Glioma stem cells (GSCs) contribute to tumor recurrence and drug resistance. This study characterizes the tumorigenesis of CD133+ cells and their sensitivity to pharmacological inhibition.
GSCs from human U87 and rat C6 glioblastoma cell lines were isolated via magnetic cell sorting using CD133 as a cancer stem cell marker. Cell proliferation was determined using the WST-1 assay. An intracranial mouse model and bioluminescence imaging were used to assess the effects of drugs on tumor growth in vivo.
CD133+ cells expressed stem cell markers and exhibited self-renewal and enhanced tumor formation. Minocycline (Mino) was more effective in reducing the survival rate of CD133+ cells, whereas CD133− cells were more sensitive to inhibition by the signal transducer and activator of transcription 3 (STAT3) inhibitor. Inhibition of STAT3 decreased the expression of CD133+ stem cell markers. The combination of Mino and STAT3 inhibitor synergistically reduced the cell viability of glioma cells. Furthermore, this combination synergistically suppressed tumor growth in nude mice.
The results suggest that concurrent targeting of different subpopulations of glioblastoma cells may be an effective therapeutic strategy for patients with malignant glioma.
Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8. PubMed
Stupp R, Hegi ME. Targeting brain-tumor stem cells. Nat Biotech. 2007;25:193–4. CrossRef
Annabi B, Lachambre MP, Plouffe K, Sartelet H, Beliveau R. Modulation of Invasive Properties of CD133(+) Glioblastoma Stem Cells: A Role for MT1-MMP in Bioactive Lysophospholipid Signaling. Mol Carcinigenesis. 2009;48:910–9. CrossRef
Yu DC, Chen Y, Dilley J, Li Y, Embry M, Zhang H, Nguyen N, Amin P, Oh J, Henderson DR. Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel. Cancer Res. 2001;61(2):517–25. PubMed
Yokoyama Y, Dhanabal M, Griffioen AW, Sukhatme VP, Ramakrishnan S. (2000) Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. Cancer Res. 15;60(8):2190-2196.
Yang YP, Chang YL, Huang PL, Chiou GY, Tseng LM, Chiou SH, Chen MH, Chen MT, Shih YH, Chang CH, Hsu CC, Ma HI, Wang CT, Tsai LL, Yu CC, Chang CJ. Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis. J Cell Physiol. 2012;227:976–93. CrossRefPubMed
Michalczyk K, Ziman M. Nestin structure and predicted function in cellular cytoskeletal organisation. Histol Histopathol. 2005;20:665–71. PubMed
Liu S, Liu H, Tang S, Pan Y, Ji K, Ning H, Wang S, Qi Z, Li L. Characterization of stage-specific embryonic antigen-1 expression during early stages of human embryogenesis. Oncol Rep. 2004;12:1251–6. PubMed
Bos M, Mendelsohn J, Kim YM, Albanell J, Fry DW, Baselga J. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res. 1997;3:2099–106. PubMed
Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA, Mcnamara DJ, Nelson JM, Sherwood V, Smaill JB, Trumpp-Kallmeyer S, Dobrusin EM. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci U S A. 1998;95:12022–7. CrossRefPubMedPubMedCentral
Sauveur-Michel M, Stauffer F, Schnell C, Garcia-Echeverria C. PI3K inhibitors for cancer treatment: where do we stand? Biochem Soc Trans. 2009;37:265–72. CrossRef
W.T. Liu, C.H. Lin, M. Hsiao, P.W. Gean, Minocycline inhibits glioma growth by inducing autophagy. Autophagy 7 (2011) 166-175.
Siddiqueea K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip MLR, Jove R, McLaughlin MM, Lawrence NJ, Sebtid SM, Turkson J. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Aca Sci. 2007;104:7391–6. CrossRef
Chiba T. STAT3 inhibitors for cancer therapy –the rationale and remained problems. EC Cancer. 2016;1(S1):S1–8.
Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Aca Sci. 1997;94:3801–4. CrossRef
- Synergistic inhibition of tumor growth by combination treatment with drugs against different subpopulations of glioblastoma cells
- BioMed Central
Neu im Fachgebiet Onkologie
e.Med Kampagnen-Visual, Mail Icon II