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- W4285984717 abstract "Actinic keratoses (AK) are premalignant cutaneous lesions with limited treatment options. Here we investigate GZ21T, a novel anti-tumor agent composed of curcumin, harmine, and isovanillin, in the treatment of AK. The pro-apoptotic effects of GZ21T on EGF-stimulated HaCaT cells were assessed by Annexin-V assay, and the mechanism was clarified by western blot. Treated cells were subjected to RNA-sequencing and reverse phase protein array. Differentially expressed genes (DEGs) were calculated using DESeq2 for R. Gene set enrichment analysis (GSEA) was performed using fgsea for R, and gene set variation analysis (GSVA) was conducted to evaluate GZ21T’s effect on pathways implicated in the pathogenesis of AK. Enrichment analysis was conducted on hypophosphorylated proteins using Enrichr. SKH-1 mice were exposed to UVB (500 J/m2) five times weekly for ten weeks and were subsequently treated with 0.25 grams topical GZ21T or control cream five days per week. An increase in the percentage of HaCaT cells in early (p=0.041) and late apoptosis (p=0.029) was observed with increasing GZ21T concentrations, which was partially mediated by PARP cleavage. After 40 days, GZ21T treated mice showed decreased lesion count (p=0.028) and tumor surface area (p=0.026). We identified 92 DEGs between control and GZ21T treated HacaT cells, with upregulation of TP53 and NOTCH1 tumor-suppressor genes. GSEA showed that GZ21T downregulates KRAS and mTOR signaling. GSVA revealed upregulation of transforming growth factor-beta (TGF-β) secretion and NOTCH signaling with downregulation of MAPK1 and 3 activation (p<0.05 for all). Proteomic analysis demonstrated downregulation of ErbB, mTOR, HIF-1, and PI3K-AKT signaling. In conclusion, GZ21T inhibits the growth of AK through suppression of targets related to MAPK, PI3K-AKT, HIF-1, and mTOR signaling." @default.
- W4285984717 created "2022-07-20" @default.
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- W4285984717 date "2022-08-01" @default.
- W4285984717 modified "2023-09-23" @default.
- W4285984717 title "598 A novel curcumin-harmine-isovanillin compound inhibits the growth of actinic keratoses by suppressing MAPK and PI3K-AKT signaling" @default.
- W4285984717 doi "https://doi.org/10.1016/j.jid.2022.05.607" @default.
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