Unlocking the pharmacological benefits of verticinone

INTRODUCTION

Fritillaria imperialis L., known in Iranian traditional medicine as “Laleh vazhgon” or “Ashke Maryam,” belongs to the Liliaceae family and possesses considerable ethnomedicinal significance.^[1] Conventionally, it has been utilized for the management of musculoskeletal pain, including joint pain, chronic daily headaches, and back pain. Verticinone, a naturally occurring isosteroidal alkaloid predominantly isolated from various species of F. imperialis L., has garnered increasing scientific interest in recent years due to its promising pharmacological activities, notably its anti-inflammatory and anticancer properties.^[2] Emerging research suggests that verticinone may modulate key biological pathways, such as apoptosis and cell cycle regulation, positioning it as a significant subject of inquiry within medicinal chemistry and pharmacology.^[3] While traditional medicine has long employed verticinone for its therapeutic benefits, particularly in the treatment of inflammation and pain, ongoing scientific investigation continues to validate these historical applications.^[4]

Verticinone exhibits distinctive physicochemical characteristics that underpin its biological activity. This compound typically presents as a white to off-white crystalline powder, characterized by the molecular formula C₂₇H₄₃NO₃.^[1,4] Its solubility profile indicates limited aqueous solubility, yet enhanced solubility in organic solvents, including ethanol and methanol, a feature that aids in its extraction and formulation for pharmaceutical purposes.^[5] Furthermore, verticinone demonstrates a comparatively low log P-value, implying advantageous permeability across biological membranes.^[6] These inherent physicochemical attributes are fundamental to elucidating the behavior of verticinone within biological systems and its potential utility in therapeutic applications.

The current studies are exploring the mechanisms of action of verticinone, focusing on its effects on key signaling pathways involved in inflammation and cancer progression. Preliminary findings suggest that it modulates the expression of various cytokines and growth factors, contributing to its anti-inflammatory properties.^[7] Verticinone and imperialine are both naturally occurring alkaloids extracted from various plants, and they have garnered attention for their pharmacological properties, particularly in the fields of anticancer and anti-inflammatory research. In addition, verticinone has shown promise in enhancing the sensitivity of cancer cells to conventional therapies, which could lead to more effective treatment regimens.^[8] However, more extensive clinical trials are necessary to establish its safety and efficacy for human use. If proven effective, verticinone could play a crucial role in developing new treatments for diseases related to inflammation and cancer, representing a significant advancement in modern medicine.^[9]

The study aims to explore the pharmacological effects of verticinone, hypothesizing that this alkaloid possesses significant anti-inflammatory and anticancer properties that can be harnessed for therapeutic applications. Specifically, the objectives include investigating the mechanisms by which verticinone induces apoptosis in cancer cells and modulates inflammatory pathways, as well as assessing its efficacy in enhancing the effectiveness of conventional cancer treatments. In addition, the study seeks to evaluate the safety profile of verticinone through in vitro and in vivo models, aiming to establish a comprehensive understanding of its potential benefits and limitations in clinical settings. By elucidating these effects, the research aspires to contribute valuable insights into the development of new treatment strategies for diseases associated with inflammation and cancer.

ANTICANCER EFFECTS

Verticinone’s mechanisms of action against cancer

Verticinone demonstrates notable anticancer properties through diverse mechanisms, principally by inducing apoptosis and differentiation in malignant cells. Investigations have revealed that verticinone effectively impedes the proliferation of immortalized and cancerous oral keratinocytes, leading to cell cycle arrest and apoptosis through a caspase-dependent pathway.^[10] Moreover, verticinone enhances differentiation in human promyelocytic leukemia HL-60 cells, suggesting a potential therapeutic strategy when used in conjunction with all-trans retinoic acid (ATRA).^[11] The underlying mechanisms of action involve the induction of apoptosis, characterized by elevated cytochrome c levels and altered expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) proteins, alongside cell cycle arrest at the G₀/G₁ phase, thereby inhibiting further cellular division and proliferation.^[10,12] In addition, verticinone promotes differentiation toward granulocytes in Human Leukemia 60 cells (HL-60) cells, a process considered critical for effective leukemia treatment.^[11]

Therapeutically, the synergistic effect of verticinone with ATRA suggests its potential to reduce the dosages of conventional therapies while enhancing their efficacy.^[11,13] Verticinone promotes programmed cell death in cancer cells by activating caspase pathways vital for apoptosis and alters the expression of anti-apoptotic proteins like Bcl-2, leading to increased cancer cell death.^[14] This compound also inhibits critical signaling pathways, including phosphatidylinositol 3’-kinase-protein kinase B and signal transducer and activator of transcription 3 (STAT3), which are often dysregulated in cancer.^[15] By interfering with these pathways, verticinone can suppress tumor growth and metastasis.^[16] In addition, it has been shown to sensitize-resistant cancer cells to conventional chemotherapy, potentially overcoming multidrug resistance.^[17] This sensitization results from the modulation of drug transporters and increased bioavailability of chemotherapeutic agents.^[14] This approach may lead to more effective and sustainable therapeutic options, addressing the challenges of cancer recurrence and resistance. As research continues to uncover the full spectrum of verticinone’s pharmacological effects, it holds promise for the development of innovative treatment modalities in oncology.

Figure 1 provides an overview of the key mechanisms that contribute to the anti-cancer properties of verticinone.

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Figure 1:

Verticinone’s anti-cancer mechanisms.

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ANTI-INFLAMMATORY AND ANALGESIC ACTIVITIES

Therapeutic potential of verticinone in pain and inflammation

Alkaloids derived from F. imperialis are extensively acknowledged for their varied therapeutic applications within Iranian traditional medicine. They are utilized for the relief of numerous conditions, including joint pain, chronic daily headaches, dental discomfort, muscle pain, dysmenorrhea, sore throats, and rheumatism.^[26] Notably, verticinone exhibits an antineuropathic effect, potentially mediated through the promotion of signal STAT3 phosphorylation. Furthermore, its antinociceptive activity is partially modulated by the nitric oxide (NO)-cyclic guanosine monophosphate-potassium channel pathway, alongside the activation of transient receptor potential vanilloid, peroxisome proliferator-activated receptor, opioid, and gamma-aminobutyric acid receptors. This alkaloid may therefore play a significant role in mediating antinociceptive, antineuropathic, and antimigraine effects.^[1]

A summary of the primary mechanisms underlying the anti-inflammatory and analgesic effects of verticinone is illustrated in Figure 2.

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Figure 2:

Mechanisms of verticinone’s anti-inflammatory and analgesic effects. TRPV: Transient receptor potential vanilloid, PPAR: Peroxisome proliferator-activated receptor, GABA: Gamma-aminobutyric acid, STAT: Signal transducer and activator of transcription, MAPK: Mitogen-activated protein kinase, NF-κB: Nuclear factor kappa B, NO-cGMP: Nitric oxide-cyclic guanosine monophosphate.

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ANTITUSSIVE AND EXPECTORANT PROPERTIES

In traditional Chinese medicine, the unprocessed bulb of this plant has been a vital treatment for alleviating coughs and reducing mucus production.^[27] Verticinone exhibits significant antitussive and expectorant properties, positioning it as a promising candidate for cough treatment. Research indicates that verticinone acts through central and peripheral mechanisms, effectively reducing cough reflex and enhancing mucus clearance. The antitussive effect of verticinone is linked to its interaction with central opioid receptors, as demonstrated in studies utilizing naloxone to block its effects.^[28] This compound has shown a significant reduction in cough induced by irritants, particularly effective in citric acid-induced models.^[29] In addition, verticinone facilitates expectoration by modulating respiratory secretions, aiding mucus clearance from the airways.^[30] Its combination with other bioactive compounds, such as cholic acid, enhances its expectorant activity, improving therapeutic outcomes. Studies also indicate that verticinone and its derivatives, such as verticinone cholic acid ester, possess low toxicity and non-addictive properties, making them suitable for clinical use.^[29]

SEDATIVE EFFECTS

The sedative effects of verticinone have been documented in various pharmacological studies, revealing its potential in managing conditions such as anxiety and insomnia. It is believed that verticinone exerts its sedative properties by modulating neurotransmitter systems, particularly through the inhibition of acetylcholinesterase, which enhances cholinergic signaling and induces relaxation. This compound has demonstrated efficacy in alleviating symptoms associated with neurological disorders, positioning it as a promising alternative to conventional sedatives.^[30] Furthermore, research suggests that verticinone may be more effective than traditional sedatives like valerian extract, offering a treatment option with minimal side effects.^[19,31] However, while verticinone shows significant potential, other substances, such as gamma-pyrones, also exhibit sedative effects and are utilized in various therapeutic contexts, underscoring the diverse options available for managing sedative needs.^[32]

HYPOGLYCEMIC POTENTIAL

A prior in vitro investigation by the author assessed the effects of verticinone on β-TC6 pancreatic and C2C12 skeletal muscle cells, with a focus on cellular viability, the activity of carbohydrate-hydrolyzing enzymes (a-amylase and a-glucosidase), insulin secretion, glucose uptake, and the levels of advanced glycation end products (AGEs), including 3-deoxyglucosone, methylglyoxal, and pentosidine, as well as glyoxalase I activity. The findings suggest a potential hypoglycemic effect associated with verticinone; however, elevated concentrations were correlated with increased AGE levels, underscoring the necessity for further research to fully elucidate its safety profile and efficacy.^[33]

VERTICINONE AGAINST TOXOPLASMA GONDII

Verticinone has been identified as a potential drug to combat T. gondii, a parasite responsible for toxoplasmosis. Researchers focused on a specific protein in the parasite called Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1), which is crucial for its survival. They analyzed protein sequences to find a match with TgCDPK1 and identified a target protein (3HX4) that closely resembles it. Using a drug database, they performed docking studies to see how well various molecules could bind to this target protein. Verticinone stood out because it showed strong binding energy, indicating it could effectively attach to the protein and potentially inhibit the parasite. Furthermore, it was found to have minimal toxic side effects, making it a promising candidate for treating toxoplasmosis.^[4]

ANTI-FIBROTIC EFFECTS

The study conducted by Yuan et al.³⁴ investigated the effects of alkaloids extracted from Fritillaria cirrhosa on pulmonary fibrosis in a bleomycin-induced animal model. The findings demonstrated that verticinone exhibited protective effects against pulmonary fibrosis in rats, as supported by biochemical analyses and histopathological evaluations. Furthermore, western blot analysis revealed that verticinone reduced the expression of alpha-smooth muscle actin and collagen I, decreased the phosphorylated NF-kB/NF-kB ratio, and increased IkBa levels, indicating that its protective mechanisms are mediated, at least in part, through the inhibition of the NF-kB signaling pathway.^[34]

PHARMACOKINETICS

The pharmacokinetics of verticinone reveal significant insights into its absorption, distribution, metabolism, and excretion. Studies indicate that verticinone exhibits gender-dependent pharmacokinetic profiles, with male rats showing a higher oral bioavailability (45.8%) compared to females (2.74%). In addition, verticinone demonstrates widespread tissue distribution, particularly in non-brain organs, and is metabolized more in females than males, with <4% excreted unchanged in males and <1% in females.^[6] This suggests notable gender differences in pharmacokinetics, likely mediated by cytochrome P450 enzymes, similar to other compounds like ent-verticilide (another steroidal alkaloid).^[35]

OVERVIEW OF IDENTIFIED ALKALOIDS IN F. IMPERIALIS L

The diverse array of alkaloids identified in F. imperialis L., along with their corresponding physicochemical properties and biological activities, is systematically compared in Table 1. This table provides a comprehensive overview of the current knowledge regarding these compounds, including their reported abundance within the plant, molecular characteristics such as formula and weight, and documented pharmacological effects ranging from anticholinergic and enzyme inhibitory actions to potential anticancer properties. Furthermore, the table highlights the limited quantitative data on alkaloid levels and underscores the need for further research to fully elucidate the therapeutic potential and safety profiles of these compounds, particularly in relation to the traditional uses of F. imperialis.^[11,36-38]

CURRENT LIMITATIONS AND FUTURE PERSPECTIVES

While the preclinical studies highlighted in this review demonstrate promising pharmacological activities for verticinone, several limitations warrant consideration. Further research is essential to fully elucidate its therapeutic potential and ensure its safe clinical application. Key areas that require attention include comprehensive formulation studies to optimize delivery and bioavailability, rigorous Phase I, II, and III clinical trials to evaluate efficacy and safety in human populations, and detailed investigations into its long-term safety profile, potential toxicities, and drug-drug interactions. In addition, further studies should explore the precise mechanisms of action of verticinone in various disease models and identify potential biomarkers for its therapeutic effects.

CONCLUSION

In summary, verticinone, an iso-steroidal alkaloid from F. imperialis L., demonstrates significant pharmacological potential, particularly in oncology and inflammation management. It is ability to induce apoptosis and inhibit cancer cell proliferation positions it as a valuable agent for enhancing conventional treatments and addressing multidrug resistance. In addition, verticinone exhibits anti-inflammatory, analgesic, and sedative properties, making it a versatile candidate for various therapeutic applications. Its favorable physicochemical characteristics support its bioavailability and interaction with key biological pathways, such as MAPK and NF-kB. While preliminary findings are encouraging, further clinical trials are necessary to confirm its safety and efficacy for broader therapeutic use.