Skip to main content

Advertisement

SpringerLink
Log in

13-Oxyingenol dodecanoate, a cytotoxic ingenol derivative, induces mitochondrial apoptosis and caspase-dependent Akt decrease in K562 cells

  • Original Article
  • Published:
Tumor Biology

Abstract

13-Oxyingenol dodecanoate (13OD) is an ingenol derivative prepared from Chinese traditional medicine Euphorbia kansui without any report about its bioactivity. The present study demonstrated for the first time that 13OD displayed potent cytotoxicity against chronic myeloid leukemia K562 cells in vitro. 13OD inhibited proliferation, induced G2/M phase arrest, and exhibited potent apoptotic activity in K562 cells. In K562 cells, 13OD disrupted the mitochondrial membrane potential and induced high level of ROS, which played an indispensable role in 13OD-induced apoptosis. Further investigations on the molecular mechanisms revealed that total Akt protein level was decreased in a caspase-dependent way after treatment with 13OD; in addition, ERK was activated by 13OD, and this activation played a protective role in 13OD stimulation. Altogether, these results revealed that the cytotoxic ingenol derivative 13OD induced apoptosis with novel mechanisms for the proapoptotic function in cancer cells, and suggested that 13OD may serve as a lead template for rational drug design and for future anticancer agent development.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer. 2007;7(5):345–56.

    Article  CAS  PubMed  Google Scholar 

  2. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK//STAT, Raf//MEK//ERK, PI3K//Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004;18(2):189–218.

    Article  CAS  PubMed  Google Scholar 

  3. Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Muller-Brusselbach S, et al. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia. 2005;19(10):1774–82.

    Article  CAS  PubMed  Google Scholar 

  4. Wong S-F, Mirshahidi H. Use of tyrosine kinase inhibitors for chronic myeloid leukemia: management of patients and practical applications for pharmacy practitioners. Ann Pharmacother. 2011;45(6):787–97. doi:10.1345/aph.1P784.

    Article  CAS  PubMed  Google Scholar 

  5. Roychowdhury S, Talpaz M. Managing resistance in chronic myeloid leukemia. Blood Rev. 2011;25(6):279–90. doi:10.1016/j.blre.2011.09.001.

    Article  PubMed  Google Scholar 

  6. Abreu CM, Price SL, Shirk EN, Cunha RD, Pianowski LF, Clements JE et al. Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR. PLoS One. 2014;9(5).

  7. Jiang G, Mendes EA, Kaiser P, Sankaran-Walters S, Tang Y, Weber MG, et al. Reactivation of HIV latency by a newly modified ingenol derivative via protein kinase Cdelta-NF-kappaB signaling. Aids. 2014;28(11):1555–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fujiwara M, Ijichi K, Konno K, Yokota T, Tokuhisa K, Katsuura K, et al. Ingenol derivatives, ingredient of ‘Kansui’, are highly potent inhibitor of HIV. Antivir Res. 1995;26(3):A228. doi:10.1016/0166-3542(95)94704-6.

    Article  Google Scholar 

  9. Benhadji KA, Serova M, Ghoul A, Cvitkovic E, Le Tourneau C, Ogbourne SM, et al. Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells. Br J Cancer. 2008;99(11):1808–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liang X, Grue-Sorensen G, Mansson K, Vedso P, Soor A, Stahlhut M, et al. Syntheses, biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer. Bioorg Med Chem Lett. 2013;23(20):5624–9.

    Article  CAS  PubMed  Google Scholar 

  11. Aditya S, Gupta S. Ingenol mebutate: a novel topical drug for actinic keratosis. Indian Dermatol Online J. 2013;4(3):246–9. doi:10.4103/2229-5178.115538.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tzogani K, Nagercoil N, Hemmings RJ, Samir B, Gardette J, Demolis P, et al. The European medicines agency approval of ingenol mebutate (Picato) for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults: Summary of the scientific assessment of the committee for medicinal products for human use (CHMP). Eur J Dermatol. 2014;24(4):457–63.

    CAS  PubMed  Google Scholar 

  13. Uemura D, Hirata Y, Yuh-Pan C, Hong-Yen H. New diterpene, 13-oxyingenol, derivative isolated from euphorbia kansui liou. Tetrahedron Lett. 1974;15(29):2529–32. doi:10.1016/S0040-4039(01)93197-1.

    Article  Google Scholar 

  14. Song X, Zhao Z, Qi X, Tang S, Wang Q, Zhu T et al. Identification of epipolythiodioxopiperazines HDN-1 and chaetocin as novel inhibitor of heat shock protein 90. Oncotarget. 2015;6(7):5263–74.

  15. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009;122(Pt 4):437–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zeng C-W, Zhang X-J, Lin K-Y, Ye H, Feng S-Y, Zhang H, et al. Camptothecin induces apoptosis in cancer cells via microRNA-125b-mediated mitochondrial pathways. Mol Pharmacol. 2012;81(4):578–86. doi:10.1124/mol.111.076794.

    Article  CAS  PubMed  Google Scholar 

  17. Timme CR, Gruidl M, Yeatman TJ. Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells. Apoptosis. 2013;18(10):1163–74.

    Article  CAS  PubMed  Google Scholar 

  18. Hampson P, Chahal H, Khanim F, Hayden R, Mulder A, Assi LK, et al. PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood. 2005;106(4):1362–8.

    Article  CAS  PubMed  Google Scholar 

  19. Bhagatte Y, Lodwick D, Storey N. Mitochondrial ROS production and subsequent ERK phosphorylation are necessary for temperature preconditioning of isolated ventricular myocytes. Cell Death Dis. 2012;5(3):84.

    Google Scholar 

  20. Wang X, Martindale JL, Holbrook NJ. Requirement for ERK activation in cisplatin-induced apoptosis. J Biol Chem. 2000;275(50):39435–43.

    Article  CAS  PubMed  Google Scholar 

  21. Mann KK, Colombo M, Miller Jr WH. Arsenic trioxide decreases AKT protein in a caspase-dependent manner. Mol Cancer Ther. 2008;7(6):1680–7.

    Article  CAS  PubMed  Google Scholar 

  22. Kim T, Keum G, Pae AN. Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives. Expert Opin Ther Pat. 2013;23(8):919–43.

    Article  CAS  PubMed  Google Scholar 

  23. Beck R, Dejeans N, Glorieux C, Creton M, Delaive E, Dieu M, et al. Hsp90 is cleaved by reactive oxygen species at a highly conserved N-terminal amino acid motif. PLoS One. 2012;7(7):e40795. doi:10.1371/journal.pone.0040795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem. 2002;277(42):39858–66.

    Article  CAS  PubMed  Google Scholar 

  25. Martin D, Salinas M, Fujita N, Tsuruo T, Cuadrado A. Ceramide and reactive oxygen species generated by H2O2 induce caspase-3-independent degradation of Akt/protein kinase B. J Biol Chem. 2002;277(45):42943–52.

    Article  CAS  PubMed  Google Scholar 

  26. Nambudiri V. From home remedy to cancer treatment: a history of ingenol mebutate and euphorbia peplus in dermatology. J Am Acad Dermatol. 2013;68(4, Supplement 1):AB33. doi:10.1016/j.jaad.2012.12.141.

    Google Scholar 

  27. Kroemer G. Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun. 2003;304(3):433–5.

    Article  CAS  PubMed  Google Scholar 

  28. Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25(34):4798–811. doi:10.1038/sj.onc.1209608.

    Article  CAS  PubMed  Google Scholar 

  29. Polivka Jr J, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142(2):164–75. doi:10.1016/j.pharmthera.2013.12.004.

    Article  CAS  PubMed  Google Scholar 

  30. Serova M, Ghoul A, Benhadji KA, Faivre S, Le Tourneau C, Cvitkovic E, et al. Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol Cancer Ther. 2008;7(4):915–22.

    Article  CAS  PubMed  Google Scholar 

  31. Mas VM, Hernandez H, Plo I, Bezombes C, Maestre N, Quillet-Mary A, et al. Protein kinase Czeta mediated Raf-1/extracellular-regulated kinase activation by daunorubicin. Blood. 2003;101(4):1543–50.

    Article  PubMed  Google Scholar 

  32. Xiao RZ, He CM, Xiong MJ, Ruan XX, Wang LL, Chen Y, et al. Inhibition of extracellular signal-regulated kinase activity by sorafenib increases sensitivity to DNR in K562 cells. Oncol Rep. 2013;29(5):1895–901.

    CAS  PubMed  Google Scholar 

  33. Gores GJ, Kaufmann SH. Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors. Genes Dev. 2012;26(4):305–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kedei N, Lundberg DJ, Toth A, Welburn P, Garfield SH, Blumberg PM. Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004;64(9):3243–55.

    Article  CAS  PubMed  Google Scholar 

  35. Medina EA, Afsari RR, Ravid T, Castillo SS, Erickson KL, Goldkorn T. Tumor necrosis factor-{alpha} decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt. Endocrinology. 2005;146(6):2726–35.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the NSFC-Shandong Joint Fund (No. U1406402), the Natural Science Foundation of China (No. 81373323), the Natural Science Foundation of the Shandong Province (No. ZR2012CM005, No. ZR2015HM010), and the Young Talent Project at Ocean University of China (No. 201412007).

Author information

Authors and Affiliations

  1. Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China

    Ming Liu, Weiyi Zhang, Genzhu Wang, Xiaoping Song, Xin Qi & Jing Li

  2. Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden, Mem. Sun Yat-sen), Nanjing, 210014, China

    Xingzeng Zhao

  3. Nanjing Spring & Autumn Biological Engineering Co., Ltd, China, Nanjing, 210014, China

    Xiangyun Wang

Authors
  1. Ming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weiyi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Genzhu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoping Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xingzeng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiangyun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xin Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing Li.

Ethics declarations

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, M., Zhang, W., Wang, G. et al. 13-Oxyingenol dodecanoate, a cytotoxic ingenol derivative, induces mitochondrial apoptosis and caspase-dependent Akt decrease in K562 cells. Tumor Biol. 37, 6227–6238 (2016). https://doi.org/10.1007/s13277-015-4495-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4495-7

Keywords

Search

Navigation