Advertisement

Applied Microbiology and Biotechnology

, Volume 98, Issue 23, pp 9763–9775 | Cite as

Tyrosine kinase inhibitor Thiotanib targets Bcr-Abl and induces apoptosis and autophagy in human chronic myeloid leukemia cells

  • Jiajun Fan
  • Xiaochun Dong
  • Weixing Zhang
  • Xian Zeng
  • Yubin Li
  • Yun Sun
  • Shaofei Wang
  • Ziyu Wang
  • Hongjian Gao
  • Weili ZhaoEmail author
  • Dianwen JuEmail author
Applied microbial and cell physiology

Abstract

Chronic myeloid leukemia (CML) is characterized by abnormal Bcr and Abl genes and enhanced tyrosine kinase activity. Anti-CML therapy has been much improved along with the applications of tyrosine kinase inhibitors (TKIs) which selectively target Bcr-Abl and have a cytotoxic effect on CML. Recently, four-membered heterocycles as “compact modules” have attracted much interest in drug discovery. Grafting these small four-membered heterocycles onto a molecular scaffold could probably provide compounds that retain notable activity and populate chemical space otherwise not previously accessed. Accordingly, a novel TKI, Thiotanib, has been designed and synthesized. It selectively targets Bcr-Abl, inducing growth inhibition, cell cycle arrest, and apoptosis of CML cells. Meanwhile, the compound Thiotanib could also induce autophagy in CML cells. Interestingly, inhibition of autophagy promotes Thiotanib-induced apoptosis with no further activation of caspase 3, while inhibition of caspases did not affect the cell survival of CML cells. Moreover, the compound Thiotanib could inhibit phosphorylation of Akt and mTOR, increase beclin-1 and Vps34, and block the formation of the Bcl-2 and Beclin-1 complex. This indicates the probable pathway of autophagy initiation. Our results highlight a new approach for TKI reforming and further provide an indication of the efficacy enhancement of TKIs in combination with autophagy inhibitors.

Keywords

Chronic myeloid leukemia Bcr-Abl Tyrosine kinase inhibitor Compound Thiotanib Apoptosis Autophagy 

Notes

Acknowledgments

This work was supported by the Shanghai Science and Technology Fund (11431920104), and Shanghai Municipal Science & Technology Pillar Program for Bio-Pharmaceuticals (13431900102). The funders had no roles in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors declare that they have no competing financial interests.

Supplementary material

253_2014_6003_MOESM1_ESM.pdf (1.3 mb)
ESM 1 (PDF 1290 kb)

References

  1. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117:326–336PubMedCentralPubMedCrossRefGoogle Scholar
  2. Asaki T, Sugiyama Y, Hamamoto T, Higashioka M, Umehara M, Naito H, Niwa T (2006) Design and synthesis of 3-substituted benzamide derivatives as Bcr- Abl kinase inhibitors. Bioorg Med Chem Lett 16:1421–1425PubMedCrossRefGoogle Scholar
  3. Bedi A, Zehnbauer BA, Barber JP, Sharkis S, Jones R (1994) Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood 83:2038–2044PubMedGoogle Scholar
  4. Belloc F, Moreau-Gaudry F, Uhalde M, Cazalis L, Jeanneteau M, Lacombe F, Praloran V, Mahon FX. (2007) Imatinib and nilotinib induce apoptosis of chronic myeloid leukemia cells through a Bim-dependant pathway modulated by cytokines. Cancer Biol Ther 6:912–9Google Scholar
  5. Bixby D, Talpaz M (2009) Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. ASH Educ Prog Book 2009:461–476Google Scholar
  6. Boularan C, Kamenyeva O, Cho H, Kehrl JH (2014) Resistance to inhibitors of cholinesterase (Ric)-8A and Gαi contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps)34 activity. Plos One 9:e86680PubMedCentralPubMedCrossRefGoogle Scholar
  7. Burkhard JA, Wagner B, Fischer H, Schuler F, Müller K, Carreira EM (2010) Synthesis of azaspirocycles and their evaluation in drug discovery. Angew Chem Int Ed Engl 49:3524–3527PubMedCrossRefGoogle Scholar
  8. Chan LL, Shen D, Wilkinson AR, Patton W, Lai N, Chan E, Kuksin D, Lin B, Qiu J (2012) A novel image-based cytometry method for autophagy detection in living cells. Autophagy 8:1371–1382PubMedCentralPubMedCrossRefGoogle Scholar
  9. Cortez D, Stoica G, Pierce JH, Pendergast AM (1996) The BCR-ABL tyrosine kinase inhibits apoptosis by activating a Ras-dependent signaling pathway. Oncogene 13:2589PubMedGoogle Scholar
  10. Du YW, Chen JG, Bai HL, Huang HY, Wang J, Li SL, Liu GC, Jiang Q, Chai J, Zhao YP, Ma YF (2011) A novel agonistic anti-human death receptor 5 monoclonal antibody with tumoricidal activity induces caspase- and mitochondrial-dependent apoptosis in human leukemia Jurkat cells. Cancer Biother Radiopharm 26:143–152PubMedCrossRefGoogle Scholar
  11. Faderl S, Talpaz M, Estrov Z, O´Brien S, Kurzrock R, Kantarjian HM (1999) The biology of chronic myeloid leukemia. N Engl J Med 341:164–172PubMedCrossRefGoogle Scholar
  12. Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891–2906PubMedCrossRefGoogle Scholar
  13. Jin S, White E (2007) Role of autophagy in cancer: management of metabolic stress. Autophagy 3:28–31PubMedCentralPubMedCrossRefGoogle Scholar
  14. Kim JE, Yoon S, Choi BR, Kim KP, Cho YH, Jung W, Kim DW, Oh S, Kim DE (2013) Cleavage of BCR-ABL transcripts at the T315I point mutation by DNAzyme promotes apoptotic cell death in imatinib-resistant BCR-ABL leukemic cells. Leukemia 27:1560–1568Google Scholar
  15. Kompella A, Adibhatla BRK, Muddasani PR, Rachakonda S, Gampa VK, Dubey PK (2012) A facile total synthesis for large-scale production of imatinib base. Org Process Res Dev 16:1794–1804CrossRefGoogle Scholar
  16. Kumari S, Mehta SL, Li PA (2012) Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium. PLoS One 7:e39382PubMedCentralPubMedCrossRefGoogle Scholar
  17. Li X, Fan Z (2010) The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex. Cancer Res 70:5942–5952PubMedCentralPubMedCrossRefGoogle Scholar
  18. Li X, Lu Y, Pan T, Fan Z (2010) Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy 6:1066–1077PubMedCentralPubMedCrossRefGoogle Scholar
  19. Li Y, Zhu H, Zeng X, Fan J, Qian X, Wang S, Wang Z, Sun Y, Wang X, Wang W, Ju D (2013) Suppression of autophagy enhanced growth inhibition and apoptosis of interferon-β in human glioma cells. Mol Neurobiol 47:1000–1010PubMedCrossRefGoogle Scholar
  20. Lugo TG, Pendergast A-M, Muller AJ, Witte ON (1990) Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247:1079PubMedCrossRefGoogle Scholar
  21. Maru Y (2012) Molecular biology of chronic myeloid leukemia. Cancer Sci 103:1601–1610PubMedCrossRefGoogle Scholar
  22. Mofarrahi M, Guo Y, Haspel J, Choi AM, Davis EC, Gouspillou G, Hepple RT, Godin R, Burelle Y, Hussain SN (2013) Autophagic flux and oxidative capacity of skeletal muscles during acute starvation. Autophagy 9:1604–1620PubMedCrossRefGoogle Scholar
  23. Mughal A, Aslam HM, Khan AM, Saleem S, Umah R, Saleem M (2013) Bcr-Abl tyrosine kinase inhibitors—current status. Infect Agent Cancer 8:23PubMedCentralPubMedCrossRefGoogle Scholar
  24. Ohanian M, Cortes J, Kantarjian H, Jabbour E (2012) Tyrosine kinase inhibitors in acute and chronic leukemias. Expert Opin Pharmacother 13:927–938PubMedCrossRefGoogle Scholar
  25. Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P (2008) Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 90:313–323PubMedCrossRefGoogle Scholar
  26. Proenca CC, Stoehr N, Bernhard M, Seger S, Genoud C, Roscic A, Paganetti P, Liu S, Murphy LO, Kuhn R, Bouwmeester T, Galimberti I (2013) Atg4b-dependent autophagic flux alleviates Huntington’s disease progression. PLoS One 8:e68357PubMedCentralPubMedCrossRefGoogle Scholar
  27. Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330:1344–1348PubMedCentralPubMedCrossRefGoogle Scholar
  28. Ren R (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5:172–183PubMedCrossRefGoogle Scholar
  29. Russell RC, Yuan HX, Guan KL (2014) Autophagy regulation by nutrient signaling. Cell Res 24:42–57PubMedCrossRefGoogle Scholar
  30. Sun MX, Huang L, Wang R, Yu YL, Li C, Li PP, Hu XC, Hao HP, Ishag HA, Mao X (2012) Porcine reproductive and respiratory syndrome virus induces autophagy to promote virus replication. Autophagy 8:1434–1447PubMedCrossRefGoogle Scholar
  31. Tait SW, Green DR (2008) Caspase-independent cell death: leaving the set without the final cut. Oncogene 27:6452–6461PubMedCentralPubMedCrossRefGoogle Scholar
  32. Tanida I (2011) Autophagy basics. Microbiol Immunol 55:1–11PubMedCrossRefGoogle Scholar
  33. Tatarkova Z, Kuka S, Petráš M, Račay P, Lehotský J, Dobrota D, Kaplan P (2012) Why mitochondria are excellent targets for cancer therapy. Klin Onkol 25:421–426PubMedGoogle Scholar
  34. Tsai SC, Yang JS, Peng SF, Lu CC, Chiang JH, Chung JG, Lin MW, Lin JK, Amagaya S, Wai-Shan Chung C, Tung TT, Huang WW, Tseng MT (2012) Bufalin increases sensitivity to AKT/mTOR-induced autophagic cell death in SK-HEP-1 human hepatocellular carcinoma cells. Int J Oncol 41:1431–1442PubMedGoogle Scholar
  35. Wang Z, Shi X, Li Y, Zeng X, Fan J, Sun Y, Xian Z, Zhang G, Wang S, Hu H, Ju D (2014) Involvement of autophagy in recombinant human arginase-induced cell apoptosis and growth inhibition of malignant melanoma cells. Appl Microbiol Biotechnol 98:2485–2494PubMedCrossRefGoogle Scholar
  36. Wong PM, Puente C, Ganley IG, Jiang X (2013) The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 9:124–137PubMedCentralPubMedCrossRefGoogle Scholar
  37. Wuitschik G, Rogers-Evans M, Müller K, Fischer H, Wagner B, Schuler F, Polonchuk L, Carreira EM (2006) Angew Chem Int Ed 45:7736–7739CrossRefGoogle Scholar
  38. Wuitschik G, Carreira EM, Wagner B, Fischer H, Parrilla I, Schuler F, Rogers-Evans M, Müller K (2010) J Med Chem 53:3227–3246PubMedCrossRefGoogle Scholar
  39. Yuan HX, Russell RC, Guan KL (2013) Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy 9:1983–1995PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jiajun Fan
    • 1
  • Xiaochun Dong
    • 1
  • Weixing Zhang
    • 1
  • Xian Zeng
    • 1
  • Yubin Li
    • 1
  • Yun Sun
    • 1
  • Shaofei Wang
    • 1
  • Ziyu Wang
    • 1
  • Hongjian Gao
    • 1
  • Weili Zhao
    • 1
    • 2
    Email author
  • Dianwen Ju
    • 1
    Email author
  1. 1.School of PharmacyFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Key Laboratory for Special Functional Materials of the Ministry of EducationHenan UniversityKaifengPeople’s Republic of China

Personalised recommendations