title: Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT-737 on HNSCC.
abstract: Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. HNSCC is frequently characterized by overexpression of anti-apoptotic Bcl-2 family members. Increased levels of these anti-apoptotic proteins have been associated with radio- and chemoresistance and poor clinical outcome. The aim of this study was to evaluate combined effects of radiation and ABT-737, a BH3-mimetic molecule, in HNSCC. Although ABT-737, as a single agent, was largely ineffective at promoting HNSCC cell death, we found that combining ABT-737 and radiation induced strong synergistic apoptosis in HNSCC cell lines and delayed tumoral growth in vivo. Moreover, we demonstrated for the first time that ABT-737, alone or in combination with radiation, can efficiently eliminate cancer stem cells (CSCs). Altogether, our results indicate that therapy targeting anti-apoptotic Bcl-2 family members could be a highly effective potential adjuvant to radiotherapy capable of targeting CSCs in HNSCC and therefore overcoming cancer recurrence and metastasis.
authors.affiliation: Université Lyon I, Faculté de Médecine-Lyon-Sud, Oullins, France.|Laboratoire de Radiobiologie Cellulaire et Moléculaire, EMR3738, Oullins, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gilormini
authors.affiliation: Université Lyon I, Faculté de Médecine-Lyon-Sud, Oullins, France.|Laboratoire de Radiobiologie Cellulaire et Moléculaire, EMR3738, Oullins, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Malesys
authors.affiliation: Université Lyon I, Faculté de Médecine-Lyon-Sud, Oullins, France.|Laboratoire de Radiobiologie Cellulaire et Moléculaire, EMR3738, Oullins, France.
authors.forename: Emma
authors.initials: E
authors.lastname: Armandy
authors.affiliation: UMS3444 BioSciences Gerland-Lyon Sud, PBES, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Manas
authors.affiliation: Université Lyon I, Faculté de Médecine-Lyon-Sud, Oullins, France.|Laboratoire de Radiobiologie Cellulaire et Moléculaire, EMR3738, Oullins, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Guy
authors.affiliation: Université Lyon I, Faculté de Médecine-Lyon-Sud, Oullins, France.|Laboratoire de Radiobiologie Cellulaire et Moléculaire, EMR3738, Oullins, France.|Institut de Cancérologie L. Neuwirth, St Etienne, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Magné
authors.affiliation: Université Lyon I, Faculté de Médecine-Lyon-Sud, Oullins, France.|Laboratoire de Radiobiologie Cellulaire et Moléculaire, EMR3738, Oullins, France.|Hospices-Civils-de-Lyon, CHLS, Pierre-Bénite, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Rodriguez-Lafrasse
authors.affiliation: Université Lyon I, Faculté de Médecine-Lyon-Sud, Oullins, France.|Laboratoire de Radiobiologie Cellulaire et Moléculaire, EMR3738, Oullins, France.|Hospices-Civils-de-Lyon, CHLS, Pierre-Bénite, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Ardail
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides
keywords: ABT-737; Bcl-2 family; cancer stem cells; head and neck squamous cell carcinoma; radiation