Skip to main content

Advertisement

SpringerLink
Log in

Structure-activity relationships of antineoplastic ring-substituted ether phospholipid derivatives

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Previous studies have shown that alkylphosphocholines (APCs) exhibit strong antineoplastic activity against various tumour cell lines in vitro and in several animal models. The current study was designed to investigate the influence of cycloalkane rings on the antiproliferative activity of APCs against a panel of eight human and animal cell lines (PC3, MCF7, A431, Hela, PC12, U937, K562, CHO). Specifically, we explored the effect of the presence of 4-alkylidenecyclohexyl and cycloalkylidene groups in alkoxyethyl and alkoxyphosphodiester ether lipids, respectively. In addition, the haemolytic activity of the new ring-substituted ether phospholipids (EP) was evaluated.

Methods

Cells were exposed to various concentrations of the compounds for 72 h. The cytotoxicity was determined with the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] dye reduction assay. Similarly, red blood cells were distributed in 96-well microplates and treated with the test compounds at concentrations ranging from 100 to 6.25 μM for 1 h. After centrifugation, the absorbance of the supernatants was measured at 550 nm.

Results

The majority of the compounds tested exhibited significant cytotoxic activity which depended on both the ring size and position with respect to the phosphate moiety, as well as the head group. Among the cycloalkylidene series the 11-adamantylideneundecyl-substituted N-methylmorpholino EP 13 was the most potent and exhibited broad-spectrum anticancer activity comparable to or superior to that of hexadecylphosphocholine (HePC). All the adamantylidene-substituted EPs were nonhaemolytic (concentration that exhibits 50% haemolytic activity, HC50, >100 μM). Furthermore, the cyclohexylidene-substituted analogues were more potent against the cell lines tested, with the exception of U937 and K562, than the cyclodecapentylidene-substituted compounds. Hydrogenation of the double bond in the cycloalkylidene-substituted EPs (compounds 14 and 15) resulted in improvement of anticancer activity. Among the 2-(4-alkylidenecyclohexyloxy)ethyl EPs, 2-(4-hexadylidenecyclohexyloxy)ethyl phosphocholine (22) possessed the highest broad-spectrum cytotoxic activity than all the other analogues of this series and was nonhaemolytic (HC50 >100 μM). In general, the 2-(4-alkylidenecyclohexyloxy)ethyl-substituted EPs were more active against the more resistant cell lines U937, K562 and CHO than HePC.

Conclusions

The presence of cycloalkane rings in the lipid portion of APCs reduces haemolytic effects compared to HePC and in several analogues results in improved antineoplastic activity.

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

Similar content being viewed by others

References

  1. Aroca JD, Sanchez-Pinera P, Corbalan-Garcia S, Conesa-Zamora P, deGodos A, Comez-Fernandez JC (2001) Correlation between the effect of the antineoplastic ether lipid 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine on the membrane and the activity of protein kinase Cα. Eur J Biochem 268:6369–6378

    Google Scholar 

  2. Arthur G, Bittman R (1998) The inhibition of cell signaling pathways by antitumor ether lipids. Biochim Biophys Acta 1390:85–102

    Google Scholar 

  3. Avlonitis N, Lekka E, Detsi A, Koufaki M, Calogeropoulou T, Scoulica E, Siapi E, Kyrikou I, Mavromoustakos T, Tsotinis A, Golic Grdadolnik S, Makriyannis A (2003) Antileishmanial ring-substituted ether phospholipids. J Med Chem 46:755–767

    Google Scholar 

  4. Berkovic D (1998) Cytotoxic etherphospholipid analogues. Gen Pharmacol 31:511–517

    Google Scholar 

  5. Berkovic D, Grundel O, Berkovic K, Wildfang I, Hess CF, Schmoll HJ (1997) Synergistic cytotoxic effects of ether phospholipid analogues and ionizing radiation in human carcinoma cells. Radiother Oncol 43:293–301

    Google Scholar 

  6. Berkovic D, Berkovic K, Binder C, Haase D, Fleer EAM (2002) Hexadecylphosphocholine does not influence phospholipase D and sphingomyelinase activity in human leukemia cells. J Exp Ther Oncol 2:213–218

    Google Scholar 

  7. Brachwitz H, Vollgraf C (1995) Analogs of alkyllysophospholipids: chemistry, effects on the molecular level and their consequences for normal and malignant cells. Pharmacol Ther 66:39–82

    Google Scholar 

  8. Croft SL, Seifert K, Duchene M (2003) Antiprotozoal activities of phospholipid analogues. Mol Biochem Parasitol 126:165–172

    Google Scholar 

  9. Crul M, Rosing H, deKlerk GJ, Dubbelman R, Traiser M, Reichert S, Knebel NG, Schellens JHM, Beijnen JH, ten Bokkel Huinink WW (2002) Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 38:1615–1621

    Google Scholar 

  10. Eibl H, Kaufmann-Kolle P (1995) Medical application of synthetic phospholipids as liposomes and drugs. J Liposome Res 5:131

    Google Scholar 

  11. Erdlenbruch B, Jendrossek V, Gerriets A, Vetterlein F, Eibl H, Lakomek M (1999) Erucylphosphocholine:pharmacokinetics, biodistribution and CNS-accumulation in the rat after intravenous administration. Cancer Chemother Pharmacol 44:484–490

    Google Scholar 

  12. Fleer EAM, Kim D-J, Nagel GA, Eibl H, Unger C (1990) Cytotoxic activity of lysophosphatidylcholine analogues on human lymphoma raji cells. Oncology 13:295

    Google Scholar 

  13. Gajate C, Santos-Beneit AM, Macho A, Lazaro MdC, Hernandez-De Rojas A, Modolell M, Munoz E, Mollinedo F (2000) Involvement of mitochondria and caspase-3 in ET-18-OCH(3)-induced apoptosis of human leukemic cells. Int J Cancer 86:208–218

    Google Scholar 

  14. Gajate C, Fonteriz RI, Cabaner C, Alvares-Noves G, Alvarez-Rodriguez Y, Modolell M, Mollinedo F (2000) Intracellular triggering of Fas, independently of FasL, as a new mechanism of antitumor ether lipid-induced apoptosis. Int J Cancer 85:674–682

    Google Scholar 

  15. Grosman N (1999) Effect of anti-neoplastic agents edelfosine (ET-18-OCH3), ilmofosine (BM 41.440) and the hexadecylphosphocholines D-20133 and D-21266 on histamine release from isolated rat mast cells. Immunopharmacology 44:211–221

    Google Scholar 

  16. Hanson PK, Malone L, Birchmore JL, Nichols JW (2003) Lemp3p is essential for the uptake and potency of alkylphosphocholine drugs, edelfosine and miltefosine. J Biol Chem 278:36041–36050

    Google Scholar 

  17. Hilgard P, Stekar J, Voegeli R, Engel J, Schumacher E, EIbl H, Unger C, Berger M (1988) Characterisation of the antitumor activity of hexadecylphosphocholine (D18506). Eur J Clin Oncol 24:1457

    Google Scholar 

  18. Jendorssek V, Erdlenbruch B, Hunold A, Kugler W, Eibl H, Lakomek M. (1999) Erucylphosphocholine, a novel antineoplastic ether lipid, blocks growth and induces apoptosis in brain tumor cell lines in vitro. Int J Oncol 14:15–22

    Google Scholar 

  19. Jendorssek V, Hammersen K, Erdlenbruch B, Kugler W, Krugener R, Eibl H, Lakomek M. (2002) Structure-activity relationships of alkylphosphocholine derivatives: antineoplastic action on brain tumor cell lines in vitro. Cancer Chemother Pharmacol 50:71–79

    Google Scholar 

  20. Jendorssek V, Muller I, Eibl H, Belka C (2003) Intracellular mediators of erucylphosphocholine-induced apoptosis. Oncogene 22:2621

    Google Scholar 

  21. Kaufmann-Kolle P, Kotting J, Drevs J, Berger MR, Unger C, Eibl H (1992) Intravenous application of alkylphosphocholines:comparison of different homologues in lamellar structures. J Cancer Res Clin Oncol 120 [Supp l]:R14

    Google Scholar 

  22. Kaufmann-Kolle P, Drevs J, Berger MR, Kotting J, Marschner N, Unger C, Eibl H (1994) Pharmacokinetic behavior and antineoplastic activity of liposomal hexadecylphosphocholine. Cancer Chemother Pharmacol 34:393

    Google Scholar 

  23. Konstantinov SM, Eibl H, Berger MR (1998) Alkylphosphocholines induce apoptosis in HL-60 and U-937 leukemic cells. Cancer Cemother Pharmacol 41:210–216

    Google Scholar 

  24. Konstantinov SM, Topashka-Ancheva M, Benner A, Berger MR (1998) Alkylphosphocholines: effects on human leukemic cell lines and normal bone marrow cells. Int J Cancer 77:778–786

    Google Scholar 

  25. Kotting J, Marschner NW, Neumuller W, Unger C, Eibl H (1992) Hexadecylphosphocholine and octadecyl-methyl-glycero-3-phosphocholine: a comparison of haemolytic activity, serum binding and tissue distribution. In: Eibl H, Hilgard P, Unger C (eds) Alkylphosphocholines: new drugs in cancer therapy (Progress in experimental tumor research, vol 34). Karger-Verlag, Basel, p 131

  26. Koufaki M, Polychroniou V, Calogeropoulou T, Tsotinis A, Drees M, Fiebig HH, LeClerc HR, Makriyannis A (1996) Alkyl and alkoxyethyl antineoplastic phospholipids. J Med Chem 39:2609–2614

    Google Scholar 

  27. Mollinedo F, Martinez-Dalman R, Modolell M (1993) Early and selective induction of apoptosis in human leukemic cells by the alkyl-lysophospholipid ET-18-OCH3. Biochem Biophys Res Commun 192:603–609

    Google Scholar 

  28. Mollinedo F, Fernandez-Luna FJ, Gajate C, Martin-Martin B, Benito A, Martinez-Dalmau R, Modolell M (1997) Selective induction of apoptosis in cancer cells by the ether lipid ET-18-OCH3 (edelfosine): molecular structural requirements, cellular uptake, and protection by Bcl-3 and Bcl-XL. Cancer Res 57:1320–1328

    Google Scholar 

  29. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Google Scholar 

  30. Planting AST, Stoter G, Verweij J (1993) Phase II study of daily oral miltefosine (hexadecylphosphocholine) in advanced colorectal cancer. Eur J Cancer 29a:518–519

    Google Scholar 

  31. Ruiter GA, Zerp SF, Bartelink H, van Blitterswijk WJ, Verheij M (1999) Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res 59:2457–2463

    Google Scholar 

  32. Ruiter GA, Verheij M, Zerp SF, van Blitterswijk WJ (2001) Alkyl-lysophospholipids as anticancer agents and enhancers of radiation-induced apoptosis. Int J Radiat Oncol Biol Phys 49:415–419

    Google Scholar 

  33. Rybczynska M, Spitaler M, Knebel NG, Boeck G, Grunicke H, Hofmann J (2001) Effects of miltefosine on various biochemical parameters in a panel of tumor cell lines with different sensitivities. Biochem Pharmacol 62:765–772

    Google Scholar 

  34. Sobottka SB, Berger MR, Eibl H (1993) Structure-activity relationships of four anti-cancer alkylphosphocholine derivatives in vitro and in vivo. Int J Cancer 53:418

    Google Scholar 

  35. Spruss T, Bernhardt G, Schonenberger H, Engel J (1993) Antitumour activity of miltefosine alone and after combination with platinum complexes on MXT mouse mammary carcinoma models. J Cancer Res Clin Oncol 19:142–149

    Google Scholar 

  36. Stekar J, Hilgard P, Klenner T (1995) Opposite effect of miltefosine on the antineoplastic activity and haematological toxicity of cyclophosphamide. Eur J Cancer 3:372–374

    Google Scholar 

  37. Unger C, Eibl H (1991) Hexadecyl phosphocholine: preclinical and the first clinical results of a new antitumor drug. Lipids 26:1412–1417

    Google Scholar 

  38. Unger C, Damenz W, Fleer EAM, Kim DJ, Breiser A, Hilgard P, Engel J, Nagel G, Eibl H (1989) Hexadecylphosphocholine, a new ether lipid. Acta Oncol 28:213–217

    Google Scholar 

  39. Verweij J, Planting A, van der Burg M, Stoter GA (1992) A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumors. J Cancer Res Clin Oncol 118:606–608

    Google Scholar 

Download references

Acknowledgements

This work was supported in part by the GSRT program 02PRAXE83. P. Papazafiri acknowledges support from the GSRT program EPAN YB/39.

Author information

Authors and Affiliations

  1. Department of Animal and Human Physiology, School of Biology, University of Athens, Panepistimiopolis, 15784, Athens, Greece

    Panagiota Papazafiri

  2. Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635, Athens, Greece

    Nicolaos Avlonitis, Panagiotis Angelou, Theodora Calogeropoulou & Maria Koufaki

  3. Department of Clinical Bacteriology, Parasitology, Zoonoses and Geographical Medicine, School of Medicine, University of Crete, 76309, Heraklion, Greece

    Efi Scoulica & Irene Fragiadaki

Authors
  1. Panagiota Papazafiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicolaos Avlonitis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Panagiotis Angelou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Theodora Calogeropoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Koufaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Efi Scoulica
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Irene Fragiadaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theodora Calogeropoulou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Papazafiri, P., Avlonitis, N., Angelou, P. et al. Structure-activity relationships of antineoplastic ring-substituted ether phospholipid derivatives. Cancer Chemother Pharmacol 56, 261–270 (2005). https://doi.org/10.1007/s00280-004-0935-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-004-0935-6

Keywords

Search

Navigation