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Evaluation of BH3 mimetics as a combination therapy with irradiation in head and neck squamous cell carcinoma.
Korelin, Katja; Oostveen, Mayke; Wahbi, Wafa; Ianevski, Filipp; Cavalcante, Bruno; Turunen, Laura; Belevich, Ilya; Al-Samadi, Ahmed; Salo, Tuula.
Afiliación
  • Korelin K; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki 00014, Finland. Electronic address: katja.korelin@helsinki.fi.
  • Oostveen M; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki 00014, Finland.
  • Wahbi W; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki 00014, Finland.
  • Ianevski F; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00290, Finland.
  • Cavalcante B; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki 00014, Finland; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Brazil; Department of Pathology and Forensic Medicine, School of Medicine, Federal University of Bahia, Salvador 4011
  • Turunen L; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00290, Finland.
  • Belevich I; Electron Microscopy Unit, Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki 00014, Finland.
  • Al-Samadi A; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki 00014, Finland; Institute of Dentistry, School of Medicine, Kuopio Campus, University of Eastern Finland, Kuopio, Finlan
  • Salo T; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki 00014, Finland; Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90014, Finland; Medical Resear
Biomed Pharmacother ; 175: 116719, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38749173
ABSTRACT

INTRODUCTION:

Head and neck squamous cell carcinoma (HNSCC) is a common cancer with a five-year survival rate around 60%, indicating a need for new treatments. BH3 mimetics are small molecules that inhibit anti-apoptotic Bcl-2 family proteins, resulting in apoptosis induction.

METHODS:

We performed a high-throughput screen using a Myogel matrix to identify the synergy between irradiation and the novel BH3 mimetics A-1155463, A-1331852, and navitoclax in 12 HNSCC cell lines, normal (NOF) and cancer-associated fibroblasts (CAF), and dysplastic keratinocytes (ODA). Next, we examined synergy in an apoptosis assay, followed by a clonogenic assay and a Myogel spheroid on selected HNSCC cell lines. Finally, we applied zebrafish larvae xenograft to validate the effects of navitoclax and A-1331852.

RESULTS:

All three BH3 mimetics exhibited a strong synergy with irradiation in eight HNSCC cell lines and ODAs, but not in NOFs and CAFs. A-1155463 and A-1331852 induced apoptosis and reduced proliferation, and together with irradiation, significantly increased apoptosis and arrested proliferation. A-1331852 and navitoclax significantly decreased the clonogenicity compared with the control, and combination treatment led to a decreased clonogenicity compared with monotherapy or irradiation. However, unlike navitoclax or A-1155463, only A-1331852 significantly reduced cancer cell invasion. Furthermore, in spheroid and zebrafish, irradiation appeared ineffective and failed to significantly increase the drug effect. In the zebrafish, A-1331852 and navitoclax significantly reduced the tumor area and metastasis.

CONCLUSIONS:

Our findings encourage the further preclinical investigation of BH3 mimetics, particularly A-1331852, as a single agent or combined with irradiation as a treatment for HNSCC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pez Cebra / Apoptosis / Carcinoma de Células Escamosas de Cabeza y Cuello / Neoplasias de Cabeza y Cuello Límite: Animals / Humans Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pez Cebra / Apoptosis / Carcinoma de Células Escamosas de Cabeza y Cuello / Neoplasias de Cabeza y Cuello Límite: Animals / Humans Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia