13-Oxyingenol dodecanoate, a cytotoxic ingenol derivative, induces mitochondrial apoptosis and caspase-dependent Akt decrease in K562 cells
- 243 Downloads
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.
Keywords13-Oxyingenol dodecanoate Apoptosis Euphorbia kansui mTOR Akt
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).
Compliance with ethical standards
Conflicts of interest
- 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).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.CrossRefPubMedPubMedCentralGoogle 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.PubMedGoogle 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.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
- 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.CrossRefPubMedGoogle Scholar