title: Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer.
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.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zeuner
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Francescangeli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Contavalli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Zapparelli
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Palermo 90128, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Apuzzo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Eramo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Baiocchi
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: M L
authors.initials: ML
authors.lastname: De Angelis
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Biffoni
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sette
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Palermo 90128, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Todaro
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Palermo 90128, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: De Maria
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein