Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression

Oncogene volume 21, pages 2805–2814 (2002)Cite this article

Abstract

Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Abedi H, Zachary I . 1997 J. Biol. Chem. 272: 15442–15451

  • Akhter S, Nath SK, Tse CM, Williams J, Zasloff M, Donowitz M . 1999 Am. J. Physiol. 276: C136–C144

  • Alvarez AA, Krigman HR, Whitaker RS, Dodge RK, Rodriguez GC . 1999 Clin. Cancer Res. 5: 587–591

  • Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, Soper JT, Dodge R, Clarke-Pearson D, Marks P, McKenzie S, Yin S, Bast Jr RC . 1990 Cancer Res. 50: 4087–4091

  • Chazin V, Kaleko M, Miller A, Slamon DJ . 1992 Oncogene 7: 1859–1865

  • Chen Q, Williams JI, Anderson M, Kinney WK, Zasloff M . 1999 Clin. Cancer Res. 11: 3768s

  • Disaia PJ, Sinkovics J, Rulege FN, Smith JP . 1972 Am. J. Obstet. Gynecol. 114: 979–989

  • Eckhardt SG . 1999 Hospital Pract. 1: 63–78

  • Ellis RE, Yuan JY, Horvitz HR . 1991 Annu. Rev. Cell. Biol. 7: 663–698

  • Ferrara N, Winer J, Burton T, Rowland A, Siegel M, Phillips HS, Terrell T, Keller GA, Levinson AD . 1993 J. Clin. Invest. 91: 160–170

  • Folkman J . 1971 New Engl. J. Med. 285: 1182–1186

  • Folkman J, Haudenschild C . 1980 Nature 288: 551–556

  • Gimbrone Jr MA, Leapman SB, Cotran RS, Folkman J . 1972 J. Exp. Med. 136: 261–276

  • Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY . 1993 Mol. Biol. Cell 4: 121–133

  • Hellstrom I, Goodman G, Pullman J, Yang Y, Hellstrom KE . 2001 Cancer Res. 61: 2420–2423

  • Juhl H, Downing SG, Wellstein A, Czubayko F . 1997 J. Biol. Chem. 272: 29482–29486

  • Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT . 1989 Science 240: 1309–1312

  • Kolfschoten GM, Pinedo HM, Scheffer PG, Schluper HM, Erkelens CA, Boven E . 2000 Gynecol. Oncol. 76: 362–368

  • Kroll J, Waltenberger J . 1997 J. Biol. Chem. 272: 32521–32527

  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N . 1989 Science 246: 1306–1309

  • Luna LG . 1968 Manual of Histologic Staining: Methods of the Armed Forces Institute of Pathology New York, NY: McGraw-Hill

    Google Scholar 

  • Moore KS, Wehrli S, Roder H, Rogers M, Forrest Jr JN, McCrimmon D, Zasloff M . 1993 Proc. Natl. Acad. Sci. USA 90: 1354–1358

  • Morales DE, McGowan KA, Grant DS, Maheshwari S, Bhartiya D, Cid MC, Kleinman HK, Schnaper HW . 1995 Circulation 91: 755–763

  • Mustonen T, Alitalo K . 1995 J. Cell. Biol. 129: 895–898

  • O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J . 1997 Cell 88: 277–285

  • Ozols RF . 1999 Semin. Oncol. 26: 84–89

  • Paley PJ, Staskus KA, Gebhard K, Mohanraj D, Twiggs LB, Carson LF, Ramakrishnan S . 1997 Cancer 80: 98–106

  • Patnaik A, Rowinsky E, Hammond L, Thurman A, Hidalgo M, Siu L, Moczygemba J, Williams J, Holroyd K, Nelson K, Von Hoff D, Eckhardt S . 1999 Proc. Am. Soc. Clin. Oncol. 622: 1999

  • Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ, Slamon D . 1997 Oncogene 15: 537–547

  • Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS . 1997 Am. J. Pathol. 151: 1523–1530

  • Pietras RJ, Fendly BM, Chazin VR, Pegram MD, Howell SB, Slamon DJ . 1994 Oncogene 9: 1829–1838

  • Pietras RJ, Roberts JA . 1981 J. Biol. Chem. 256: 8536–8544

  • Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R . 2000 Cancer Res. 60: 6039–6044

  • Rousseau S, Houle F, Landry J, Huot J . 1997 Oncogene 15: 2169–2177

  • Schiller JH, Bittner G . 1999 Clin. Cancer Res. 5: 4287–4294

  • Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett S, Bridges A, Przybranowski S, Leopold WR, Saltiel A . 1999 Nature Med. 5: 810–816

  • Sills Jr AK, Williams JI, Tyler BM, Epstein DS, Sipos EP, Davis JD, McLane MP, Pitchford S, Cheshire K, Gannon FH, Kinney WA, Chao TL, Donowitz M, Laterra J, Zasloff M, Brem H . 1998 Cancer Res. 58: 2784–2792

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF . 1989 Science 244: 707–712

  • Soker S, Fidder H, Neufeld G, Klagsbrun M . 1996 J. Biol. Chem. 271: 5761–5767

  • Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M . 1998 Cell 92: 735–745

  • Steller H . 1995 Science 267: 1445–1449

  • Teicher BA, Williams JI, Takeuchi H, Ara G, Herbst RS, Buxton D . 1998 Anticancer Res. 18: 2567–2573

  • Williams JI . 1999 Squalamine-a new angiostatic steroid. In Antiangiogenic Agents Teicher BA (ed.) Totowa, NJ: Humana Press

    Google Scholar 

  • Williams JI, Weitman S, Gonzalez C, Jundt C, Marty J, Stringer S, Hunt J, Holroyd K, McLane M, Zasloff M, von Hoff DD . 2001 Clin. Cancer Res. 7: 724–733

  • Wong Y, Cheung T, Lam S, Lu H, Zhuang Y, Chan M, Chung T . 1995 Gynecol. Obstet. Invest. 40: 209–212

  • Yamamoto S, Konishi I, Mandai M, Kuroda H, Komatsu T, Nanbu K, Sakahara H, Mori T . 1997 Br. J. Cancer 76: 1221–1227

  • Zebrowski BK, Liu W, Ramirez K, Akagi Y, Milles GB, Ellis LM . 1999 Ann. Surg. Oncol. 6: 373–378

Download references

Acknowledgements

We dedicate this article to the memory of Dr James A Roberts (1947–2001), Professor of Gynecologic Oncology at Stanford University, a friend and a leader in ovarian cancer research who provided many helpful discussions. We also thank Dr Kenneth Holroyd, Dr Dennis J Slamon, Dr Mark Pegram and Dr Rebecca Rausch for advice in the execution of this work. This work was supported by grants from the National Institutes of Health (R29CA60835), the United States Department of Defense Ovarian Cancer Research Program (OC990068), and the Stiles Program in Integrative Oncology.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Hematology-Oncology and Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, 90095, California, CA, USA

    Dan Li & Richard J Pietras

  2. Genaera Corporation, Plymouth Meeting, Pennsylvania, 19462, PA, USA

    Jon I Williams

Authors
  1. Dan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jon I Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard J Pietras
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard J Pietras.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, D., Williams, J. & Pietras, R. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. Oncogene 21, 2805–2814 (2002). https://doi.org/10.1038/sj.onc.1205410

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205410

Keywords

This article is cited by

Search

Advanced search

Quick links