Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically a...

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Bibliographic Details
Published in:	Cell death and differentiation Vol. 21; no. 12; pp. 1877 - 1888
Main Authors:	Zeuner, A, Francescangeli, F, Contavalli, P, Zapparelli, G, Apuzzo, T, Eramo, A, Baiocchi, M, De Angelis, M L, Biffoni, M, Sette, G, Todaro, M, Stassi, G, De Maria, R
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-12-2014 Nature Publishing Group
Subjects:	631/532/71 631/80/82 692/699/67/1612/1350 692/700/565/1436/2185 Animals Antineoplastic Agents - pharmacology Apoptosis bcl-X Protein - antagonists & inhibitors bcl-X Protein - metabolism Biochemistry Biomedical and Life Sciences Biphenyl Compounds - pharmacology Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Biology Cell Cycle Analysis Cell Line, Tumor Cell Proliferation Cell Survival - drug effects Female Humans Life Sciences Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Lung Neoplasms - pathology Mice, Inbred NOD Mice, SCID Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - physiology Nitrophenols - pharmacology Original Paper Piperazines - pharmacology Stem Cells Sulfonamides - pharmacology Tumor Burden Xenograft Model Antitumor Assays
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Summary:	Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-X L is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-X L inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-X L . In vivo , ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-X L for their survival and indicate Bcl-X L inhibition as a potential therapeutic avenue in NSCLC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1350-9047 1476-5403
DOI:	10.1038/cdd.2014.105