6533b7d9fe1ef96bd126b8e8

RESEARCH PRODUCT

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

Matilde TodaroFederica FrancescangeliM L De AngelisGiovanni SetteR De MariaGiorgio StassiTiziana ApuzzoG ZapparelliPaola ContavalliAdriana EramoAnn ZeunerMauro BiffoniMarta Baiocchi

subject

Lung NeoplasmsMice SCIDPharmacologyPiperazinesAntineoplastic AgentNitrophenolsMiceMice Inbred NODCarcinoma Non-Small-Cell LungCytotoxic T cellNon-Small-Cell Lungeducation.field_of_studySulfonamidesTumorAnimals; 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; Molecular Biology; Cell BiologyTumor BurdenAnimals; 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 ProteinNeoplastic Stem CellsFemaleStem cellHumanmedicine.drugXenograft Model Antitumor AssayCell SurvivalPopulationbcl-X ProteinAntineoplastic AgentsBiologySCIDSulfonamideCell LineCancer stem cellCell Line TumormedicineAnimalsHumanseducationLung cancerPiperazineMolecular BiologyCell ProliferationSettore MED/04 - Patologia GeneraleOriginal PaperNitrophenolAnimalCell growthCarcinomaBiphenyl CompoundsCell Biologymedicine.diseaseXenograft Model Antitumor AssaysGemcitabineLung NeoplasmCell cultureBiphenyl CompoundCancer researchInbred NODNeoplastic Stem Cell

description

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.

yearjournalcountryeditionlanguage
2014-07-18
10.1038/cdd.2014.105http://hdl.handle.net/10447/163835