Annals of Hematology

, Volume 91, Issue 2, pp 173–181 | Cite as

The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells

  • Raminder Singh
  • Julia Fröbel
  • Ron-Patrick Cadeddu
  • Ingmar Bruns
  • Thomas Schroeder
  • Daniela Brünnert
  • Christian Matthias Wilk
  • Luiz Fernando Zerbini
  • Rainer Haas
  • Akos CzibereEmail author
Original Article


Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. Treatment of patients suffering from high-risk AML as defined by clinical parameters, cytogenetics, and/or molecular analyses is often unsuccessful. OSI-461 is a pro-apoptotic compound that has been proposed as a novel therapeutic option for patients suffering from solid tumors like prostate or colorectal carcinoma. But little is known about its anti-proliferative potential in AML. Hence, we treated bone marrow derived CD34+ selected blast cells from 20 AML patients and the five AML cell lines KG-1a, THP-1, HL-60, U-937, and MV4-11 with the physiologically achievable concentration of 1 μM OSI-461 or equal amounts of DMSO as a control. Following incubation with OSI-461, we found a consistent induction of apoptosis and an accumulation of cells in the G2/M phase of the cell cycle. In addition, we demonstrate that the OSI-461 mediated anti-proliferative effects observed in AML are associated with the induction of the pro-apoptotic cytokine mda-7/IL-24 and activation of the growth arrest and DNA-damage inducible genes (GADD) 45α and 45γ. Furthermore, OSI-461 treated leukemia cells did not regain their proliferative potential for up to 8 days after cessation of treatment following the initial 48 h treatment period with 1 μM OSI-461. This indicates sufficient targeting of the leukemia-initiating cells in our in vitro experiments through OSI-461. The AML samples tested in this study included samples from patients who were resistant to conventional chemotherapy and/or had FLT3-ITD mutations demonstrating the high potential of OSI-461 in human AML.


AML OSI-461 GADD45 Growth arrest Apoptosis 



We would like to thank Annemarie Koch for excellent technical assistance.

Financial support

A.C. and I.B. are supported by grants from Leukämie Liga e.V. Düsseldorf, Germany and the Forschungskommission of the Heinrich-Heine-University, Düsseldorf, Germany. A.C. is further supported by the Deutsche Krebshilfe through a Dr. Mildred Scheel fellowship award and by a research fellowship award from the European Association of Hematology (EHA). L.F.Z. is supported by Department of Defense grants PC051217 and OC0060439.


  1. 1.
    Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S et al (2011) Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19(1):138–152PubMedCrossRefGoogle Scholar
  2. 2.
    Betz BL, Hess JL (2010) Acute myeloid leukemia diagnosis in the 21st century. Arch Pathol Lab Med 134(10):1427–1433, ReviewPubMedGoogle Scholar
  3. 3.
    Czibere A, Prall WC, Zerbini LF, Grall F, Craigie EC, Ulrich SD et al (2005) The nonsteroidal anti-inflammatory drug Exisulind selectively induces apoptosis via JNK in secondary acute myeloid leukemia after myelodysplastic syndrome. Cell Cycle 4(6):812–817PubMedCrossRefGoogle Scholar
  4. 4.
    Czibere A, Prall WC, Zerbini LF, Jäger M, Kobbe G, Knipp S et al (2006) Exisulind induces apoptosis in advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia/MDS. Br J Haematol 135(3):355–357PubMedCrossRefGoogle Scholar
  5. 5.
    Yang BX, Duan YJ, Dong CY, Zhang F, Gao WF, Cui XY et al (2011) Novel functions for mda-7/IL-24 and IL-24 delE5: regulation of differentiation of acute myeloid leukemic cells. Mol Cancer Ther 10(4):615–625PubMedCrossRefGoogle Scholar
  6. 6.
    Rahmani M, Mayo M, Dash R, Sokhi UK, Dmitriev IP, Sarkar D et al (2010) Melanoma differentiation associated gene-7/interleukin-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by endoplasmic reticulum stress. Mol Pharmacol 78(6):1096–1104PubMedCrossRefGoogle Scholar
  7. 7.
    O'Bryant CL, Lieu CH, Leong S, Boinpally R, Basche M, Gore L et al (2009) A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state. Cancer Chemother Pharmacol 63(3):477–489PubMedCrossRefGoogle Scholar
  8. 8.
    Griffiths GJ (2000) Exisulind cell pathway. Curr Opin Investig Drugs 1(3):386–391, ReviewPubMedGoogle Scholar
  9. 9.
    Haanen C (2001) Sulindac and its derivatives: a novel class of anticancer agents. Curr Opin Investig Drugs 2:677–683PubMedGoogle Scholar
  10. 10.
    Xiao D, Deguchi A, Gundersen GG, Oehlen B, Arnold L, Weinstein IB (2006) The sulindac derivatives OSI-461, OSIP486823, and OSIP487703 arrest colon cancer cells in mitosis by causing microtubule depolymerization. Mol Cancer Ther 5(1):60–67PubMedCrossRefGoogle Scholar
  11. 11.
    Oida Y, Gopalan B, Miyahara R, Inoue S, Branch CD, Mhashilkar AM et al (2005) Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer. Mol Cancer Ther 4(2):291–304PubMedGoogle Scholar
  12. 12.
    Lim JT, Piazza GA, Han EK, Delohery TM, Li H, Finn TS et al (1999) Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines. Biochem Pharmacol 58(7):1097–1107PubMedCrossRefGoogle Scholar
  13. 13.
    Arber N, Kuwada S, Leshno M, Sjodahl R, Hultcrantz R, Rex D et al (2006) Sporadic adenomatous polyp regression with exisulind is effective but toxic: a randomised, double blind, placebo controlled, dose–response study. Gut 55(3):367–373PubMedCrossRefGoogle Scholar
  14. 14.
    Govindan R, Wang X, Baggstrom MQ, Burdette-Radoux S, Hodgson L, Vokes EE et al (2009) A phase II study of carboplatin, etoposide, and exisulind in patients with extensive small cell lung cancer: CALGB 30104. J Thorac Oncol 4(2):220–226PubMedCrossRefGoogle Scholar
  15. 15.
    Dawson NA, Halabi S, Ou SS, Biggs DD, Kessinger A, Vogelzang N et al (2008) A phase II study of estramustine, docetaxel, and exisulind in patients with hormone-refractory prostate cancer: results of cancer and leukemia group B trial 90004. Clin Genitourin Cancer 6(2):110–116PubMedCrossRefGoogle Scholar
  16. 16.
    Resta LP, Pili R, Eisenberger MA, Spitz A, King S, Porter J et al (2011) A phase I study of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors potentially responsive to mitoxantrone. Cancer Chemother Pharmacol 67(2):431–438PubMedCrossRefGoogle Scholar
  17. 17.
    Zerbini LF, Czibere A, Wang Y, Correa RG, Otu H, Joseph M et al (2006) A novel pathway involving melanoma differentiation associated gene-7/interleukin-24 mediates nonsteroidal anti-inflammatory drug-induced apoptosis and growth arrest of cancer cells. Cancer Res 66(24):11922–11931PubMedCrossRefGoogle Scholar
  18. 18.
    Gupta P, Walter MR, Su ZZ, Lebedeva IV, Emdad L, Randolph A et al (2006) BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis. Cancer Res 66(16):8182–8191PubMedCrossRefGoogle Scholar
  19. 19.
    Sauane M, Su ZZ, Gupta P, Lebedeva IV, Dent P, Sarkar D et al (2008) Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis. Proc Natl Acad Sci USA 105(28):9763–9768PubMedCrossRefGoogle Scholar
  20. 20.
    Abu-Duhier FM, Goodeve AC, Wilson GA, Gari MA, Peake IR, Rees DC et al (2000) FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol 111(1):190–195PubMedCrossRefGoogle Scholar
  21. 21.
    Czibere A, Bruns I, Kröger N, Platzbecker U, Lind J, Zohren F et al (2010) 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis. Bone Marrow Transplant 45(5):872–876PubMedCrossRefGoogle Scholar
  22. 22.
    Kuendgen A, Germing U (2009) Emerging treatment strategies for acute myeloid leukemia (AML) in the elderly. Cancer Treat Rev 35(2):97–120, ReviewPubMedCrossRefGoogle Scholar
  23. 23.
    Zerbini LF, Wang Y, Czibere A, Correa RG, Cho JY, Ijiri K et al (2004) NF-kappa B-mediated repression of growth arrest- and DNA-damage-inducible proteins 45alpha and gamma is essential for cancer cell survival. Proc Natl Acad Sci USA 101(37):13618–13623PubMedCrossRefGoogle Scholar
  24. 24.
    Yacoub A, Gupta P, Park MA, Rhamani M, Hamed H, Hanna D et al (2008) Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. Mol Cancer Ther 7(2):314–329PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Raminder Singh
    • 1
  • Julia Fröbel
    • 1
  • Ron-Patrick Cadeddu
    • 1
  • Ingmar Bruns
    • 1
  • Thomas Schroeder
    • 1
  • Daniela Brünnert
    • 1
  • Christian Matthias Wilk
    • 1
  • Luiz Fernando Zerbini
    • 2
  • Rainer Haas
    • 1
  • Akos Czibere
    • 1
    • 3
    Email author
  1. 1.Department of Hematology, Oncology and Clinical ImmunologyHeinrich Heine UniversityDüsseldorfGermany
  2. 2.International Center for Genetic Engineering and Biotechnology (ICGEB) and Medical Biochemistry Division, Faculty of Health SciencesUniversity of Cape TownCape TownSouth Africa
  3. 3.Beth Israel Deaconess Medical Center, Department of HematologyHarvard Medical SchoolBostonUSA

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