Abstract

Despite treatment advances, head and neck squamous cell carcinoma (HNSCC) still poses a significant global health challenge. Combination therapies have emerged as more effective strategies than traditional chemotherapy in clinical practice by improving tumor response rates and patient survival while minimizing treatment-related toxicity. This study investigates the anticancer effects of metformin and verteporfin (Yes-associated protein 1 [YAP1] inhibitor) alone or in combination in HNSCC using vitro and in vivo approaches. Quantitative RT-PCR analysis of HNSCC cell lines reveals upregulation of YAP1 and related genes in the Hippo signaling pathway. Cell viability assays demonstrate a beneficial synergistic effect between metformin and verteporfin in inhibiting HNSCC tumor growth. In male BALB/cAJcl-nu/nu mice harboring HNSCC tumor xenografts, intraperitoneal administration of metformin and verteporfin enhances the inhibitory effect on tumor growth and suppresses YAP1 nuclear translocation when compared to vehicle or monotherapies. Furthermore, combination of these drugs reduces tumor cell proliferation (marked by Ki-67) and inhibits phosphoS6 ribosomal protein, as observed through immunofluorescent and immunohistochemical (IHC) analyses. The in vivo study underscores the therapeutic potential of the dual targeting approach with metformin and verteporfin in treating HNSCC, with minimal toxicity.