Using Flavonoid Substitution Status to Predict Anticancer Effects in Human Melanoma Cancers: An In Vitro Study

Simple Summary The rising incidence of skin cancer, particularly melanoma, over the last few decades requires natural-product-based treatments with a lack of side effects. To evaluate the anticancer potential of 37 structurally diverse flavonoids, cytotoxic tests, DNA biosynthesis inhibition levels, and apoptosis pathways involved in cell death were investigated in A375 and C32 melanoma cells. Compounds 1, 6, 15, and 37 reduced the viability of cell lines via the intrinsic (caspase-9) and extrinsic (caspase-8) pathways of apoptosis, where 16 and 17 mainly influenced DNA biosynthesis in cancer cells. In our study, we performed an anticancer analysis of compound 15 (5,6-dihydroxyflavone) for the first time. Although our data provide new insights into the molecular mechanisms of flavonoid-induced toxicity, in vivo studies are needed to assess their anti-cancer activities, especially flavonoid-core-containing hydroxyl groups.Abstract Skin cancers are a dominant type of cancer that impacts millions per year. Cancer is a heterogeneous disease triggered by the irreversible impairment of cellular homeostasis and function. In this study, we investigated the activity of 37 structurally diverse flavonoids to find potentially active substances using two melanoma cell lines: C32 and A375. First, the cytotoxic potential and DNA biosynthesis inhibition of flavonoids were tested to determine the most active compounds in cancer and normal cells. Second, the molecular mechanism of the anticancer activity of flavonoids was elucidated using Western blot and immunofluorescence analyses. Compounds 1, 6, 15, and 37 reduced the viability of A375 and C32 cell lines via the intrinsic and extrinsic pathways of apoptosis, whereas 16 and 17 acted in a higher degree via the inhibition of DNA biosynthesis. In our experiment, we demonstrated the anticancer activity of compound 15 (5,6-dihydroxyflavone) for the first time. The in vitro studies pointed out the importance of the flavonoid core in hydroxyl groups in the search for potential drugs for amelanotic melanoma.