Lycorine

Target of Action

Lycorine, a naturally active alkaloid, has been shown to have inhibitory effects on a variety of cancers . The primary targets of this compound in the treatment of glioblastoma (GBM) include 10 key target genes: AKT1, SRC, HSP90AA1, HRAS, MMP9, BCL2L1, IGF1, MAPK14, STAT1, and KDR . These genes play an important role in the therapeutic effect of this compound on GBM . In addition, this compound has been found to target the Wnt/β-catenin pathway in multiple myeloma stem cell-like cells .

Mode of Action

This compound interacts with its targets by docking to them, thereby inhibiting their activity . For instance, this compound has been found to inhibit the activation of PDGFRα by docking to it . It also attenuates the phosphorylation of PDGFRα . The molecular docking results showed that this compound had strong binding efficiency with the 10 key genes .

Biochemical Pathways

This compound acts on GBM by multiple pathways, including inducing apoptosis and reactive oxygen species production . Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these pathways play a significant role in the action of this compound .

Result of Action

The use of this compound has been found to induce apoptosis in U-87 MG glioblastoma cells . It also inhibits the proliferation of myeloma cells from cell lines or patients, mainly through decreasing ALDH1+ cells . Moreover, this compound exhibits cytostatic effects by targeting the actin cytoskeleton rather than by inducing apoptosis in cancer cells .

Action Environment

The environmental conditions that influence this compound production are crucial to understand, as they can impact the compound’s action, efficacy, and stability . There isn’t much information about how the genes in the this compound biosynthesis pathway respond to different types of light in lycoris seedlings or how light quality affects this compound accumulation

Biochemical Properties

Lycorine interacts with various enzymes, proteins, and other biomolecules. It has been found to inhibit acetylcholinesterase and topoisomerase . The nature of these interactions contributes to its multiple biological functions and pharmacological effects .

Cellular Effects

This compound influences cell function by impacting cell signaling pathways, gene expression, and cellular metabolism . It has shown strong pharmacological effects on many diseases, including anti-leukemia, anti-tumor, anti-angiogenesis, anti-virus, anti-bacteria, anti-inflammation, and antimalaria .

Molecular Mechanism

This compound exerts its effects at the molecular level through binding interactions with biomolecules, enzyme inhibition or activation, and changes in gene expression . For instance, it has been found to have strong binding efficiency with key genes involved in glioblastoma multiforme (GBM), inducing apoptosis and reactive oxygen species production .

Temporal Effects in Laboratory Settings

Over time, this compound has shown stability and long-term effects on cellular function in both in vitro and in vivo studies . It has been produced sustainably in in vitro culture due to the pharmaceutical industries dramatically increasing demand for it .

Dosage Effects in Animal Models

The effects of this compound vary with different dosages in animal models . It exhibits numerous pharmacological effects on various diseases with very low toxicity and mild side effects .

Metabolic Pathways

This compound is involved in metabolic pathways formed by a coupling reaction of L-phenylalanine and L-tyrosine through intermediate o-methylnorbelladine—a common precursor of all Amaryllidaceae alkaloids .

Synthetic Routes and Reaction Conditions

Lycorine can be synthesized through several methods. One notable synthetic route involves the use of cyclopropyl acyliminium ion expansion and rearrangement, followed by a Diels-Alder reaction to construct the key diene intermediate . This method, developed by Boeckman et al., is considered one of the most elegant synthetic routes for this compound .

Industrial Production Methods

Industrial production of this compound typically involves extraction from plant sources. Air-dried powdered bulbs of plants like Sternbergia fischeriana are used to isolate this compound . Advanced techniques such as in vitro plant cell suspension cultures and bioreactors are also employed to produce this compound sustainably .

Types of Reactions

Lycorine undergoes various chemical reactions, including oxidation, reduction, and substitution. It is known to inhibit protein synthesis and may inhibit ascorbic acid biosynthesis .

Common Reagents and Conditions

Common reagents used in this compound reactions include oxidizing agents for oxidation reactions and reducing agents for reduction reactions. Specific conditions vary depending on the desired reaction and product.

Major Products Formed

Major products formed from this compound reactions include derivatives with enhanced biological activities. For example, dihydrothis compound, generated through the hydrogenation of this compound, has been used clinically due to its better resistance against amebic dysentery and lower toxicity .

Lycorine is a naturally occurring alkaloid that has garnered attention for its diverse range of pharmacological activities, particularly in the realm of cancer research. Studies have explored its potential as an anti-cancer agent, demonstrating its effects on various cancer cell lines and tumor models .

Scientific Research Applications

Anti-Cancer Activity: this compound has demonstrated anticancer activities in several studies . It exhibits selective cytotoxicity effects on leukemia, cervical cancer, and multiple myeloma . Research indicates that this compound can decrease proliferation, migration, invasion, and survival of prostate cancer cell lines . In vivo experiments have shown that this compound reduces both the weight and volume of prostate cancer xenografts and inhibits cancer growth and metastasis in multiple organs, improving survival rates in mice .

Mechanism of Action in Cancer Cells: this compound's anti-cancer effects are linked to its ability to interfere with key signaling pathways involved in cancer development and progression . It inhibits the activation of EGF-induced JAK/STAT signaling and multiple STAT3 downstream targets, such as cyclin D1, Bcl-2, Bcl-xL, matrix metalloproteinase 2 (MMP2), and the EMT promoter Twist . In colorectal cancer cells, this compound may induce cell cycle arrest and exert cytostatic effects by activating ROS/p38 and AKT signaling pathways . It can also downregulate the protein expression levels of MMP-2, MMP-7, and MMP-9, and reverse the EMT process in CRC cells .

Effects on Cell Cycle Arrest: this compound can induce cell cycle arrest in cancer cells . In HCT116 cells, this compound treatment results in a significantly higher proportion of cells in the G2/M phase, while in LoVo cells, it leads to a significantly higher ratio of cells in the S and G2/M phases . this compound also downregulated the protein expression levels of cyclin D1 and cyclin E1, and increased p21 and Smad4 protein expression levels .

Other Pharmacological Effects: this compound possesses strong pharmacological effects on many diseases, including anti-leukemia, anti-tumor, anti-angiogenesis, anti-virus, and anti-bacteria . It has a strong anti-acetylcholinesterase effect .

Safety in the Central Nervous System: In vitro studies suggest that this compound regulates immune cells, indicating its involvement as a cellular mechanism underlying the suppression of pain .

Tumor Xenograft Studies: this compound is effective against tumor xenografts and has effectively inhibited tumor growth in B16F10 melanoma-bearing mice, HL-60 xenografted SCID mice, ovarian cancer Hey1B bearing nude mice, and multiple myeloma (MM) cell xenografted NOD/SCID mice .

Tables

Table 1: this compound's Effects on Prostate Cancer Cell Lines (in vitro)

Table 2: this compound's Impact on Colorectal Cancer (CRC) Cell Lines (in vitro)

Case Studies

Prostate Cancer Xenograft Model: In vivo experiments using a PC-3M-luc orthotopic xenograft model demonstrated that this compound inhibits prostate cancer growth and metastasis . Intraperitoneal administration of this compound reduced both the weight and volume of ectopically PC-3M subcutaneous xenografts by approximately 80% without causing obvious toxicity .

Colorectal Cancer Cell Lines: this compound inhibited cell proliferation in HCT116, LoVo, and SW480 cells, with IC50 values of 1.4, 3.8, and 1.3 µmol/l, respectively, following treatment for 72 hours .

Lycorine is unique among alkaloids due to its rigid ring skeleton and contiguous chiral centers . Similar compounds include:

Galanthamine: Used in the treatment of Alzheimer’s disease.

Lycoramine: Used for treating post-polio syndrome.

Dihydrothis compound: Used clinically for its lower toxicity and resistance against amebic dysentery.

These compounds share structural similarities with this compound but have distinct pharmacological properties and applications.

Lycorine is a natural alkaloid derived from various plants, particularly those in the Amaryllidaceae family. It has garnered significant attention due to its diverse biological activities, including anti-cancer, antiviral, and neuroprotective properties. This article provides a comprehensive overview of the biological activity of this compound, supported by research findings and data tables.

This compound's chemical structure is characterized by a benzylphenethylamine backbone, which is crucial for its biological activity. The compound exhibits multiple mechanisms of action, primarily through the inhibition of various cellular pathways associated with cancer and viral infections.

• Inhibition of DNA Topoisomerase I : this compound has been shown to inhibit DNA topoisomerase I, an enzyme critical for DNA replication in cancer cells. This inhibition leads to cytostatic effects rather than cytotoxicity, making it a potential candidate for cancer therapy .
• Autophagy-Associated Apoptosis : Research indicates that this compound can induce autophagy-associated apoptosis by targeting MEK2, a key regulator in cancer signaling pathways. This mechanism enhances the therapeutic efficacy when combined with other agents like vemurafenib in colorectal cancer models .
• Cell Cycle Arrest : this compound has been found to induce cell cycle arrest in various cancer cell lines, specifically at the G2/M phase, thereby inhibiting cell proliferation and migration .

Anticancer Activity

This compound exhibits significant anticancer properties across various cancer types:

• Breast and Prostate Cancer : It promotes LRP6 phosphorylation and Wnt signaling transduction, which are beneficial against breast and prostate cancers .
• Bladder Cancer : In bladder cancer cell lines, this compound enhances sensitivity to gemcitabine, a common chemotherapeutic agent .
• Leukemia : Studies have demonstrated that this compound suppresses tumor growth in leukemia models (HL-60 cell line) through apoptosis induction .

Antiviral Activity

This compound has been identified as an effective inhibitor of Hepatitis C Virus (HCV), acting by downregulating Hsc70 expression in host cells. However, its cytotoxicity limits its clinical application as an antiviral agent .

Neuroprotective Effects

This compound exhibits analgesic properties superior to common analgesics like aspirin and indomethacin. It also shows anticonvulsant effects in animal models, indicating potential use in treating neurological disorders .

Table 1: Summary of Biological Activities of this compound

Case Studies

• Colorectal Cancer Study : A study demonstrated that this compound treatment led to significant apoptosis in HCT116-derived xenografts, with enhanced effects observed when combined with vemurafenib .
• Bladder Cancer Sensitivity : In T24 and 5637 bladder cancer cells, this compound increased gemcitabine sensitivity by approximately 40-60%, indicating its potential as an adjunct therapy .
• Cytotoxicity Studies : Structure-activity relationship studies revealed that modifications to this compound's structure could reduce its cytotoxicity while maintaining antiviral efficacy against HCV .