Anticancer Effects of Genistein and Its Interaction with Temozolomide in Human Melanoma, Neuroblastoma and Glioblastoma Cells

(1) Background: Melanoma, glioblastoma, and neuroblastoma have distinct cellular origins, biological characteristics, and clinical behavior. Although these tumors differ in their origins, they exhibit aggressive biological features and may develop treatment resistance. New therapeutic options are constantly being sought. This study aimed to evaluate the anticancer potential of genistein, a soy-derived isoflavone, and investigate the pharmacodynamic interactions between genistein and temozolomide in human melanoma, neuroblastoma, and glioblastoma cell lines. (2) Methods: Genistein’s potential for inhibiting cell viability, induction of cytotoxicity, and modulating apoptosis-related protein expression was assessed in eight cell lines. The interaction of the genistein + temozolomide combination (in a fixed 1:1 ratio) was assessed using isobolographic analysis. (3) Results: Genistein inhibited cell viability in a concentration-dependent manner. IC50 values ranged from approximately 40 to 110 μM in melanoma, 27 to 60 μM in neuroblastoma, and 37 to 83 μM in glioblastoma cell lines. Genistein treatment induced changes in apoptosis-related protein expression, including Bax and Bcl-2. The genistein + temozolomide combination produced additive interactions in the tested melanoma cell lines, whereas strong antagonism was observed in the neuroblastoma and glioblastoma models. These differences may reflect tumor-type-specific biological characteristics. (4) Conclusions: The findings provide comparative insights into genistein–temozolomide interactions across the investigated tumor models. Further studies are needed to clarify the underlying molecular mechanisms and evaluate the potential therapeutic relevance of this combination. Additional preclinical investigations are required to establish its efficacy, safety, and tolerability before clinical implications can be determined.