Lycorine

This study identified key enzyme-encoding genes involved in the biosynthesis of lycorine and galanthamine in Zephyranthes candida, and predicted four critical therapeutic targets of lycorine for liver hepatocellular carcinoma (LIHC). Amaryllidaceae alkaloids (AAs) comprise a unique class of isoquinoline alkaloids mainly found in plants of the Amaryllidaceae family. Zephyranthes candida (Lindl.) Herb., a bulbous geophyte within this family, produces lycorine and galanthamine as its characteristic isoquinoline alkaloids. In this study, an in-depth analysis of the biosynthesis of these compounds in various tissues of the plant was conducted using transcriptomics and bioinformatics. Transcriptome databases were generated for roots, leaves, and bulbs of Z. candida. Key enzymes and differentially expressed genes (DEGs) associated with lycorine and galanthamine biosynthesis were screened, leading to the identification of two genes, ZcTYDC (DN4967_1) and ZcN4OMT (DN3779), based on correlation analysis. Subsequently, phylogenetic, structural modeling and molecular docking analyses of key enzymes were undertaken, followed by a detailed assessment of their characteristics and functions. A correlation was identified between the expression of genes encoding transcription factors (TFs) and major AAs biosynthetic enzymes in Z. candida. The expression levels of selected genes were determined by quantitative real-time polymerase chain reaction (qPCR), while the contents of lycorine and galanthamine in each tissue were detected by high-performance liquid chromatography (HPLC). Critical targets of lycorine in liver hepatocellular carcinoma (LIHC)-MMP9, IGF1, SRC, and CCNA2-were predicted using network pharmacology, gene expression profiling interactive analysis (GEPIA2), molecular docking, and visualization. This study provides a theoretical basis for further research on the biosynthesis of AAs, as well as support for the therapeutic application of lycorine in LIHC.

The plant family Amaryllidaceae is embellished with a diverse array of antiproliferative alkaloid principles. Chief amongst these are the lycorine alkaloids, which have attracted considerable attention as potential anticancer drugs. This account tracks developments in the field with these substances encompassing the years 2015-2019. Twenty-nine compounds were screened against nearly eighty cancer cell lines representing seventeen different types of cancer. Submicromolar level activities were recorded against leukemia, myeloma and breast cancer cells. The response of lycorine (IC₅₀ 0.6 μM) to HL-60 myeloid leukemia cells was particularly striking. Promising activities were also documented from in vivo models of brain, lung, colon, prostate and breast cancer cells (in the 5-10 mg/kg/day dosage range). The screenings indicated these compounds to be efficacious without attendant detrimental effects towards control animals. Structure-activity relationship studies afforded useful insight to the elements of the anticancer pharmacophore, such as the necessity for the A-ring methylenedioxy and C-ring hydroxy functionalities. The mechanisms of action were intensively examined, with over twenty individual areas identified wherein such probes have been made. Of prominence here was the apoptosis-inducing abilities of lycorine against (amongst others) leukemia, pancreatic, bladder, liver and bone cancer cells, involving the modulation of key mediators such as caspase-3, p53, PARP, Bax and Bcl-2. Useful insights also emerged from docking studies undertaken with various cancer-related proteins, such as VEGF, HDAC, PI3Kα, c-Met kinase and EGFR. The lycorine alkaloids have proved to be highly versatile entities, readily embracing multiple facets of anticancer drug discovery.