Salinomycin inhibits the tumor growth of glioma stem cells by selectively suppressing glioma-initiating cells

Chen,Tunan; Yi,Liang; Li,Fei; Hu,Rong; Hu,Shengli; Yin,Yi; Lan,Chuan; Li,Zhao; Fu,Chuhua; Cao,Liu; Chen,Zhi; Xian,Jishu; Feng,Hua

doi:10.3892/mmr.2014.3027

Salinomycin inhibits the tumor growth of glioma stem cells by selectively suppressing glioma-initiating cells

Authors:
- Tunan Chen
- Liang Yi
- Fei Li
- Rong Hu
- Shengli Hu
- Yi Yin
- Chuan Lan
- Zhao Li
- Chuhua Fu
- Liu Cao
- Zhi Chen
- Jishu Xian
- Hua Feng
View Affiliations

Affiliations: Department of Neurosurgery, Southwest Hospital, Chongqing 400038, P.R. China, Department of Neurosurgery, Daping Hospital, Chongqing 400042, P.R. China
Published online on: December 1, 2014 https://doi.org/10.3892/mmr.2014.3027
Pages: 2407-2412
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

Glioma‑initiating cells are a small population of cells that have the ability to undergo self‑renewal and initiate tumorigenesis. In the present study, the potential role of salinomycin, a polyether antibiotic, on the suppression of glioma cell growth was investigated. GL261 glioma cells were maintained in a stem‑cell‑like status [GL261 neurospheres (GL261‑NS)] or induced for differentiation [GL261 adherent cells (GL261‑AC)]. It was demonstrated that salinomycin significantly reduced the cell viability of GL261‑NS and GL261‑AC cells in a dose‑dependent manner, with a more substantial inhibition of GL261‑NS proliferation (P<0.05). The inhibitory effect of salinomycin on cell growth was more effective than that of 1‑(4‑amino‑2‑methyl‑5‑pyrimid l)‑methyl‑3‑(2‑chloroethyl)‑3‑nitrosourea hydrochloride and vincristine (P<0.05). Salinomycin depleted GL261‑NS from tumorspheres and induced cell apoptosis. In addition, salinomycin prolonged the median survival time of glioma‑bearing mice (P<0.05). Therefore, the present study indicated that salinomycin may preferentially inhibit glioma‑initiated cell growth by inducing apoptosis, suggesting that salinomycin may provide a valuable therapeutic strategy for the treatment of malignant glioma.

View Figures

View References

1	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
2	Stiles CD and Rowitch DH: Glioma stem cells: a midterm exam. Neuron. 58:832–846. 2008. View Article : Google Scholar : PubMed/NCBI
3	Vescovi AL, Galli R and Reynolds BA: Brain tumour stem cells. Nat Rev Cancer. 6:425–436. 2006. View Article : Google Scholar : PubMed/NCBI
4	Natsume A, Kinjo S, Yuki K, et al: Glioma-initiating cells and molecular pathology: implications for therapy. Brain Tumor Pathol. 28:1–12. 2011. View Article : Google Scholar : PubMed/NCBI
5	Eramo A, Ricci-Vitiani L, Zeuner A, et al: Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 13:1238–1241. 2006. View Article : Google Scholar : PubMed/NCBI
6	Miyazaki Y, Shibuya M, Sugawara H, Kawaguchi O and Hirsoe C: Salinomycin, a new polyether antibiotic. J Antibiot (Tokyo). 27:814–821. 1974. View Article : Google Scholar
7	Mitani M, Yamanishi T, Miyazaki Y and Ōtake N: Salinomycin effects on mitochondrial ion translocation and respiration. Antimicrob Agents Chemother. 9:655–660. 1976. View Article : Google Scholar : PubMed/NCBI
8	Gupta PB, Onder TT, Jiang G, et al: Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 138:645–659. 2009. View Article : Google Scholar : PubMed/NCBI
9	Riccioni R, Dupuis Ml, Bernabei M, et al: The cancer stem cell selective inhibitor salinomycin is a p-glycoprotein inhibitor. Blood Cells Mol Dis. 45:86–92. 2010. View Article : Google Scholar : PubMed/NCBI
10	Fuchs D, Heinold A, Opelz G, Daniel V and Naujokat C: Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem Biophys Res Commun. 390:743–749. 2009. View Article : Google Scholar : PubMed/NCBI
11	Franklin KBJ and Paxinos G: The Mouse Brain in Stereotaxic Coordinates. 2nd edition. Academic Press; San Diego: pp. 49–95. 1997
12	Bao S, Wu Q, McLendon RE, et al: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
13	Piccirillo SG, Reynolds BA, Zanetti N, et al: Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 444:761–765. 2006. View Article : Google Scholar : PubMed/NCBI
14	Galli R, Binda E, Orfanelli U, et al: Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64:7011–7021. 2004. View Article : Google Scholar : PubMed/NCBI
15	Singh SK, Hawkins C, Clarke ID, et al: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
16	Singh SK, Clarke ID, Terasaki M, et al: Identification of a cancer stem cell in human brain tumors. Cancer Res. 63:5821–5828. 2003.PubMed/NCBI
17	Beier D, Hau P, Proescholdt M, et al: CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67:4010–4015. 2007. View Article : Google Scholar : PubMed/NCBI
18	Joo KM, Kim SY, Jin X, et al: Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest. 88:808–815. 2008. View Article : Google Scholar : PubMed/NCBI
19	Yi L, Zhou C, Wang B, et al: Implantation of GL261 neurospheres into C57/BL6 mice: A more reliable syngeneic graft model for research on glioma-initiating cells. Int J Oncol. 43:477–484. 2013.PubMed/NCBI
20	Sarkaria JN, Kitange GJ, James CD, et al: Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res. 14:2900–2908. 2008. View Article : Google Scholar : PubMed/NCBI
21	Singh A and Settleman J: EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 29:4741–4751. 2010. View Article : Google Scholar : PubMed/NCBI
22	Kim KY, Yu SN, Lee SY, et al: Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization. Biochem Biophys Res Commun. 413:80–86. 2011. View Article : Google Scholar : PubMed/NCBI