Evaluation of BH3 mimetics as a combination therapy with irradiation in head and neck squamous cell carcinoma
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Updated: Jun 26, 2025
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Katja Korelin1, Mayke Oostveen2, Wafa Wahbi1
1Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki 00014, Finland; Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki 00014, Finland.
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.
Insights
Novel BH3 mimetics show promise in treating head and neck squamous cell carcinoma (HNSCC). Combination therapy with irradiation significantly enhances apoptosis and reduces tumor growth, particularly with A-1331852.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Head and neck squamous cell carcinoma (HNSCC) has a moderate survival rate, necessitating novel therapeutic strategies.
- BH3 mimetics are a class of small molecules designed to induce apoptosis by targeting anti-apoptotic proteins of the Bcl-2 family.
Purpose of the Study:
- To investigate the synergistic effects of novel BH3 mimetics with irradiation in HNSCC.
- To evaluate the efficacy of BH3 mimetics in reducing HNSCC cell proliferation, clonogenicity, invasion, and metastasis.
Main Methods:
- High-throughput screening of BH3 mimetics (A-1155463, A-1331852, navitoclax) in combination with irradiation using a Myogel matrix.
- Assays included apoptosis, clonogenic survival, Myogel spheroids, and zebrafish xenografts to assess anti-cancer effects.
Main Results:
- BH3 mimetics synergized with irradiation in most HNSCC cell lines and dysplastic keratinocytes, but not in normal or cancer-associated fibroblasts.
- A-1331852 demonstrated significant reduction in HNSCC invasion and metastasis in zebrafish models.
- Combined treatment with BH3 mimetics and irradiation significantly increased apoptosis and reduced proliferation and clonogenicity.
Conclusions:
- BH3 mimetics, especially A-1331852, show potential as single agents or in combination with irradiation for HNSCC treatment.
- Further preclinical studies are warranted to explore the therapeutic application of these BH3 mimetics in HNSCC.
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