title: Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation.
abstract: 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(+)/ALDH(high) 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(+)/ALDH(high) 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(+)/ALDH(high) 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.
authors: Université de Lyon, 69622, Lyon, France.
authors: Gérald
authors: G
authors: Bertrand
authors: Mira
authors: M
authors: Maalouf
authors: Antony
authors: A
authors: Boivin
authors: Priscillia
authors: P
authors: Battiston-Montagne
authors: Michael
authors: M
authors: Beuve
authors: Antonin
authors: A
authors: Levy
authors: Patrice
authors: P
authors: Jalade
authors: Claudia
authors: C
authors: Fournier
authors: Dominique
authors: D
authors: Ardail
authors: Nicolas
authors: N
authors: Magné
authors: Gersende
authors: G
authors: Alphonse
authors: Claire
authors: C
authors: Rodriguez-Lafrasse
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D002244:Carbon / Q000737:chemistry*; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007477:Ions / Q000737:chemistry; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000528:radiation effects*; D017785:Photons; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured
chemical_list: D007477:Ions; D002244:Carbon
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