Stem Cell Reviews and Reports

, Volume 10, Issue 1, pp 114–126 | Cite as

Targeting Head and Neck Cancer Stem Cells to Overcome Resistance to Photon and Carbon Ion Radiation

  • Gérald Bertrand
  • Mira Maalouf
  • Antony Boivin
  • Priscillia Battiston-Montagne
  • Michael Beuve
  • Antonin Levy
  • Patrice Jalade
  • Claudia Fournier
  • Dominique Ardail
  • Nicolas Magné
  • Gersende Alphonse
  • Claire Rodriguez-LafrasseEmail author


Although promising new radiation therapy techniques such as hadrontherapy are currently being evaluated in the treatment of head and neck malignancies, local control of head and neck squamous cell carcinoma (HNSCC) remains low. Here, we investigated the involvement of cancer stem-like cells (CSCs) in a radioresistant HNSCC cell line (SQ20B). Stem-like cells SQ20B/SidePopulation(SP)/CD44+/ALDHhigh were more resistant to both photon and carbon ion irradiation compared with non-CSCs. This was confirmed by a BrdU labeling experiment, which suggests that CSCs were able to proliferate and to induce tumorigenicity after irradiation. SQ20B/SP/CD44+/ALDHhigh were capable of an extended G2/M arrest phase in response to photon or carbon ion irradiation compared with non-CSCs. Moreover, our data strongly suggest that resistance of CSCs may result from an imbalance between exacerbated self-renewal and proliferative capacities and the decrease in apoptotic cell death triggering. In order to modulate these processes, two targeted pharmacological strategies were tested. Firstly, UCN-01, a checkpoint kinase (Chk1) inhibitor, induced the relapse of G2/M arrest and radiosensitization of SQ20B-CSCs. Secondly, all-trans retinoic acid (ATRA) resulted in an inhibition of ALDH activity, and induction of the differentiation and radiosensitization of SQ20B/SP/CD44+/ALDHhigh cells. The combination of ATRA and UCN-01 treatments with irradiation drastically decreased the surviving fraction at 2Gy of SQ20B-CSCs from 0.85 to 0.38 after photon irradiation, and from 0.45 to 0.21 in response to carbon ions. Taken together, our results suggest that the combination of UCN-01 and ATRA represent a promising pharmacological-targeted strategy that significantly sensitizes CSCs to photon or carbon ion radiation.


Hadrontherapy Photon irradiation Carbon ion irradiation Radiosensitization Cancer stem cells HNSCC 



We thank all those who participated in the experiments at GANIL and GSI. We acknowledge the contribution of the flow cytometry platform of UFR BioSciences Gerland-Lyon-Sud (UMS3444/US8). This work was achieved within the scientific framework of ETOILE and Labex-PRIMES (ANR-11LABX-0063).. It was supported by the Contrat-Plan-Etat-Region and the Ligue contre le Cancer (Ain).

Conflict of Interest

No conflict of interest.

Supplementary material

12015_2013_9467_MOESM1_ESM.ppt (261 kb)
ESM 1 (PPT 261 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Gérald Bertrand
    • 1
    • 2
    • 3
  • Mira Maalouf
    • 1
    • 2
    • 3
  • Antony Boivin
    • 1
    • 2
    • 3
  • Priscillia Battiston-Montagne
    • 1
    • 2
    • 3
  • Michael Beuve
    • 1
    • 2
    • 6
  • Antonin Levy
    • 5
  • Patrice Jalade
    • 4
  • Claudia Fournier
    • 7
  • Dominique Ardail
    • 1
    • 2
    • 3
  • Nicolas Magné
    • 1
    • 2
    • 3
  • Gersende Alphonse
    • 3
    • 4
  • Claire Rodriguez-Lafrasse
    • 1
    • 2
    • 3
    • 4
    • 8
    Email author
  1. 1.Université de LyonLyonFrance
  2. 2.Université Lyon I, Faculté de Médecine-Lyon-SudOullinsFrance
  3. 3.Laboratoire de Radiobiologie Cellulaire et Moléculaire, EMR3738OullinsFrance
  4. 4.Hospices-Civils-de-Lyon, CHLSPierre-BéniteFrance
  5. 5.Département de Radiothérapie Oncologique, IGRUniversité Paris XIVillejuifFrance
  6. 6.IPNL, LIRIS, CNRSVilleurbanneFrance
  7. 7.Biophysics DepartmentGSI Helmholtz Center for HeavyIonResearchDarmstadtGermany
  8. 8.Laboratoire de Radiobiologie Cellulaire et MoléculaireUFR Médicale Lyon-Sud, BP12Oullins cedexFrance

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