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

Ruggero De Maria Marchiano, Paola Contavalli, A. Zeuner, F. Francescangeli, P. Contavalli, G. Zapparelli, T. Apuzzo, A. Eramo, M. Baiocchi, M. L. De Angelis, M. Biffoni, G. Sette, M. Todaro, G. Stassi

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60 Citazioni (Scopus)

Abstract

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-XL 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-XL 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-XL. 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-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC.
Lingua originaleEnglish
pagine (da-a)1877-1888
Numero di pagine12
RivistaCell Death and Differentiation
Volume21
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Animals
  • Antineoplastic Agents
  • Biphenyl Compounds
  • Carcinoma, Non-Small-Cell Lung
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Female
  • Humans
  • Lung Neoplasms
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplastic Stem Cells
  • Nitrophenols
  • Piperazines
  • Sulfonamides
  • Tumor Burden
  • Xenograft Model Antitumor Assays
  • bcl-X Protein

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