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Schwartz J, Niu X, Walton E, et al. Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia . Am J Transl Res. 2016;8(9):3893-3902
Schwartz, J., Niu, X., Walton, E., Hurley, L., Lin, H., Edwards, H., Taub, J. W., Wang, Z., & Ge, Y. (2016). Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia . American journal of translational research, 8(9), 3893-3902.
Schwartz, Jonathan, et al. "Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia ." American journal of translational research vol. 8,9 (2016): 3893-3902.
Schwartz J, Niu X, Walton E, Hurley L, Lin H, Edwards H, Taub JW, Wang Z, Ge Y. Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia . Am J Transl Res. 2016 Sep 15;8(9):3893-3902. eCollection 2016. PMID: 27725868; PMCID: PMC5040686.
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Am J Transl Res. 2016 Sep 15;8(9):3893-3902. eCollection 2016.

Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia .

American journal of translational research

Jonathan Schwartz, Xiaojia Niu, Eric Walton, Laura Hurley, Hai Lin, Holly Edwards, Jeffrey W Taub, Zhihong Wang, Yubin Ge

Affiliations

  1. Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan Detroit, MI, USA.
  2. National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology & Engineering, The Ministry of Education, School of Life Sciences, Jilin University Changchun, China.
  3. MD/PhD Program, School of Medicine, Wayne State University Detroit, MI, USA.
  4. Cancer Biology Graduate Program, School of Medicine, Wayne State University Detroit, MI, USA.
  5. Department of Hematology and Oncology, The First Hospital of Jilin University Changchun, China.
  6. Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State UniversityDetroit, MI, USA; Department of Oncology, School of Medicine, Wayne State UniversityDetroit, MI, USA.
  7. Division of Pediatric Hematology/Oncology, Children's Hospital of MichiganDetroit, MI, USA; Department of Pediatrics, School of Medicine, Wayne State UniversityDetroit, MI, USA.
  8. Department of Pediatrics, School of Medicine, Wayne State UniversityDetroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State UniversityDetroit, MI, USA; Department of Oncology, School of Medicine, Wayne State UniversityDetroit, MI, USA.

PMID: 27725868 PMCID: PMC5040686

Abstract

Cure rates for acute myeloid leukemia (AML) remain suboptimal; thus new treatment strategies are needed for this deadly disease. Poor clinical outcomes have been associated with overexpression of the anti-apoptotic Bcl-2 family proteins Bcl-2, Bcl-xL, and Mcl-1, which have garnered great interest as therapeutic targets. While the Bcl-2-selective inhibitor ABT-199 has demonstrated promising preclinical anti-leukemic activities, intrinsic drug resistance remains a problem. In our most recent study, we identified Mcl-1 sequestration of Bim as a mechanism of intrinsic resistance to ABT-199 in AML cells, thus upregulating Bim could overcome such resistance. Histone deacetylase (HDAC) inhibitors (HDACI) are a class of agents that have been confirmed to upregulate Bim. This prompted our hypothesis that combining an HDACI with ABT-199 would overcome intrinsic resistance to ABT-199 and result in synergistic anti-leukemic activity against AML. In this study, we investigated the anti-leukemic activity of panobinostat, a pan-HDACI, in combination with ABT-199 in AML cell lines and primary patient samples. We found that the combined drug treatment resulted in synergistic induction of cell death in both AML cell lines and primary patient samples. Panobinostat treatment resulted in upregulation of Bim, which remained elevated in the presence of ABT-199. In addition, shRNA knockdown of Bim in AML cell lines significantly attenuated apoptosis induced by combined panobinostat and ABT-199. Our results provide compelling evidence that Bim plays a key role in the combined anti-leukemic activity of panobinostat and ABT-199 against AML, and support clinical evaluation of combined panobinostat and ABT-199 in the treatment of AML.

Keywords: ABT-199; Bcl-2; Bim; acute myeloid leukemia; panobinostat

References

  1. Blood. 2006 Feb 15;107(4):1570-81 - PubMed
  2. Pediatr Blood Cancer. 2014 Oct;61(10):1767-73 - PubMed
  3. N Engl J Med. 2016 Jan 28;374(4):311-22 - PubMed
  4. Cancer Biol Ther. 2015 ;16(12 ):1784-93 - PubMed
  5. Nat Med. 2013 Feb;19(2):202-8 - PubMed
  6. PLoS One. 2011 Feb 16;6(2):e17138 - PubMed
  7. Cell Death Dis. 2015 Jan 15;6:e1593 - PubMed
  8. Pharmacol Rev. 2006 Sep;58(3):621-81 - PubMed
  9. Clin Cancer Res. 2016 Sep 1;22(17):4440-51 - PubMed
  10. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16090-5 - PubMed
  11. Blood. 2009 Sep 24;114(13):2744-52 - PubMed
  12. PLoS One. 2013 Nov 11;8(11):e79106 - PubMed
  13. Cancer Lett. 2009 Aug 8;280(2):233-41 - PubMed
  14. Mol Cell Biol. 2009 Dec;29(23 ):6149-69 - PubMed
  15. Leukemia. 2014 Jul;28(7):1557-60 - PubMed
  16. Leuk Res. 1997 Apr;21(4):343-50 - PubMed
  17. Clin Cancer Res. 2011 Jun 15;17(12):3956-68 - PubMed
  18. Leukemia. 2015 Jun;29(6):1267-78 - PubMed
  19. Cancer Cell. 2013 Jul 8;24(1):120-9 - PubMed
  20. Leuk Lymphoma. 2012 Dec;53(12 ):2362-70 - PubMed
  21. Clin Cancer Res. 2010 Nov 15;16(22):5499-510 - PubMed
  22. J Hematol Oncol. 2014 Aug 01;7:53 - PubMed
  23. Leukemia. 2007 Aug;21(8):1773-82 - PubMed
  24. CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29 - PubMed
  25. J Pharmacol Exp Ther. 2001 Sep;298(3):865-72 - PubMed
  26. J Natl Cancer Inst. 2005 Feb 2;97(3):226-31 - PubMed
  27. Oncotarget. 2016 Jun 7;7(23):34785-99 - PubMed
  28. Drugs. 2015 Apr;75(6):695-704 - PubMed
  29. Oncogene. 2007 Aug 13;26(37):5541-52 - PubMed

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