancies, including gliomas. Vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α) have been investigated as potent mediators of tumor angiogenesis. We investigated whether four major chemotherapeutic agents (ACNU, cisplatin, etoposide, and SN38) showed an angiosuppressive effect in vitro.

Method

The effects of ACNU, cisplatin, etoposide, and SN38 for endothelial cells were assessed by cell growth inhibition assay (WST-8 assay) and vessel formation assay (angiogenesis kit). The inhibitory effects of the HIF-1α and VEGF expression of glioma cells after SN38 treatment were assessed by real-time RT-PCR, Western blot, and ELISA.

Results

SN38, but not other chemotherapeutic agents, selectively inhibited endothelial cell proliferation and three-dimensional tube formations at the 0.01 μM. Furthermore, SN38 significantly decreased the HIF-1α and VEGF expression of glioma cells in a dose- and time-dependent manner under normoxic and hypoxic conditions. SN38 has dual angiosuppressive actions, including both the inhibition of endothelial proliferation and tube formation, and the inhibition of the angiogenic cascade in glioma cells.

Conclusion

SN38 is an attractive agent as both a direct and indirect angiogenesis inhibitor and provides the anti-glioma agents with an angiosuppressive function.

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.

Similar content being viewed by others

References

  • Allegrini G, Goulette AF, Darnowski WJ, Calabresi P (2004) Thrombospondin-1 plus irinotecan: a novel antiangiogenenis-chemotherapeutic combination that inhibits the growth of advanced human colon tumor xenografts in mice. Cancer Chemother Pharmacol 3:261–266

    Google Scholar 

  • Arthur TW, Vernon ER, Sage EH, Reed JM (1998) Growth factors reverse the impaired sprouting of microvessels from aged mice. Microvasc Res 55:260–270

    CAS  PubMed  Google Scholar 

  • Ashby LS, Shapiro WR (2001) Intra-arterial cisplatin plus oral etoposide for the treatment of recurrent malignant glioma: a phase II study. J Neurooncol 51:67–86

    CAS  PubMed  Google Scholar 

  • Bacher M, Schrader J, Thompson N, Kuschela K, Gemsa D, Waeber G, Schlegel J (2003) Up-regulation of macrophage migration inhibitory factor gene and protein expression in glial tumor cells during hypoxic and hypoglycemic stress indicates a critical role for angiogenesis in glioblastoma multiforme. Am J Pathol 162:11–17

    CAS  PubMed  Google Scholar 

  • Bisacchi D, Bebelli R, Vanzetto C, Ferrari N, Tosetti F, Albini A (2003) Anti-angiogenesis and angioprevention: mechanisms, problems and perspectives. Cancer Detect Prev 27:229–238

    CAS  PubMed  Google Scholar 

  • Brwoder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886

    CAS  PubMed  Google Scholar 

  • Buckner JC, Reid JM, Wright K, Kaufmann SH, Erlichman C, Ames M, Cha S, O’Fallon JR, Schaaf LJ, Miller LL (2003) Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group. Cancer 97:2352–2358

    CAS  PubMed  Google Scholar 

  • Carmeliet P, Rakesh JK (2000) Angiogenesis in cancer and other diseases. Nature 14:249–257

    Google Scholar 

  • Christopher WP, Peter JR (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684

    Article  CAS  PubMed  Google Scholar 

  • Clements KM, Jones BC, Cumming M, Daoud SS (1999) Antiangiogenic potential of camptothecin and topotecan. Cancer Chemother Pharmacol 44:411–416

    Article  CAS  PubMed  Google Scholar 

  • Folkman J (2003) Angiogenesis and proteins of the hemostatic system. J Thromb Haemost 1:1681–1682

    CAS  PubMed  Google Scholar 

  • Gasparini G (1999) The rationale and future potential of angiogenesis inhibitors in neoplasia. Drugs 58:17–38

    CAS  Google Scholar 

  • Hanahan D, Beregers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105:1045–1047

    CAS  PubMed  Google Scholar 

  • Harris AL (2002) Hypoxia—a key regulatory factor in tumor growth. Nat Rev Cancer 2:38–47

    CAS  PubMed  Google Scholar 

  • Hayot C, Farinelle S, De Decker R, Decaestecker C, Darro F, Kiss R, Van Damme M (2002) In vitro pharmacological characterizations of the anti-angiogenic and anti-tumor cell migration properties mediated by microtubule-affecting drugs, with special emphasis on the organization of the actin cytoskeleton. Int J Oncol 21:417–425

    CAS  PubMed  Google Scholar 

  • Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739

    CAS  PubMed  Google Scholar 

  • Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS (2000) Continuous low-dose therapy with vinblastin and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15-R24

    CAS  PubMed  Google Scholar 

  • Kobayashi M, Kondo M, Mitsui Y (1991) Establishment of human endothelial cell lines in a serum-free culture and its application for expression of transfected prepro endothelin gene. Human Cell 4:296–304

    CAS  PubMed  Google Scholar 

  • Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW (2004) Hypoxia-inducible factor (HIF-1)α: its protein stability and biological functions. Exp Mol Med 36:1–12

    CAS  PubMed  Google Scholar 

  • Man S, Bocci G, Francia G, Green SK, Jothy S, Hanahan D, Bohlen P, Hicklin DJ, Bergers G, Kerbel RS (2002) Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62:2731–2735

    CAS  PubMed  Google Scholar 

  • McCrudden KW, Yokoi A, Thosani A, Soffer SZ, Kim ES, Huang J, Manley C, O’toole K, Yamashiro DJ, Kandel JJ, Middlesworth W (2002) Topotecan is anti-angiogenic in experimental hepatoblastoma. J Pediatr Surg 37:857–861

    PubMed  Google Scholar 

  • Nakashio A, Fujita N, Tsuruo T (2002) Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K-Akt signaling pathway. Int J Cancer 98:36–41

    CAS  PubMed  Google Scholar 

  • O’Leary J, Muggia MF (1998) Camptothecins: a review of development and schedules of administration. Eur J Cancer 34:1500–1508

    PubMed  Google Scholar 

  • O’Leary J, Shapiro RL, Ren CJ, Chuang N, Cohen HW, Potmesil M (1999) Antiangiogenic effects of camptothecin analogues 9-amino-20(S)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model. Clin Cancer Res 5:181–187

    PubMed  Google Scholar 

  • Parker JR, Fryehauf PJ, Mehta R, Filka E, Cloughesy T (2004) A prospective blinded study of the predictive value of an extreme drug resistance assay in patients receiving CPT-11 for recurrent glioma. J Neurooncol 66:365–375

    PubMed  Google Scholar 

  • Parney IF, Chang SM (2003) Current chemotherapy for glioblastoma. Cancer J 9:149–156

    CAS  PubMed  Google Scholar 

  • Petrangolini G, Pratesi G, De Cesare M, Supino R, Pisano C, Marcellini M, Giordano V, Laccabue D, Lanzi C, Zunino F (2003) Antiangiogenic effects of the novel camptothecin ST1481 (Gimatecan) in human tumor xenografts. Mol Cancer Res 1:863–870

    CAS  PubMed  Google Scholar 

  • Pili R, Donehower RC (2003) Is HIF-1α a valid therapeutic target?. J Natl Cancer Inst 95:498–499

    PubMed  Google Scholar 

  • Rapisarda A, Uranchimeg B, Scudiero DA, Selby M, Sausville EA, Shoemaker RH, Melillo G (2002) Identification of small molecule inhibitors of Hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res 62:4316–4324

    CAS  PubMed  Google Scholar 

  • Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Malillo G (2004) Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res 64:1475–1482

    CAS  PubMed  Google Scholar 

  • Reardon DA, Friedman HS, Powell JB Jr, Gilbert M, Yung WK (2003) Irinotecan: promising activity in the treatment of malignant glioma. Oncology (Huntingt) 17:9–14

  • Safran M, Kaelin WG Jr (2003) HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest 111:779–783

    CAS  PubMed  Google Scholar 

  • Schirner M (2000) Antiangiogenic chemotherapeutic agents. Cancer Metastasis Rev 19:67–73

    CAS  PubMed  Google Scholar 

  • Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  CAS  PubMed  Google Scholar 

  • Soffer SZ, Kim E, Moore JT, Huang J, Yokoi A, Manley C, O’Toole K, Middlesworth W, Stolar C, Yamashiro D, Kandel J (2001) Novel use of an established agent: topotecan is anti-angiogenic in experimental Wilms tumor. J Pediatr Surg 36:1781–1784

    CAS  PubMed  Google Scholar 

  • Sun X, Kanwar JR, Leung E, Lehnert K, Wang D, Krissansen GW (2001) Gene transfer of antisense hypoxia inducible factor-1 alpha enhances the therapeutic efficacy of cancer immunotherapy. Gene Ther 8:638–645

    CAS  PubMed  Google Scholar 

  • Takano S, Gately S, Neville ME, Herblin WF, Gross JL, Engelhard H, Perricone M, Eidsvoog K, Brem S (1994) Suramin, an anticancer and angiosuppressive agent, inhibits endothelial cell binding of basic fibroblast growth factor, migration, proliferation, and induction of urokinase-type plasminogen activator. Cancer Res 54:2654–2660

    CAS  PubMed  Google Scholar 

  • Takano S, Yoshii Y, Kondo S, Suzuki H, Maruno T, Shirai S, Nose T (1996) Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56:2185–2190

    CAS  PubMed  Google Scholar 

  • Takano S, Tsuboi K, Matsumura A, Nose T (2003) Anti-vascular endothelial growth factor antibody and nimustine as combined therapy: effects on tumor growth and angiogenesis in human glioblastoma xenografts. Neuro-oncol 5:1–7

    Google Scholar 

  • Tanaka M, Tanaka T, Harata M, Suzuki T, Mitsui Y (1998) Triplet repeat-containing ribosomal protein L14 gene in immortalized human endothelial cell line (t-HUE4). Biochem Biophys Res Commun 243:531–537

    CAS  PubMed  Google Scholar 

  • Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, Katschinski DM, Wenger RH (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22:3213–3220

    CAS  PubMed  Google Scholar 

  • Xiao D, Tan W, Li M, Ding J (2001) Antiangiogenic potential of 10-hydroxycamptothecin. Life Sci 69:1619–1628

    CAS  PubMed  Google Scholar 

  • Yabushita H, Shimizu M, Noguchi M, Kishida T, Narumiya H, Sawaguchi K, Noguchi M (2003) Vascular endothelial growth factor activating matrix metalloproteinase in ascitic fluid during peritoneal dissemination of ovarian cancer. Oncol Rep 10:89–95

    CAS  PubMed  Google Scholar 

  • Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW (2003) YC1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 95:516–525

    CAS  PubMed  Google Scholar 

  • Yoshida J, Kajita Y, Wakabayashi T, Sugita K (1994) Long-term follow-up results of 175 patients with malignant glioma: importance of radical tumor resection and postoperative adjuvant therapy with interferon, ACNU and radiation. Acta Neurochir (Wien) 127:55–59

    Google Scholar 

  • Zagzag D (1995) Angiogenic growth factors in neural embryogenesis and neoplasia. Am J Pathol 146:293–309

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge Dr. Youji Mitsui, (Laboratory of Physiological Chemistry, Tokushima Bunri University), Dr. Hiroshi Kanma (Laboratory of Cellular Pathology, University of Tsukuba), and Dr. Kazumasa Isobe (Laboratory of Clinical Pathology, University of Tsukuba) for useful discussion, and Ms. Makiko Miyakawa and Yoshiko Tsukada for their excellent technical assistance

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan

    Hiroshi Kamiyama, Shingo Takano, Koji Tsuboi & Akira Matsumura

Authors
  1. Hiroshi Kamiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shingo Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koji Tsuboi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akira Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shingo Takano.

Additional information

This study was supported by a Grant-in-Aid for Scientific Research from Japanese Ministry of Education, Science, and Culture and by a grant provided by the Tsukuba Advanced Research Alliance

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kamiyama, H., Takano, S., Tsuboi, K. et al. Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells. J Cancer Res Clin Oncol 131, 205–213 (2005). https://doi.org/10.1007/s00432-004-0642-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-004-0642-z

Keywords

Search

Navigation