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01-01-2011 | Original Article

Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity

Authors: Deyan Y. Yosifov, Plamen T. Todorov, Maya M. Zaharieva, Kaloyan D. Georgiev, Bissera A. Pilicheva, Spiro M. Konstantinov, Martin R. Berger

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2011

Abstract

Purpose

Erufosine is an i.v. injectable alkylphosphocholine which is active against various haematological malignancies in vitro. In the present study, its effects on multiple myeloma (MM) cell lines and on murine and human hematopoietic progenitor cells (HPCs) were investigated.

Methods

The following MM cell lines were used: RPMI-8226, U-266 and OPM-2. The cytotoxicity of erufosine against these cell lines was determined by the MTT-dye reduction assay. Bcl-2, Bcl-X_L and pAkt expression levels, activation of caspases, as well as cleavage of PARP, were studied by Western blotting. Migration was evaluated by a modified Boyden-chamber assay. The haematologic toxicity of erufosine was assessed using clonogenicity assays with normal HPCs of murine or human origin.

Results

Significant cytotoxic activity of erufosine against the MM cell lines was found. Comparison of the characteristics of erufosine-induced cell death in the three cell lines revealed a complex mode of action with apoptotic mechanisms prevailing in OPM-2 cells and non-apoptotic mechanisms prevailing in U-266 cells. The sensitivity of the MM cell lines to erufosine-induced apoptosis correlated inversely with the Bcl-X_L expression level. Erufosine participated in synergistic interactions with various drugs. Furthermore, it showed potent migration-inhibiting activity in RPMI-8226 cells. Erufosine was not toxic to normal HPCs of murine or human origin and even stimulated progenitors from human umbilical cord blood to form granulocyte/macrophage colonies. Moreover, erufosine ameliorated the toxicity of bendamustine to murine HPCs.

Conclusions

Overall, the data presented reveal that erufosine could have potential as an antimyeloma drug and deserves further development.

Activation of caspases and PARP cleavage in RPMI-8226 cells in response to erufosine has been published before [22].

Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRefPubMed

Piazza FA, Gurrieri C, Trentin L, Semenzato G (2007) Towards a new age in the treatment of multiple myeloma. Ann Hematol 86:159–172CrossRefPubMed

Rajkumar SV, Palumbo A (2007) Management of newly diagnosed myeloma. Hematol Oncol Clin North Am 21:1141–1156 ix–xCrossRefPubMed

Stellrecht CM, Phillip CJ, Cervantes-Gomez F, Gandhi V (2007) Multiple myeloma cell killing by depletion of the MET receptor tyrosine kinase. Cancer Res 67:9913–9920CrossRefPubMed

Merchionne F, Perosa F, Dammacco F (2007) New therapies in multiple myeloma. Clin Exp Med 7:83–97CrossRefPubMed

Gajate C, Mollinedo F (2007) Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 109:711–719CrossRefPubMed

Eibl H, Engel J (1992) Synthesis of hexadecylphosphocholine (miltefosine). Prog Exp Tumor Res 34:1–5PubMed

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 77:778–786CrossRefPubMed

Konstantinov SM, Eibl H, Berger MR (1999) BCR-ABL influences the antileukaemic efficacy of alkylphosphocholines. Br J Haematol 107:365–380CrossRefPubMed

10.

Georgieva MC, Konstantinov SM, Topashka-Ancheva M, Berger MR (2002) Combination effects of alkylphosphocholines and gemcitabine in malignant and normal hematopoietic cells. Cancer Lett 182:163–174CrossRefPubMed

11.

Zaharieva MM, Konstantinov SM, Pilicheva B, Karaivanova M, Berger MR (2007) Erufosine: a membrane targeting antineoplastic agent with signal transduction modulating effects. Ann N Y Acad Sci 1095:182–192CrossRefPubMed

12.

Rubel A, Handrick R, Lindner LH, Steiger M, Eibl H, Budach W et al (2006) The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro. Radiat Oncol 1:6CrossRefPubMed

13.

Vink SR, van der Luit AH, Klarenbeek JB, Verheij M, van Blitterswijk WJ (2007) Lipid rafts and metabolic energy differentially determine uptake of anti-cancer alkylphospholipids in lymphoma versus carcinoma cells. Biochem Pharmacol 74:1456–1465CrossRefPubMed

14.

Oberle C, Massing U, Krug HF (2005) On the mechanism of alkylphosphocholine (APC)-induced apoptosis in tumour cells. Biol Chem 386:237–245CrossRefPubMed

15.

van der Luit AH, Vink SR, Klarenbeek JB, Perrissoud D, Solary E, Verheij M et al (2007) A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. Mol Cancer Ther 6:2337–2345CrossRefPubMed

16.

Nieto-Miguel T, Gajate C, Mollinedo F (2006) Differential targets and subcellular localization of antitumor alkyl-lysophospholipid in leukemic versus solid tumor cells. J Biol Chem 281:14833–14840CrossRefPubMed

17.

Chiarini F, Del Sole M, Mongiorgi S, Gaboardi GC, Cappellini A, Mantovani I et al (2008) The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism. Leukemia 22:1106–1116CrossRefPubMed

18.

Berger MR, Tsoneva I, Konstantinov SM, Eibl H (2003) Induction of apoptosis by erucylphospho-N,N,N-trimethylammonium is associated with changes in signal molecule expression and location. Ann N Y Acad Sci 1010:307–310CrossRefPubMed

19.

Hideshima T, Catley L, Raje N, Chauhan D, Podar K, Mitsiades C et al (2007) Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. Br J Haematol 138:783–791CrossRefPubMed

20.

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

21.

Fiegl M, Lindner LH, Juergens M, Eibl H, Hiddemann W, Braess J (2008) Erufosine, a novel alkylphosphocholine, in acute myeloid leukemia: single activity and combination with other antileukemic drugs. Cancer Chemother Pharmacol 62:321–329CrossRefPubMed

22.

Yosifov DY, Konstantinov SM, Berger MR (2009) Erucylphospho-N,N,N-trimethylpropylammonium shows substantial cytotoxicity in multiple myeloma cells. Ann N Y Acad Sci 1171:350–358CrossRefPubMed

23.

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

24.

Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C et al (2006) Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 107:4053–4062CrossRefPubMed

25.

Huston A, Leleu X, Jia X, Moreau AS, Ngo HT, Runnels J et al (2008) Targeting Akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment. Clin Cancer Res 14:865–874CrossRefPubMed

26.

Jernberg-Wiklund H, Pettersson M, Carlsson M, Nilsson K (1992) Increase in interleukin 6 (IL-6) and IL-6 receptor expression in a human multiple myeloma cell line, U-266, during long-term in vitro culture and the development of a possible autocrine IL-6 loop. Leukemia 6:310–318PubMed

27.

Naumann U, Wischhusen J, Weit S, Rieger J, Wolburg H, Massing U et al (2004) Alkylphosphocholine-induced glioma cell death is BCL-X(L)-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation. Cell Death Differ 11:1326–1341CrossRefPubMed

28.

Gajate C, Mollinedo F (2001) The antitumor ether lipid ET-18-OCH(3) induces apoptosis through translocation and capping of Fas/CD95 into membrane rafts in human leukemic cells. Blood 98:3860–3863CrossRefPubMed

29.

Jendrossek V, Muller I, Eibl H, Belka C (2003) Intracellular mediators of erucylphosphocholine-induced apoptosis. Oncogene 22:2621–2631CrossRefPubMed

30.

Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ et al (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687CrossRefPubMed

31.

Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK (2007) Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015–070) in multiple myeloma. Blood 109:5430–5438CrossRefPubMed

32.

Kline MP, Rajkumar SV, Timm MM, Kimlinger TK, Haug JL, Lust JA et al (2007) ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia 21:1549–1560CrossRefPubMed

33.

Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS (1999) Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 93:3044–3052PubMed

34.

Tu Y, Xu FH, Liu J, Vescio R, Berenson J, Fady C et al (1996) Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide. Blood 88:1805–1812PubMed

35.

Panaretakis T, Pokrovskaja K, Shoshan MC, Grander D (2002) Activation of Bak, Bax, and BH3-only proteins in the apoptotic response to doxorubicin. J Biol Chem 277:44317–44326CrossRefPubMed

36.

Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X et al (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA 99:14374–14379CrossRefPubMed

37.

Tu Y, Renner S, Xu F, Fleishman A, Taylor J, Weisz J et al (1998) BCL-X expression in multiple myeloma: possible indicator of chemoresistance. Cancer Res 58:256–262PubMed

38.

Amundson SA, Myers TG, Scudiero D, Kitada S, Reed JC, Fornace AJ Jr (2000) An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res 60:6101–6110PubMed

39.

Kawamura C, Kizaki M, Yamato K, Uchida H, Fukuchi Y, Hattori Y et al (2000) Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. Blood 96:2005–2011PubMed

40.

Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A et al (1997) Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278:1966–1968CrossRefPubMed

41.

Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2:1093–1103PubMed

42.

Rokudai S, Fujita N, Hashimoto Y, Tsuruo T (2000) Cleavage and inactivation of antiapoptotic Akt/PKB by caspases during apoptosis. J Cell Physiol 182:290–296CrossRefPubMed

43.

Gills JJ, Dennis PA (2009) Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 11:102–110CrossRefPubMed

44.

Konstantinov SM, Georgieva MC, Topashka-Ancheva M, Eibl H, Berger MR (2002) Combination with an antisense oligonucleotide synergistically improves the antileukemic efficacy of erucylphospho-N,N,N-trimethylpropylammonium in chronic myeloid leukemia cell lines. Mol Cancer Ther 1:877–884PubMed

45.

Stekar J, Hilgard P, Klenner T (1995) Opposite effect of miltefosine on the antineoplastic activity and haematological toxicity of cyclophosphamide. Eur J Cancer 31A:372–374CrossRefPubMed

46.

Catley L, Hideshima T, Chauhan D, Neri P, Tassone P, Bronson R et al (2007) Alkyl phospholipid perifosine induces myeloid hyperplasia in a murine myeloma model. Exp Hematol 35:1038–1046CrossRefPubMed

47.

Nieto-Miguel T, Gajate C, Gonzalez-Camacho F, Mollinedo F (2008) Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy. Oncogene 27:1779–1787CrossRefPubMed

48.

Chen YR, Tan TH (1998) Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin. Oncogene 17:173–178CrossRefPubMed

49.

Gajate C, An F, Mollinedo F (2003) Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. Clin Cancer Res 9:1535–1545PubMed

Title: Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity
Authors: Deyan Y. Yosifov
Plamen T. Todorov
Maya M. Zaharieva
Kaloyan D. Georgiev
Bissera A. Pilicheva
Spiro M. Konstantinov
Martin R. Berger
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1273-5

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Abstract

Purpose

Methods

Results

Conclusions

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