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 Manuscript
  • Published:

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4

Leukemia volume 17, pages 52–59 (2003)Cite this article

Abstract

The mechanism by which aplidine, a marine natural product in early clinical development as an anticancer agent, induces cell growth inhibition and apoptosis has been investigated in the human leukemia cell line MOLT-4. This cell line is characterized not only by the ability to secrete VEGF, but also for the presence on its surface of the VEGF receptor-1 (VEGFR-1). Previous studies from our laboratory concerned with evaluating early changes in gene expression induced by aplidine in MOLT-4 cells have shown that the drug decreases the expression of VEGFR-1 (Marchini et al. Proc Am Assoc Cancer Res 2000; 41: 833). Here, we report the ability of aplidine to block the VEGF/VEGFR-1 loop. We found that aplidine blocked VEGF secretion that was temporally followed by a decrease in both VEGF and VEGFR-1 production. Aplidine did not directly affect either VEGF transcription or stabilization of its mRNA. Transfection of MOLT-4 cells with an antisense VEGF cDNA construct, resulted in inhibition of colony formations. One clone, transfected with sense VEGF cDNA, secreting 8–10 times more VEGF than parental cells, was less sensitive to aplidine-induced cytotoxicity and apoptosis than control cells. Moreover, addition of VEGF in the medium decreased the activity of aplidine in MOLT-4 cells. These data demonstrate that aplidine inhibits the growth and induces apoptosis in MOLT-4 cells through the inhibition of VEGF secretion which blocks the VEGF/VEGFR-1 autocrine loop necessary for the growth of these cells.

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
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  1. Faircloth, JG, Rinehart, K, Nunez de Castro, I & Jimeno, J. Dehydrodidemnin B a new marine derived antitumour agent with activity against experimental tumour models. Ann Oncol, (1996). 7, 34

    Google Scholar 

  2. Depenbrock, H, Peter, R, Faircloth, GT, Manzanares, I, Jimeno, J & Hanauske, AR. In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells. Br J Cancer, (1998). 78, 739–744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Urdiales, JL, Morata, P, Nunez de Castro, I & Sanchez-Jimenez, F Antiproliferative effect of dehydrodidemnin B (DDB), a depsipeptide isolated from Mediterranean tunicates. Cancer Lett, (1996). 102, 31–37.

    Article  CAS  PubMed  Google Scholar 

  4. Lobo, C, Garcia-Pozo, SG, De Castro, IN & Alonso, FJ Effect of dehydrodidemnin B on human colon carcinoma cell lines. Anticancer Res, (1997). 17, 333–336.

    CAS  PubMed  Google Scholar 

  5. Geldof, AA, Mastbergen, SC, Henrar, RE & Faircloth, GT Cytotoxicity and neurocytotoxicity of new marine anticancer agents evaluated using in vitro assays. Cancer Chemother Pharmacol, (1999). 44, 312–318.

    Article  CAS  PubMed  Google Scholar 

  6. Armand, JP, Ady-Vago, N, Faivre, S, Chieze, S, Baudin, E, Ribrag, V, Lecot, F, Iglesias, L, Lopez-Lazaro, L, Guzman, C, Jimeno, J, Ducreux, M, Le Chevalier, T & Raymond, E Phase I and pharmacokinetic study of aplidine (APL) given as a 24-hour continuous infusion every other week (q2w) in patients (pts) with solid tumor (ST) and lymphoma (NHL). Proc 37th ASCO Annual Meeting, San Francisco, May 12–15, (2001). 20, 120a

    Google Scholar 

  7. Paz-Ares, L, Anthony, A, Pronk, L, Twelves, C, Alonso, S, Cortes-Funes, H, Celli, N, Gomez, C, Lopez-Lazaro, L, Guzman, C, Jimeno, J & Kaye, S Phase I clinical and pharmacokinetic study of aplidine, a new marine didemnin, administered as a 24-hour infusion weekly. Proc 11th NCI-EORTC-AACR Symposium, Amsterdam, November 7–10, (2000). 11, 86

    Google Scholar 

  8. Maroun, J, Belanger, K, Seymour, L, Soulieres, D, Charpentier, D, Goel, R, Stewart, D, Tomiak, E, Jimeno, J & Matthews, S Phase I study of aplidine (APL) in a 1 hour daily infusion × 5 weeks in patients (pts) with solid tumors and low and intermediate grade non Hodgkin's lymphomas: a National Cancer Institute of Canada–Clinical Trials Group (NCIC-CTG) study. Proc of the European Society for Medical Oncology Meeting, Hamburg, October 13–17, (2000). 134

  9. Bowman, A, Izquierdo, M, Jodrell, D, Martinez, M, Cicchella, B, Jimeno, J, Guzman, C, Germa-Lluch, J, Celli, N & Smyth, J Phase I clinical and pharmacokinetic (PK) study of the marine compound aplidine (APL), administered as a 1 hour weekly infusion. Proc 37th ASCO Annual Meeting. San Francisco, May 12–15, (2001). 20, 120a

    Google Scholar 

  10. Erba, E, Bassano, L, Di Liberti, G, Muradore, I, Chiorino, G, Ubezio, P, Vignati, S, Codegoni, A, Desiderio, AM, Faircloth, G, Jimeno, J & d'Incalci, M Cell cycle phase perturbations and apoptosis induced by aplidine. Br J Cancer, (2002). 86, 1510–1511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Erba, E, Ronzoni, S, Bergamaschi, D, Bassano, L, Desiderio, AM, Faircloth, G, Jimeno, J & d'Incalci, M Mechanism of antileukemic activity of Aplidine. Proc Am Assoc Cancer Res, (1999). 40, 3

    Google Scholar 

  12. Marchini, S, Contegno, F, d'Incalci, M, Broggini, M & Faircloth, GT Gene expression profile in human leukemic MOLT-4 cells treated with the marine compound aplidine. Proc Am Assoc Cancer Res, (2000). 41, 833

    Google Scholar 

  13. Ferrara, N Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res, (2000). 55, 15–35.

    CAS  PubMed  Google Scholar 

  14. Veikkola, T, Karkkainen, M, Claesson-Welsh, L & Alitalo, K Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res, (2000). 60, 203–212.

    CAS  PubMed  Google Scholar 

  15. Watanabe, Y & Dvorak, HF Vascular permeability factor/vascular endothelial growth factor inhibits anchorage-disruption-induced apoptosis in microvessel endothelial cells by inducing scaffold formation. Exp Cell Res, (1997). 233, 340–349.

    Article  CAS  PubMed  Google Scholar 

  16. Watanabe, Y, Lee, SW, Detmar, M, Ajioka, I & Dvorak, HF Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells. Oncogene, (1997). 14, 2025–2032.

    Article  CAS  PubMed  Google Scholar 

  17. Gerber, HP, Dixit, V & Ferrara, N Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem, (1998). 273, 13313–13316.

    Article  CAS  PubMed  Google Scholar 

  18. Bellamy, WT, Richter, L, Frutiger, Y & Grogan, TM Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res, (1999). 59, 728–733.

    CAS  PubMed  Google Scholar 

  19. Boocock, CA, Charnock-Jones, DS, Sharkey, AM, McLaren, J, Barker, PJ, Wright, KA, Twentyman, PR & Smith, SK Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst, (1995). 87, 506–516.

    Article  CAS  PubMed  Google Scholar 

  20. Ferrer, FA, Miller, LJ, Lindquist, R, Kowalczyk, P, Laudone, VP, Albertsen, PC & Kreutzer, DL Expression of vascular endothelial growth factor receptors in human prostate cancer. Urology, (1999). 54, 567–572.

    Article  CAS  PubMed  Google Scholar 

  21. Hatva, E, Bohling, T, Jaaskelainen, J, Persico, MG, Haltia, M & Alitalo, K Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol, (1996). 148, 763–775.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Langer, I, Vertongen, P, Perret, J, Fontaine, J, Atassi, G & Robberecht, P Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in human neuroblastomas. Med Pediatr Oncol, (2000). 34, 386–393.

    Article  CAS  PubMed  Google Scholar 

  23. Speirs, V & Atkin, SL Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary cultures of epithelial and stromal cells derived from breast tumours. Br J Cancer, (1999). 80, 898–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ferrara, N VEGF: an update on biological and therapeutic aspects. Curr Opin Biotechnol, (2000). 11, 617–624.

    Article  CAS  PubMed  Google Scholar 

  25. Strizzi, L, Catalano, A, Vianale, G, Orecchia, S, Casalini, A, Tassi, G, Puntoni, R, Mutti, L & Procopio, A Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol, (2001). 193, 468–475.

    Article  CAS  PubMed  Google Scholar 

  26. Bachelder, RE, Crago, A, Chung, J, Wendt, MA, Shaw, LM, Robinson, G & Mercurio, AM Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res, (2001). 61, 5736–5740.

    CAS  PubMed  Google Scholar 

  27. Bellamy, WT, Richter, L, Sirjani, D, Roxas, C, Glinsmann-Gibson, B, Frutiger, Y, Grogan, TM & List, AF Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood, (2001). 97, 1427–1434.

    Article  CAS  PubMed  Google Scholar 

  28. Dias, S, Hattori, K, Heissig, B, Zhu, Z, Wu, Y, Witte, L, Hicklin, DJ, Tateno, M, Bohlen, P, Moore, MA & Rafii, S Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA, (2001). 98, 10857–10862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. von Marschall, Z, Cramer, T, Hocker, M, Burde, R, Plath, T, Schirner, M, Heidenreich, R, Breier, G, Riecken, EO, Wiedenmann, B & Rosewicz, S De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop. Gastroenterology, (2000). 119, 1358–1372.

    Article  CAS  PubMed  Google Scholar 

  30. Gerber, HP, McMurtrey, A, Kowalski, J, Yan, M, Keyt, BA, Dixit, V & Ferrara, N Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem, (1998). 273, 30336–30343.

    Article  CAS  PubMed  Google Scholar 

  31. Pidgeon, GP, Barr, MP, Harmey, JH, Foley, DA & Bouchier-Hayes, DJ Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. Br J Cancer, (2001). 85, 273–278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Minowada, J, Onuma, T & Moore, GE Rosette-forming human lymphoid cell lines. I. Establishment and evidence for origin of thymus-derived lymphocites. J Natl Cancer Inst, (1972). 49, 891–895.

    CAS  PubMed  Google Scholar 

  33. Vikhanskaya, F, Marchini, S, Marabese, M, Galliera, E & Broggini, M P73a overexpression is associated with resistance to treatment with DNA-damaging agents in a human ovarian cancer cell line. Cancer Res, (2001). 61, 935–938.

    CAS  PubMed  Google Scholar 

  34. Vikhanskaya, F, d'Incalci, M & Broggini, M p73 competes with p53 and attenuates its response in a human ovarian cancer cell line. Nucleic Acids Res, (2000). 28, 513–519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sambrook, J, Fritsch, EF & Maniatis, T Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY (1989).

    Google Scholar 

  36. Bertolini, F, Gobbi, A, Rabascio, C, Fusetti, L, Mancuso, P, Conte, D & Martinelli, G Autocrine and paracrine effects of vascular endothelial growth factor (VEGF) in lymphoid malignancies. Proc Am Assoc Cancer Res, (2000). 41, 776

    Google Scholar 

  37. Fusetti, L, Pruneri, G, Gobbi, A, Rabascio, C, Carboni, N, Peccatori, F, Martinelli, G & Bertolini, F Human myeloid and lymphoid malignancies in the non-obese diabetic/severe combined immunodeficiency mouse model: frequency of apoptotic cells in solid tumors and efficiency and speed of engraftment correlate with vascular endothelial growth factor production. Cancer Res, (2000). 60, 2527–2534.

    CAS  PubMed  Google Scholar 

  38. Carmeliet, P & Jain, RK Angiogenesis in cancer and other diseases. Nature, (2000). 407, 249–257.

    Article  CAS  PubMed  Google Scholar 

  39. de Bont, ES, Rosati, S, Jacobs, S, Kamps, WA & Vellenga, E Increased bone marrow vascularization in patients with acute myeloid leukaemia: a possible role for vascular endothelial growth factor. Br J Haematol, (2001). 113, 296–304.

    Article  CAS  PubMed  Google Scholar 

  40. Kini, AR, Peterson, LA, Tallman, MS & Lingen, MW Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid. Blood, (2001). 97, 3919–3924.

    Article  CAS  PubMed  Google Scholar 

  41. Kay, NE, Jelinek, DF & Peterson, L Angiogenesis in B-chronic lymphocytic leukemia. Leukemia Res, (2001). 25, 709–710.

    Article  CAS  Google Scholar 

  42. Padro, T, Ruiz, S, Bieker, R, Burger, H, Steins, M, Kienast, J, Buchner, T & Berdel, WE, Mesters RM. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood, (2000). 95, 2637–2644.

    CAS  PubMed  Google Scholar 

  43. Peterson, L & Kini, AR Angiogenesis is increased in B-cell chronic lymphocytic leukemia. Blood, (2001). 97, 2529

    Article  CAS  PubMed  Google Scholar 

  44. Raymond, E, Ady-Vago, N, Baudin, E, Ribrag, V, Faivre, S, Lecot, F, Wright, T, Lopez Lazaro, L, Guzman, C, Jimeno, J, Ducreux, M, Chevalier, T & Armand, JP A phase I and pharmacokinetic study of aplidine (APL) given as a 24-hour continuous infusion every other week (q2w) in patients (pts) with solid tumor (ST) and lymphoma (NHL). Proc 11th NCI-EORTC-AACR Symposium. Amsterdam, November 7–10, (2000). 86, (Abstr. 218)

Download references

Acknowledgements

This work was partially supported by a grant ICS 030.1/RF 00.192 from Ministero della Sanità, by FIRC and by CNR-MIUR.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy

    M Broggini, S V Marchini, E Galliera & M d'Incalci

  2. Department of Oncology, Laboratory of Biology and Treatment of Metastasis, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milano and Bergamo, Italy

    P Borsotti, G Taraboletti, E Erba, M Sironi & R Giavazzi

  3. PharmaMar SA, Clinical R&D, Tres Cantos, Madrid, Spain

    J Jimeno

  4. PharmaMar, Research & Development, Cambridge, MA, USA

    G T Faircloth

Authors
  1. M Broggini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S V Marchini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Galliera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Borsotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Taraboletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Erba
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Sironi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Jimeno
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G T Faircloth
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R Giavazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M d'Incalci
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Broggini, M., Marchini, S., Galliera, E. et al. Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4. Leukemia 17, 52–59 (2003). https://doi.org/10.1038/sj.leu.2402788

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402788

Keywords

This article is cited by

Search

Advanced search

Quick links