Evaluation of the biological activity of two hit compounds and its action mechanisms for drug repositioning

Abstract

I evaluated biological activity of two compounds, anhydrous alum (KAl(SO4)2) and pyrimethamine and elucidated its action mechanisms. Firstly, my research concentrated on investigating the impact of dehydrated alum (KAl(SO4)2) on melanogenesis, the intricate process responsible for the production of melanin. Melanin plays a vital role in skin pigmentation and shielding against UV radiation. In order to explore potential skin- whitening agents, scientists scrutinized the inhibitory effects of high-purity dehydrated alum (KAl(SO4)2) on melanogenesis using B16F1 melanoma cells and delved into its underlying molecular mechanisms. Dehydrated alum (KAl(SO4)2) with a purity exceeding 99%, obtained through the heat treatment of hydrated alum (KAl(SO4)2·12H2O) at 400 °C, successfully diminished melanin content without inducing cytotoxicity. The investigation uncovered that dehydrated alum represses the chief regulator of melanogenesis, microphthalmia-associated transcription factor (MITF), which governs crucial genes in melanogenesis, thereby inhibiting α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis. Furthermore, dehydrated alum impeded the phosphorylation of the cAMP response element-binding protein, a co-activator of MITF gene expression, leading to diminished MITF transcription. Notably, dehydrated alum also facilitated extracellular signal-regulated kinase phosphorylation, resulting in compromised nuclear localization of MITF. These findings offer valuable insights into the mode of action of dehydrated alum in B16F1 cells, presenting a promising avenue for cosmetic or therapeutic applications. Secondly, I have been investigated anticancer activity of pyrimethamine, an antiparasitic drug originally used for the treatment of malaria and toxoplasmosis, and its underlying molecular mechanisms. In this study, I found that pyrimethamine had an inhibitory impact on the proliferation of various cancer cells. Effectively, pyrimethamine treatment blocked proliferation of cancer cells along with S phase arrest. Also, pyrimethamine induced phosphorylation of p53 and Chk1 without regard to DNA damage. Thus, with the Pyrimethamine-induced p53 phosphorylation was mediated by Erk1/2 in HCT116 cells. Additionally, pyrimethamine triggered autophagy in a MAP kinase-dependent manner. Moreover, the compound increased the proportion of senescence cells. The multifaceted anticancer effects of pyrimethamine were uncovered in this study to underscore its potential as a promising candidate in the realm of cancer therapeutic strategies. _x000D_ <br>_x000D_ <br>Key words : Anhydrous alum; melanogenesis; MITF; CREB; ERK; Pyrimethamine; Autophagy; Senescence; p53