Toosendanin induces the apoptosis of human Ewing's sarcoma cells via the mitochondrial apoptotic pathway

Gao,Tian; Xie,An; Liu,Xuqiang; Zhan,Haibo; Zeng,Jin; Dai,Min; Zhang,Bin

doi:10.3892/mmr.2019.10224

Toosendanin induces the apoptosis of human Ewing's sarcoma cells via the mitochondrial apoptotic pathway

Authors:
- Tian Gao
- An Xie
- Xuqiang Liu
- Haibo Zhan
- Jin Zeng
- Min Dai
- Bin Zhang
View Affiliations

Affiliations: Department of Orthopedics, Multidisciplinary Therapy Center of Musculoskeletal Tumor, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: May 9, 2019 https://doi.org/10.3892/mmr.2019.10224
Pages: 135-140
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Toosendanin, a triterpenoid extracted from the root bark of Melia toosendan, has its origin from traditional Chinese medicine and has been used as a non‑polluting and pesticide‑free plant insecticide in China for fruit and vegetable production. In recent years, toosendanin has been found to inhibit tumor cell proliferation and promote tumor cell apoptosis. Ewing's sarcoma (ES) is the second most common primary malignant bone and soft tissue tumor in children and adolescents. Although the overall prognosis of ES has improved, the 5‑year survival rate has not significantly increased. To analyze the role of toosendanin on ES progression, CCK‑8 viability assay, flow cytometry, Hoechst 33258 staining and western blotting were performed. The present results suggested that toosendanin suppressed cell viability and induced apoptosis in human SK‑ES‑1 cells compared with DMSO treatment. In addition, in the present study, toosendanin was found to upregulate the expression of Bax and downregulate the expression of Bcl‑2, altering the Bax/Bcl‑2 ratio. Additionally, toosendanin promoted the release of cytochrome c, resulting in the activation of the mitochondrial apoptotic pathway, thus inducing the activation of caspase‑9 and caspase‑3, and the cleavage of PARP. Our results demonstrated that toosendanin inhibited the growth of ES cells in a dose‑dependent manner and triggered mitochondrial apoptotic pathway to induce apoptosis. Therefore, toosendanin can potentially be utilized as an anticancer botanical drug for the treatment of ES.

View Figures

View References

1	Ahmed S, Anuntiyo J, Malemud CJ and Haqqi TM: Biological basis for the use of botanicals in osteoarthritis and rheumatoid arthritis: A review. Evid Based Complement Alternat Med. 2:301–308. 2005. View Article : Google Scholar : PubMed/NCBI
2	Zhang K, Wang X, Wang C, Zheng H, Li T, Xiao S, Wang M, Fei C, Zhang L and Xue F: Investigation of quinocetone-induced mitochondrial damage and apoptosis in HepG2 cells and compared with its metabolites. Environ Toxicol Pharmacol. 39:555–567. 2015. View Article : Google Scholar : PubMed/NCBI
3	Zhang J, Song J, Wu D, Wang J and Dong W: Hesperetin induces the apoptosis of hepatocellular carcinoma cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species, ATP and calcium. Med Oncol. 32:1012015. View Article : Google Scholar : PubMed/NCBI
4	Pieme CA, Santosh GK, Tekwu EM, Askun T, Aydeniz H, Ngogang JY, Bhushan S and Saxena AK: Fruits and barks extracts of Zanthozyllum heitzii a spice from Cameroon induce mitochondrial dependent apoptosis and G0/G1 phase arrest in human leukemia HL-60 cells. Biol Res. 47:542014. View Article : Google Scholar : PubMed/NCBI
5	Zhou Q, Wu X, Wen C, Wang H, Wang H, Liu H and Peng J: Toosendanin induces caspase-dependent apoptosis through the p38 MAPK pathway in human gastric cancer cells. Biochem Biophys Res Commun. 505:261–266. 2018. View Article : Google Scholar : PubMed/NCBI
6	Shi YL and Li MF: Biological effects of toosendanin, a triterpenoid extracted from Chinese traditional medicine. Prog Neurobiol. 82:1–10. 2007. View Article : Google Scholar : PubMed/NCBI
7	Pei Z, Fu W and Wang G: A natural product toosendanin inhibits epithelial-mesenchymal transition and tumor growth in pancreatic cancer via deactivating Akt/mTOR signaling. Biochem Biophys Res Commun. 493:455–460. 2017. View Article : Google Scholar : PubMed/NCBI
8	Zhang T, Li J, Yin F, Lin B, Wang Z, Xu J, Wang H, Zuo D, Wang G, Hua Y and Cai Z: Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3. Oncogene. 36:6627–6639. 2017. View Article : Google Scholar : PubMed/NCBI
9	Windsor R, Strauss S, Seddon B and Whelan J: Experimental therapies in Ewing's sarcoma. Expert Opin Investig Drugs. 18:143–159. 2009. View Article : Google Scholar : PubMed/NCBI
10	Teicher BA, Bagley RG, Rouleau C, Kruger A, Ren Y and Kurtzberg L: Characteristics of human Ewing/PNET sarcoma models. Ann Saudi Med. 31:174–182. 2011. View Article : Google Scholar : PubMed/NCBI
11	Zhang Z, Huang L, Yu Z, Chen X, Yang D, Zhan P, Dai M, Huang S, Han Z and Cao K: Let-7a functions as a tumor suppressor in Ewing's sarcoma cell lines partly by targeting cyclin-dependent kinase 6. DNA Cell Biol. 33:136–147. 2014. View Article : Google Scholar : PubMed/NCBI
12	Ross KA, Smyth NA, Murawski CD and Kennedy JG: The biology of ewing sarcoma. ISRN Oncol. 2013:7597252013.PubMed/NCBI
13	Scotlandi K: Targeted therapies in Ewing's sarcoma. Adv Exp Med Biol. 587:13–22. 2006. View Article : Google Scholar : PubMed/NCBI
14	Ye C, Yu X, Zeng J, Dai M and Zhang B: Effects of baicalein on proliferation, apoptosis, migration and invasion of Ewing's sarcoma cells. Int J Oncol. 51:1785–1792. 2017. View Article : Google Scholar : PubMed/NCBI
15	Cohen GM: Caspases: The executioners of apoptosis. Biochem J. 326:1–16. 1997. View Article : Google Scholar : PubMed/NCBI
16	Singhal S, Vachani A, Antin-Ozerkis D, Kaiser LR and Albelda SM: Prognostic implications of cell cycle, apoptosis, and angiogenesis biomarkers in non-small cell lung cancer: A review. Clin Cancer Res. 11:3974–3986. 2005. View Article : Google Scholar : PubMed/NCBI
17	Viktorsson K, Lewensohn R and Zhivotovsky B: Apoptotic pathways and therapy resistance in human malignancies. Adv Cancer Res. 94:1432005. View Article : Google Scholar : PubMed/NCBI
18	Tada K, Takido M and Kitanaka S: Limonoids from fruit of Melia toosendan and their cytotoxic activity. Phytochemistry. 51:787–791. 1999. View Article : Google Scholar : PubMed/NCBI
19	Zhang B, Wang ZF, Tang MZ and Shi YL: Growth inhibition and apoptosis-induced effect on human cancer cells of toosendanin, a triterpenoid derivative from chinese traditional medicine. Invest New Drugs. 23:547–553. 2005. View Article : Google Scholar : PubMed/NCBI
20	He Y, Wang J, Liu X, Zhang L, Yi G, Li C, He X, Wang P and Jiang H: Toosendanin inhibits hepatocellular carcinoma cells by inducing mitochondria-dependent apoptosis. Planta Med. 76:1447–1453. 2010. View Article : Google Scholar : PubMed/NCBI
21	Ju J, Qi Z, Cai X, Cao P, Liu N, Wang S and Chen Y: Toosendanin induces apoptosis through suppression of JNK signaling pathway in HL-60 cells. Toxicol In Vitro. 27:232–238. 2013. View Article : Google Scholar : PubMed/NCBI
22	Wang X: The expanding role of mitochondria in apoptosis. Genes Dev. 15:2922–2933. 2001.PubMed/NCBI
23	Wang C and Youle RJ: The role of mitochondria in apoptosis*. Annu Rev Genet. 43:95–118. 2009. View Article : Google Scholar : PubMed/NCBI
24	Lu X, Ji C, Tong W, Lian X, Wu Y, Fan X and Gao Y: Integrated analysis of microRNA and mRNA expression profiles highlights the complex and dynamic behavior of toosendanin-induced liver injury in mice. Sci Rep. 6:342252016. View Article : Google Scholar : PubMed/NCBI