Skip to main content

Advertisement

SpringerLink
Log in

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

  • Applied microbial and cell physiology
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • 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 117:326–336

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 16:1421–1425

    Article  CAS  PubMed  Google Scholar 

  • Bedi A, Zehnbauer BA, Barber JP, Sharkis S, Jones R (1994) Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood 83:2038–2044

    CAS  PubMed  Google Scholar 

  • 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 6:912–9

  • 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 2009:461–476

    Google Scholar 

  • 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:e86680

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 49:3524–3527

    Article  CAS  PubMed  Google Scholar 

  • 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 8:1371–1382

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cortez D, Stoica G, Pierce JH, Pendergast AM (1996) The BCR-ABL tyrosine kinase inhibits apoptosis by activating a Ras-dependent signaling pathway. Oncogene 13:2589

    CAS  PubMed  Google Scholar 

  • 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 26:143–152

    Article  CAS  PubMed  Google Scholar 

  • Faderl S, Talpaz M, Estrov Z, O´Brien S, Kurzrock R, Kantarjian HM (1999) The biology of chronic myeloid leukemia. N Engl J Med 341:164–172

    Article  CAS  PubMed  Google Scholar 

  • Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891–2906

    Article  CAS  PubMed  Google Scholar 

  • Jin S, White E (2007) Role of autophagy in cancer: management of metabolic stress. Autophagy 3:28–31

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 27:1560–1568

    Google Scholar 

  • 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 16:1794–1804

    Article  CAS  Google Scholar 

  • Kumari S, Mehta SL, Li PA (2012) Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium. PLoS One 7:e39382

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 70:5942–5952

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li X, Lu Y, Pan T, Fan Z (2010) Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy 6:1066–1077

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 47:1000–1010

    Article  CAS  PubMed  Google Scholar 

  • Lugo TG, Pendergast A-M, Muller AJ, Witte ON (1990) Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247:1079

    Article  CAS  PubMed  Google Scholar 

  • Maru Y (2012) Molecular biology of chronic myeloid leukemia. Cancer Sci 103:1601–1610

    Article  CAS  PubMed  Google Scholar 

  • 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 9:1604–1620

    Article  CAS  PubMed  Google Scholar 

  • Mughal A, Aslam HM, Khan AM, Saleem S, Umah R, Saleem M (2013) Bcr-Abl tyrosine kinase inhibitors—current status. Infect Agent Cancer 8:23

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ohanian M, Cortes J, Kantarjian H, Jabbour E (2012) Tyrosine kinase inhibitors in acute and chronic leukemias. Expert Opin Pharmacother 13:927–938

    Article  CAS  PubMed  Google Scholar 

  • Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P (2008) Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 90:313–323

    Article  CAS  PubMed  Google Scholar 

  • 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:e68357

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330:1344–1348

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ren R (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5:172–183

    Article  CAS  PubMed  Google Scholar 

  • Russell RC, Yuan HX, Guan KL (2014) Autophagy regulation by nutrient signaling. Cell Res 24:42–57

    Article  CAS  PubMed  Google Scholar 

  • 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 8:1434–1447

    Article  CAS  PubMed  Google Scholar 

  • Tait SW, Green DR (2008) Caspase-independent cell death: leaving the set without the final cut. Oncogene 27:6452–6461

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tanida I (2011) Autophagy basics. Microbiol Immunol 55:1–11

    Article  CAS  PubMed  Google Scholar 

  • 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 25:421–426

    CAS  PubMed  Google Scholar 

  • 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 41:1431–1442

    CAS  PubMed  Google Scholar 

  • 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 98:2485–2494

    Article  CAS  PubMed  Google Scholar 

  • Wong PM, Puente C, Ganley IG, Jiang X (2013) The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 9:124–137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wuitschik G, Rogers-Evans M, Müller K, Fischer H, Wagner B, Schuler F, Polonchuk L, Carreira EM (2006) Angew Chem Int Ed 45:7736–7739

    Article  CAS  Google Scholar 

  • Wuitschik G, Carreira EM, Wagner B, Fischer H, Parrilla I, Schuler F, Rogers-Evans M, Müller K (2010) J Med Chem 53:3227–3246

    Article  CAS  PubMed  Google Scholar 

  • Yuan HX, Russell RC, Guan KL (2013) Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy 9:1983–1995

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People’s Republic of China

    Jiajun Fan, Xiaochun Dong, Weixing Zhang, Xian Zeng, Yubin Li, Yun Sun, Shaofei Wang, Ziyu Wang, Hongjian Gao, Weili Zhao & Dianwen Ju

  2. Key Laboratory for Special Functional Materials of the Ministry of Education, Henan University, Kaifeng, 475004, People’s Republic of China

    Weili Zhao

Authors
  1. Jiajun Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaochun Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weixing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xian Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yubin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shaofei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ziyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hongjian Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Weili Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dianwen Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Weili Zhao or Dianwen Ju.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 1290 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, J., Dong, X., Zhang, W. et al. Tyrosine kinase inhibitor Thiotanib targets Bcr-Abl and induces apoptosis and autophagy in human chronic myeloid leukemia cells. Appl Microbiol Biotechnol 98, 9763–9775 (2014). https://doi.org/10.1007/s00253-014-6003-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-014-6003-1

Keywords

Search

Navigation