Browsing by Author "Oostveen, Mayke"

Head and neck cancers form the seventh most common type of cancer globally, and 90% of these cancers are classified as head and neck squamous cell carcinomas (HNSCC). The 5-year survival rate for head and neck cancers remains around 50%, indicating a need for new treatment strategies. This thesis aimed to examine the potential of BH3 mimetics A 1155463, A-1331852, and navitoclax combined with irradiation, as a treatment for HNSCC. BH3 mimetics are compounds able to bind to anti-apoptotic proteins, thereby blocking their ability to exhibit anti-apoptotic effects. A high-throughput screening method was used to characterize the synergistic effects of the BH3 mimetics with different irradiation doses on the viability of twelve HNSCC, normal (NOF) and cancer-associated fibroblastic (CAF), and HPV-16 immortalized oral dysplastic keratinocyte (ODA) cell lines. Additionally, the effects of A-1155463 and A-1331852 on apoptosis and proliferation of two HNSCC cell lines (UT SCC 40 and UT-SCC-42A), in combination with 8 Gy irradiation, were measured. Effects on invasion of UT-SCC-42A cells with the irradiation-mimetic combination were tested in a 3D spheroid model. Lastly, the effect of A 1331852 and navitoclax in combination with immunotherapy drug nivolumab on donor-derived immune cell migration and apoptosis of UT-SCC-40 was assessed with a microfluidic chip assay. All three BH3 mimetics in combination with irradiation synergistically reduced viability in six to ten HNSCC cell lines and ODA cells, but not in NOF or CAF. A-1155463 and A-1331852 induced apoptosis and reduced proliferation in both tested cell lines. The addition of irradiation to the compounds significantly increased the apoptotic ratio in both cell lines and compounds. In the spheroids, A-1331852 significantly reduced cancer cell area and length of invasion both with and without irradiation. A-1155463, unlike navitoclax, had a trend in reducing HNSCC invasion. The combination of A-1331852 with nivolumab increased the immune cell migration of one out of the three donors. These results show the synergistic and apoptosis-inducing effects of the BH3 mimetics combined with irradiation, proving them plausible candidates for HNSCC treatment. The reduction of invasion by A 1331852 suggests a role for Bcl-xL in HNSCC invasion. It is proposed to further investigate the properties of A-1331852 in in vitro cocultures and in vivo studies, with and without irradiation.