Abstract
Purpose
To investigate the activity and myeloprotective properties of erufosine, a novel alkylphosphocholine (APC), on human malignant cells and normal bone marrow cells.
Methods
Human or mouse bone marrow cells were exposed to erufosine, miltefosine, perifosine, or edelfosine in CFU-GM assays. Human MDA-MB-231 breast carcinoma, Panc-1 pancreatic carcinoma, and RPMI8226 multiple myeloma cells were exposed to erufosine in colony formation assays. Colony formation of Panc-1 tumor cells and mouse bone marrow cells ex vivo were quantified following intravenous administration of erufosine to tumor-bearing mice. Western blotting methods were applied to human U87 glioblastoma cells exposed to erufosine to investigate Akt inhibition.
Results
Erufosine was less toxic to human and mouse bone marrow cells than perifosine, miltefosine, and edelfosine and was equally toxic to human and mouse CFU-GM. The human cancer cells MDA-MB-231 breast, Panc-1 pancreatic, and RPMI8226 MM cells were more sensitive to erufosine in a colony formation assay than were human bone marrow cells generating an approximately tenfold differential in IC90 values. Erufosine injected intravenously significantly reduced Panc-1 tumor cell colony formation ex vivo but not mouse bone marrow CFU-GM. Erufosine inhibited Akt phosphorylation in human U87 glioblastoma cells.
Conclusions
Erufosine offers potential as a novel therapeutic for cancer with a reduced toxicity profile to bone marrow cells compared with other agents in this class. Human cancer cells were more sensitive to erufosine than human or mouse bone marrow cells indicating a favorable therapeutic window for erufosine.
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Abbreviations
- APL:
-
Alkylphospholipid
- APC:
-
Alkylphosphocholine
- CFU-GM:
-
Colony-forming unit–granulocyte– macrophage
- IC:
-
Inhibitory concentration
- FBS:
-
Fetal bovine serum
- rm:
-
Recombinant murine
- rh:
-
Recombinant human
- GBM:
-
Glioblastoma
- IV:
-
Intravenous
- CML:
-
Chronic myeloid leukemia
- AML:
-
Acute myeloid leukemia
- MM:
-
Multiple myeloma
References
Gajate C, Mollinedo F (2000) Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 109:719–771
Mollinedo F, Fernandez-Luna JL, Gajate C, Martin-Martin B, Benito A, Martinez-Dalmau R, Modolell M (1997) Selective induction of apoptosis in cancer cells by either lipid ET-18-OCH3 (edelfosine): molecular structure requirements, cellular uptake, and protection by Bcl-2 and Bcl-X(L). Cancer Res 57:1320–1328
Berdel WE, Fink U, Rastetter J (1987) Clinical phase I pilot study of the alkyl lysophospholipid derivative ET-18-OCH3. Lipids 22:967–969
Khanavkar B, Ulbrich F, Gatzemeier U, Meyer-Schwickerath E, Lorenz J, Schreml W, Brugger R, Schick HD, Pawel JV, Nordstrom R, Drings P (1989) Treatment of non-small cell lung cancer with the alkyl lysophospholipid edelfosine. Contrib Oncol 37:224–235
van der Luit AH, Vink SR, Klarenbeek JB, Perrissoud D, Solary E, Verheij M, van Blitterswijk WJ (2007) A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. Mol Cancer Ther 6:2337–2345
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
van Blitterswijk WJ, Verheij M (2008) Anticancer alkylphopholipids: mechanism of action, cellular sensitivity and resistance, and clinical prospects. Curr Pharma Design 14:2061–2074
Hilgard P, Klenner T, Stekar J, Unger C (1993) Alkylphosphocholines: a new class of membrane-active anticancer agents. Cancer Chemother Pharmacol 32:90–95
Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, Junge K, Bryceson A, Berman J (2002) Oral miltefosine for Indian visceral leishmaniasis. NEJM 347:1739–1746
Widmer F, Wright LC, Obando D, Handke R, Ganendren R, Ellis DH, Sorrell TC (2006) Hexadecylphosphocholine (Miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis. Antimicrobial Agents Chemother 50:414–421
Leonard R, Hardy J, van Tienhoven G, Houston S, Simmonds P, David M, Mansi J (2001) Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 19:4150–4159
Dummer R, Roger J, Vogt T, Becker J, Hefner H, Sindermann H, Burg G (1992) Topical application of hexadecylphosphocholine in patients with cutaneous lymphomas. Prog Exp Tumor Res 34:160–169
Kotting J, Marschner NW, Neumuller W, Unger C, Eibl H (1992) Hexadecylphosphocholine and octadecyl-methyl-glycero-3-phosphocholine: a comparison of hemolytic activity, serum binding and tissue distribution. Prog Exp Tumor Res 34:131–142
Verweij J, Krzemieniecki K, Kok T, Poveda A, Van Pottelsberghe C, Can Glabbeke M, Mourisden H (1993) Phase II study of miltefosine (hexadecylphosphocholine) in advanced soft tissue sarcomas of the adult—an EORTC Soft Tissue and Bone Sarcoma Group study. Eur J Cancer 29A:208–209
Planting AS, Stoter G, Verweij J (1993) Phase II study of daily oral miltefosine (hexadecylphosphocholine) in advanced colorectal cancer. Eur J Cancer 29A:208–209
Verweij J, Gandia D, Planting AS, Stoter G, Armand JP (1993) Phase II study of oral miltefosine in patients with squamous cell head and neck cancer. Eur J Cancer 29A:778–779
Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, Podar K, Munshi NC, Chauhan D, Richardson PG, Anderson KC (2006) Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 107:4053–4062
Argiris A, Cohen E, Karrison T, Esparaz B, Mauer A, Ansari R, Wong S, Lu Y, Pins M, Dancey J, Vokes E. (2006) A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biol Ther 5:766–770
Crul M, Rosing H, de Klerk GJ, Dubbelman R, Traiser M, Reichert S, Knebel NG, Schellens JH, 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 tumors. Eur J Cancer 33:442–446
Ernst DS, Eisenhauer E, Wainman N, Davis M, Lohmann R, Baetz T, Belanger K, Smylie M (2005) Phase II study of perifosine in previously untreated patients with metastatic melanoma. Invest New Drugs 205(23):1–7
Knowling M, Blackstein M, Tozer R, Bramwell V, Dancey J, Dore N, Matthews S, Eisenhauer E (2006) A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs 24:435–439
Leighl NB, Dent S, Clemons M, Vandenberg TA, Tozer R, Warr DC, Crump RM, Hedley D et al (2008) A phase 2 study of perifosine in advanced or metastatic breast cancer. Breast Cancer Res Treat 108:87–92
Posadas EM, Gulley J, Alren PM, Trout A, Parnes HL, Wright J, Lee MJ, Chung EJ, Trepel JB, Sparreboom A, Chen C, Jones E, Steinberg SM, Daniels A, Giff WD, Dahut WL (2005) A phase II study of perifosine in androgen independent prostate cancer. Cancer Biol Ther 4:1133–1137
Bendell JC, Richards DA, Vukelia SJ, Campos LT, Hagenstad CT, Letzer JP, Neumunaitis JJ (2010) Randomized phase II study of perifosine in combination with capecitabine (P-CAP) versus capecitabine plus placebo (CAP) in patients with second- or third-line metastatic colon cancer (mCRC). ASCO Gastroint Cancer Sym: Abstr#447
Richard DA, Neumunaitis JJ, Vukelja SJ, Hagenstad CT, Campos LT, Letzer JP, Hermann RC, Sportelli P, Gardner LR, Bendell JC (2010) Final results of a randomized phase II study of perifosine in combination with capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with second- or third-line metastatic colorectal cancer (mCRC). J Clin Oncol 28(suppl):Abstr#3531
Greco FA, Infante JR, Burris HA, Jones SF, Kolesar J, Gardner LR, Sportelli P, Bendell JC (2010) Safety and pharmacokinetics (PK) study of perifosine plus capecitabine (P-CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC). J Clin Oncol 28(suppl):Abstr#e14086
Berger MR, Sobottka S, Konstantinov SM, Eibl H (1998) Erucylphosphocholine is the prototype of i.v. injectable alkylphosphocholines. Drugs Today 34:73–81
Kaufmann-Kolle P, Berger MR, Unger C, Systemic administration of alkylphosphocholines et al (1996) Erucylphosphocholine and liposomal hexadecylphosphocholine. Adv Exp Med Biol 416:165–168
Erdlenbruch B, Jendrossek V, Marx M, Hunold A, Eibl H, Lakomek M (1998) Antitumor effects of erucylphosphocholine on brain tumor cells in vitro and in vivo. Anticancer Res 18:2551–2558
Jendrossek 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 Onc 14:15–22
Jendrossek 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
Georgieva MC, Konstantinov SM, Topashka-Ancheva M, Berger MR (2002) Combination effects of alkylphosphocholines and gemcitabine in malignant and normal hematopoietic cells. Cancer Lett 182:163–174
Martelli AM, Papa V, Tazzari PL, Ricci F, Evangelisti C, Chiarini F et al (2010) Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms. Leukemia 24:687–698
Fiegl M, Lindner LH, Jergens 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 62:321–329
Konigs SK, Pallasch CP, Lindner LH, Schwamb J, Schulz A, Brinker R et al (2010) Erufosine, a novel alkylphosphocholine, induces apoptosis in CLL through a caspase-dependent pathway. Leuk Res 34:1064–1069
Konstantinov SM, Berger MR (1999) Human urinary bladder carcinoma cell lines respond to treatment with alkylphosphocholines. Cancer Lett 144:153–160
Yosifov DY, Todorov PT, Zaharieva MM, Georgiev KD, Pilicheva BA, Konstantinov SP, Berger MR (2010) Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity. Cancer Chemother Pharmacol 67:13–25
Lindner LH, Eibl H, Hossann M, Vogeser M (2008) Quantification of erufosine, the first intravenously applicable alkylphosphocholine, in human plasma by isotope dilution liquid chromatography-tandem mass spectrometry using a deuterated internal standard. J Chromat 869:16–19
Rubel A, Handrick R, Lindner LH, Steiger M, Eibl H, Budach W, Belka C, Jendrossek V (2006) The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro. Radiation Oncol 1:6–23
Gillis JJ, Dennis PA (2009) Perifosine: update on a novel Akt inhibitor. Curr Oncol Reports 11:102–110
Handrick R, Rubel A, Faltin H, Eibl H, Belka C, Jendrossek V (2006) Increased cytotoxicity of ionizing radiation in combination with membrane-targeted apoptosis modulators involves downregulation of protein kinase B/Akt-mediated survival-signaling. Radiother Oncol 80:199–206
Zaharieva MM, Konstantinov SM, Pilicheva B, Karaivanova M, Berger MR (2007) Erufosine, a membrane targeting antineoplastic agent with signal transduction modulating effects. Ann NY Acad Sci 1095:182–192
Yosifov DY, Dineva IK Zaharieva MM, Konstantinov SP, Berger MR (2007) The expression level of the tumor suppressor retinoblastoma protein (Rb) influences the antileukemic efficacy of erucylphospho-N,N,N-trimethylpropylammonium (ErPC3). Cancer Biol Ther 930–935
Veenman L, Alten J, Linnemannstons K, Shandalov Y, Zeno S, Lakomek M, Gavish M, Kugler W (2010) Potential involvement of F0F1-ATP(synth)ase and reactive oxygen species in apoptosis induction by the antineoplastic agent erucylphosphohomocholine in glioblastoma cell lines. Apoptosis 15:753–768
Lemeshko VV, Kugler W (2007) Synergistic inhibition of mitochondrial respiration by anticancer agent erucylphosphohomocholine and cyclosporine A. J Biol Chem 282:37303–37307
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
Ghobrial IM, Roccaro A, Hong F, Weller E, Rubin N, Leduc R, Rourke M, Chuma S et al (2010) Clinical and translation studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom’s Macroglobulinemia. Clin Cancer Res 16:1033–1041
Li Z, Tan F, Liewehr DJ, Seinberg SM, Thiele CJ (2010) In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. JNCI 102:758–770
Vink SR, van Blitterswijk W, Schellens JHM, Verheij M (2007) Rationale and clinical application of alkylphospholipid analogues in combination with radiotherapy. Cancer Treatment Rev 33:191–202
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Bagley, R.G., Kurtzberg, L., Rouleau, C. et al. Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells. Cancer Chemother Pharmacol 68, 1537–1546 (2011). https://doi.org/10.1007/s00280-011-1658-0
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DOI: https://doi.org/10.1007/s00280-011-1658-0