Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 25, Issue 9, 2025

The biological name of garlic is Allium sativum L., a familiar spice with various health benefits. These benefits are mainly attributable to the compound diversity of garlic, which includes saponins, polysaccharides, organic sulfides, and phenolic compounds. Allicin exhibits therapeutic activity such as antibacterial, anticancer, anti-inflammatory, immunomodulatory, anti-diabetic, and cardiovascular protection. This present study explores the anticancer potential of allicin, including cell line studies that examine its effects on various cancer types by analyzing the growth inhibition of cancer cells at different allicin concentrations.

This study aims to present a concise overview of allicin, update patent statistics, and provide detailed insights into its wide range of therapeutic benefits, with a particular emphasis on its anticancer properties.

A literature review has been conducted using reliable sources, including ClinicalTrials.gov, ScienceDirect, PubMed, Scopus, and other reputable foundations, to assess the true potential of allicin in cancer therapeutics.

Allicin, a naturally occurring compound in garlic, represents a promising treatment approach for cancer due to its potent anticancer properties. Cell line studies have shown that various concentrations of allicin significantly inhibit cancer cell growth, underscoring its effectiveness against cancer types such as breast, pancreatic, liver, renal, osteosarcoma, gastric, colorectal, and stomach cancers. By effectively targeting cancer cells, allicin stands out as a potential therapeutic agent.

The primary goal of the review is to highlight the anticancer potential of allicin, along with an overview of clinical and patent studies.

Hepatocellular Carcinoma (HCC) is a highly prevalent cancer worldwide, necessitating effective treatment options. However, current treatments do not provide satisfactory results. Quinacrine, a synthetic drug belonging to the 9-aminoacridine family, has demonstrated promising antitumor effects.

The objective of the current study is to evaluate the anti-HCC effect of Quinacrine and explore whether quinacrine can improve the anti-HCC response of lenvatinib in vitro and in vivo.

The HepG2 and MHCC-97H cells were treated with Quinacrine. Cell proliferation and cell apoptosis were assessed using the Cell Counting Kit-8 (CCK8) Assay, Colony Formation Assay, and Annexin V/7-AAD staining method. The invasion and migratory ability of HepG2 and MHCC-97H cells were assessed by Transwell Assay. The level of ROS of HCC cells was measured using a ROS-kit by Flow cytometric analysis. Besides, an in vivo study was performed in the Balb/c nude mice bearing MHCC-97H tumors to analyze the function of Quinacrine in tumor growth.

Quinacrine can decrease cell viability in HepG2 and MHCC-97H cells, but not affect LO2 cells. Quinacrine impaired the colony formation, invasion and migratory ability in half-maximal inhibitory concentration (IC50). Quinacrine also significantly induced apoptosis in HepG2 and MHCC-97H cells in a concentration-dependent manner. On the one hand, ROS was significantly up-regulated in HCC cells after quinacrine treatment. On the other hand, We found quinacrine blocked autophagy flux in HepG2 and MHCC-97H cells. Moreover, Quinacrine significantly enhances the anti-HCC efficacy of lenvatinib in vitro. In the mouse MHCC-97H model, We found that combination therapy with Quinacrine and lenvatinib resulted in a smaller tumor volume and weight than inoculated with lenvatinib alone.

Our findings demonstrated that quinacrine exerts anti-HCC effects and sensitizes hepatocellular carcinoma to lenvatinib. Collectively, our study provides novel therapeutic insights for managing HCC and offers a valuable strategy for future clinical interventions in this field.

Prostate cancer (PC) affects millions of men, causing high mortality rates. Despite the treatment approaches, the options for metastatic castration-resistant prostate cancer (mCRPC), a lethal form of advanced PC, are still limited. Cabazitaxel (Cbx) is the last taxane-derived chemotherapeutic approved for Docetaxel-resistant mCRPC patients. However, its effects are limited due to the activation of several pathways. Therefore, new approaches are needed to increase the efficacy of Cbx. Usnic acid (UA) is a natural product with well-known anti-tumorigenic and synergistic effects with various chemotherapeutics. Although the cytotoxicity of UA and Cbx has been evaluated on mCRPC cells, the anti-tumorigenic effect of UA combination with any taxane has not been investigated yet. Thus, we aimed to evaluate the possible synergistic effect of Cbx+UA in mCRPC cells.

Cell viability and apoptosis were analyzed using WST-1 and Annexin-V. Morphological changes were visualized by fluorescent staining. Finally, cell cycle, mitochondrial health, and ROS levels were determined.

Based on WST-1 results, 25 µM UA exhibited significant additive and synergistic effects with the use of Cbx. Annexin V and cell cycle results showed that UA significantly enhanced the Cbx efficacy at increasing doses compared to using only Cbx (**p<0.01). Moreover, combined treatment significantly increased ROS levels and mitochondrial membrane depolarization compared with Cbx alone (**p<0.01).

Thus, the results suggest that UA increased the anti-tumorigenic effects of Cbx on mCRPC cells by increasing apoptosis, causing an increase in intracellular ROS and disrupting mitochondrial health. Consequently, combining UA and Cbx offers a new combined therapeutic strategy for mCRPC treatment.

Irisquinone, an important compound extracted from Semen Irisis, has been used clinically as a radiotherapy sensitizer for lung, oesophageal, head and neck, breast and leukemia cancers. However, the mechanism by which it acts against cancer is still unclear.

The present study aims to investigate the anti-tumor activity and mechanism of Irisquinone.

The effect of Irisquinone on cell viability and proliferation was evaluated using the CCK-8 assay. Fluorescence probe (Fast-TRFS) and DTNB assay were used to observe the inhibitory effect of Irisquinone on both intracellular and extracellular thioredoxin reductase (TrxR). The level of reactive oxygen species (ROS) in tumor cells was assessed using the DCFH-DA probe. Annexin V-FITC/PI, staining and microscopy experiments, were used to examine the apoptosis and pyroptosis. Western blotting analyses confirmed that Irisquinone induced apoptosis and pyroptosis in cancer cells by inhibiting TrxR to increase ROS generation.

Our research has shown that Irisquinone has anti-proliferative effects on several cancer cell lines while having low toxicity to normal cells. The amount of ROS induced by inhibition of TrxR activated the BAX (pro-apoptotic protein) and caspase-1(the pro-pyroptotic protein) to induce apoptosis and pyroptosis.

Irisquinone showed anticancer activity through inhibiting TrxR. These results suggested that Irisquinone will be developed to be an anti-tumor drug possibility.

The alkaloids of songorine, aconitine, and benzoylaconitine, as the processed products of Aconitum soongaricum Stapf., can significantly inhibit the migration and invasion of ovarian cancer cells in vitro. Herein, we studied the in vivo role and mechanism of these natural products in processed A. soongaricum Stapf.

A xenograft tumor model was constructed. Tumor volumes and weights were calculated. HE staining assessed the histopathological changes of tumors. Inflammatory factors were detected using ELISA. Gene and protein expressions of E-cadherin, N-cadherin, PIK3CA, and AKT1 proteins were measured using RT-qPCR and immunohistochemistry. Protein expressions of E-cadherin, N-cadherin, PIK3CA, AKT1, p-PIK3CA, and p-AKT1 proteins were detected using western blot analysis.

Songorine, aconitine, and benzoylaconine significantly inhibited the growth of tumors as evidenced by decreased tumor volume and weight. The extent and scope of tumor cell necrosis were less in the songorine group compared to the vehicle group. Songorine, aconitine, and benzoylaconine significantly reduced IL-6, IL-1β, and TNF-α levels. Furthermore, songorine, aconitine, and benzoylecgonine induced down-regulation of N-cadherin and AKT1 mRNA in comparison to the vehicle group. Meanwhile, songorine, aconitine, and benzoylaconine also significantly reduced N-cadherin, p-PIK3CA, and p-AKT1 proteins, while upregulating E-cadherin protein expression in comparison to the vehicle group. These effects were further enhanced when combined with the PI3K inhibitor LY294002.

Songorine, aconitine, and benzoylaconine may inhibit ovarian cancer growth in vivo by blocking the PI3K/AKT signaling pathway. Our findings may provide evidence for the clinical application of the processed products of Aconitum soongaricum Stapf. in ovarian cancer treatment.

Xanthene derivatives are a notable class of heterocyclic compounds widely studied for their significant biological impact. These molecules, found in both natural and synthetic forms, have attracted substantial scientific interest due to their broad spectrum of biological activities. The xanthene nucleus, in particular, is associated with a range of potential pharmaceutical properties, including antibacterial, antiviral, anti-inflammatory, anticancer, and antioxidant effects. Their structural flexibility allows for modifications that can enhance specific biological functions, making them valuable candidates in medicinal chemistry and drug development.

Multi-component reactions involving two equivalents of 5,5-dimethylcyclohexane-1,3-dione with aromatic aldehydes yield xanthene derivatives that are known for their biological activity. Additionally, fused xanthene derivatives are formed through subsequent heterocyclization reactions, resulting in compounds with a broad range of biological properties.

Various Xanthene derivatives incorporating thiophene and thiazole moieties were synthesized. Compounds 3a-c were further subjected to heterocyclization reactions to produce fused xanthene derivatives with additional heterocyclic components, enhancing their biological activity. The cytotoxic effects of the synthesized compounds were assessed across six cancer cell lines. Inhibition studies on c-Met kinase and the PC-3 cell line were conducted.

Additionally, the compounds' inhibitory activity against tyrosine kinases was evaluated, and morphological changes in the A549 cell line were observed with the two most potent compounds.

The synthesized heterocyclic compounds, derived from 5,5-dimethylcyclohexane-1,3-dione and related cyclohexanone derivatives, exhibited significant inhibitory effects across various cancer cell lines. Specifically, compounds 3b, 5c, 5d, 7b, 7c, 7d, 9a, 9b, 10b, 10c, 12c, 15b, 15c, 16b, 16c, 17c, 17d, 17e, and 17f demonstrated high levels of inhibition, indicating potential for further exploration of xanthene-based heterocyclic compounds to enhance anticancer properties.