Research Progress on the Antitumor Effects of Escin and Its Mechanisms

Research Progress on the Antitumor Effects of Escin and Its Mechanisms

 Introduction

    Escin, a natural triterpenoid saponin compound extracted from the seeds of plants in the genus Aesculus, has long been used in traditional medicine for its anti-inflammatory, anti-edema, and vascular permeability-improving properties. In recent years, with increased research into the antitumor activity of natural products, escin's potential as an antitumor agent has been gradually discovered, becoming a hotspot in cancer research. A growing body of preclinical research indicates that escin and its derivatives can inhibit tumor cell proliferation, invasion, and metastasis, and induce cell death through multiple mechanisms, showing promising antitumor prospects. This article aims to systematically review the main mechanisms of escin's antitumor action, its research progress in different cancer types, the development of novel delivery systems, and the challenges and future directions for research, providing a theoretical reference for the translational research and clinical application of this compound.

Antitumor Mechanisms of Escin

   The antitumor activity of escin involves multiple pathways and targets. These interconnected mechanisms collectively form the pharmacological basis of escin's antitumor effects.

2.1 Induction of Tumor Cell Apoptosis

    Apoptosis induction is one of the primary mechanisms of escin's antitumor action. Studies show that escin can effectively induce tumor cell apoptosis through the mitochondrial pathway. Research on nanocellulose-loaded escin found that the complex exhibited significant selective cytotoxicity against lung cancer A549 and liver cancer HepG2 cells, a mechanism closely related to mitochondrial membrane potential collapse and a sharp increase in Reactive Oxygen Species (ROS) levels. Experimental data showed that after escin treatment, intracellular ROS levels surged by 300% within 6 hours, accompanied by substantial mitochondrial superoxide production, ultimately leading to tumor cell apoptosis. This disruption of mitochondrial function theoretically allows escin to circumvent resistance to traditional chemotherapy drugs in some tumor cells.

2.2 Inhibition of Tumor Cell Migration and Invasion

    Metastasis is one of the most lethal characteristics of malignant tumors and a major cause of treatment failure. Escin shows significant effects in inhibiting tumor cell migration and invasion. In colorectal cancer studies, escin effectively inhibited Trimethylamine N-oxide (TMAO)-induced migration and invasion of HCT116 cells. Scratch wound and Transwell assay results showed that cell migration and invasion abilities decreased significantly in the escin-treated group (P<0.001 and P<0.01, respectively). This inhibition was closely associated with escin's downregulation of the SRC-BTK-TRIO signaling pathway, which plays a key role in regulating cytoskeleton reorganization and cell motility. Furthermore, studies observed changes in the expression of epithelial-mesenchymal transition (EMT)-related markers after escin treatment, further suppressing the metastatic potential of tumor cells.

2.3 Induction of Ferroptosis

    Ferroptosis is a recently discovered iron-dependent, lipid peroxidation-driven form of programmed cell death that plays an important role in tumor suppression. The latest research found that escin can trigger ferroptosis in hepatocellular carcinoma by inhibiting the Nrf2-xCT/GPx4 axis. This mechanism involves the disruption of the cellular antioxidant defense system, leading to lipid peroxide accumulation and ultimately cell death. Notably, ferroptosis shows unique advantages in combating tumor cells resistant to traditional apoptosis inducers, providing a theoretical basis for escin's application in refractory tumors. The ferroptosis induced by escin, combined with its mechanism of downregulating LOXL expression to inhibit the EMT process in triple-negative breast cancer, forms the pharmacological basis for its multi-pathway antitumor effects.

2.4 Cell Cycle Arrest

Escin also exerts antitumor effects by interfering with the normal cell cycle progression of tumor cells. Studies indicate that escin can affect the expression and activity of cell cycle regulators, causing cell cycle arrest at specific checkpoints. In studies on gastric cancer SGC-7901 cells, flow cytometry detected significant changes in cell cycle distribution after escin treatment. This cycle arrest not only inhibited tumor cell proliferation but also increased cell sensitivity to apoptotic signals, creating a dual mechanism for suppressing tumor growth.

Table 1: Main Antitumor Mechanisms of Escin

  Application of Escin in Specific Cancer Types

3.1 Colorectal Cancer

   Colorectal cancer is a common gastrointestinal malignancy worldwide with persistently high incidence and mortality rates. In research on escin against colorectal cancer, regulation of the SRC-BTK-TRIO signaling pathway has been confirmed as one of its primary mechanisms. Experimental studies show that escin effectively inhibits TMAO-induced proliferation, migration, and invasion of HCT116 cells. Specific data indicate that escin intervention significantly inhibits cancer cell proliferation (P<0.01) and reduces their migration (P<0.001) and invasion (P<0.01) abilities, while downregulating the expression of SRC (P<0.05), BTK (P<0.01), and TRIO (P<0.05) proteins. These findings not only reveal the specific mechanism of escin against colorectal cancer but also provide new potential targets for its treatment.

3.2 Liver Cancer

    Hepatocellular carcinoma is the most common primary liver malignancy, usually with a poor prognosis due to difficulties in early diagnosis and frequent treatment resistance. Recent studies have found that escin shows unique advantages in liver cancer treatment. A study published in 2025 systematically explored the mechanism of escin in treating liver cancer using a combination of network pharmacology, molecular docking, and in vivo experimental validation. Simultaneously, another study confirmed that escin can inhibit hepatocellular carcinoma by triggering ferroptosis, specifically through inhibiting the Nrf2-xCT/GPx4 axis. These studies reveal the multi-target characteristics of escin against liver cancer from different perspectives, providing new ideas for its treatment.

3.3 Gastric Cancer

    Gastric cancer is a common malignant tumor globally, with the SGC-7901 cell line often used as an experimental model. As early as 2009, studies focused on the effect and mechanism of escin against SGC-7901 cells in vitro. That study used the MTT assay to observe the inhibitory effect of the drug on SGC-7901 tumor cell proliferation, flow cytometry to detect changes in the tumor cell cycle, and FITC-Annexin V/PI double staining to detect tumor cell apoptosis. These experimental methods provided a reliable technical path for evaluating the anti-gastric cancer activity of escin and laid a methodological foundation for subsequent research.

3.4 Ovarian Cancer

    Ovarian cancer is a common gynecological malignancy. Due to its occult early symptoms, most patients are diagnosed at an advanced stage, resulting in poor treatment outcomes. The latest research published in August 2025 revealed BNIP3 as a potential target and prognostic biomarker for escin in treating ovarian cancer. This discovery not only clarifies the mechanism of escin against ovarian cancer but also provides a new biomarker for its prognosis assessment, holding significant clinical translational value.

Table 2: Overview of Escin Research in Different Cancer Types

4 Novel Delivery Systems and Combination Therapy Strategies

4.1 Development of Nano-Delivery Systems

    Escin faces challenges in clinical application such as poor water solubility, inadequate stability, and limited targeting. To overcome these limitations, researchers have developed various novel delivery systems. A targeted escin delivery system based on Cellulose Nanofibers (CNF) reported in 2025 represents a major breakthrough in this field.

This delivery system uses laboratory-synthesized cellulose nanofibers (CNF) as carriers. Multi-dimensional characterization including UV-Vis, FTIR, and SEM-EDX confirmed efficient drug loading. Molecular docking showed a binding energy of -8.4 kcal/mol (Ki=6.88×10⁻⁷⁷ M), indicating a very strong interaction between escin and the carrier. Researchers optimized the optimal ratio using response surface methodology: when the drug and CNF were combined at a 10:3 ratio, the Encapsulation Efficiency (EE%) soared to 92%, and the Drug Loading (DL%) simultaneously reached 15.8%.

Most notably, the system exhibited intelligent pH-responsive properties: in a simulated tumor microenvironment (pH 5.0), the cumulative release reached 85% over 72 hours, while only 35% was released at physiological pH 7.4, equivalent to an intelligent missile with a "tumor GPS". This characteristic enables escin to selectively kill tumor cells while reducing impact on normal tissues. Cell experiments confirmed that this nano-system's killing efficiency for lung cancer A549 and liver cancer HepG2 cells was 8 times higher than that for normal lung cells L132.

4.2 Synergistic Therapy Strategies

The combination of escin with existing anticancer therapies shows promising synergistic effects. Studies indicate that combining escin with platinum-based drugs (like cisplatin) can significantly reduce the IC50 value by 3-5 times. This synergistic mechanism involves P-gp efflux pump inhibition and Bcl-2/Bax ratio regulation, helping to overcome tumor cell drug resistance.

Furthermore, escin can simultaneously alleviate tumor-associated inflammation and osteoclast activation in the bone metastasis microenvironment through NF-κB/IL-6 crosstalk, demonstrating a "one-drug, multiple-target" therapeutic characteristic. This multi-target mechanism gives escin significant clinical potential in treating cancer patients complicated with inflammation, osteoporosis, and other conditions.

5 Challenges and Future Directions

Although significant progress has been made in escin antitumor research, several challenges remain before its successful translation into a clinical anticancer drug.

5.1 Limitations of Current Research

Most current studies on escin's antitumor effects remain at the preclinical stage, including cell experiments and a limited number of animal studies. While these studies demonstrate escin's antitumor potential, there is still a considerable distance to clinical application. Data on escin's in vivo pharmacokinetic properties, bioavailability, and long-term safety are still insufficient and require systematic evaluation.

Furthermore, escin's therapeutic window and dose-dependent toxicity are also issues requiring focused attention. Some studies suggest that high doses of escin may cause cardiomyocyte calcium overload risk. Although this toxicity is also common in other saponin compounds, clinically applicable doses must be determined through rigorous safety evaluations.

5.2 Future Research Directions

Future research on escin's antitumor effects should focus on the following directions:

First, there is a need to strengthen escin structure optimization and derivative development. Improving its water solubility and stability while reducing toxic side effects through structural modification. The chemical structure of escin A has been clarified [C₅₅H₈₆O₂₄, molecular weight 1131.26], with its C27 free hydroxyl group and F-ring open structure being key to activity, providing clear targets for structural optimization.

Second, escin combination therapy regimens should be explored. Based on the synergistic effects between escin and chemotherapy drugs like cisplatin, systematically evaluating its efficacy and safety when combined with existing standard treatment regimens may lead to the development of more effective combination strategies.

Third, there is a need to promote more translational medicine and clinical research. Based on completed preclinical studies, early-stage clinical trials should be initiated as soon as possible to evaluate the safety, tolerability, and preliminary efficacy of escin in humans, providing a basis for its eventual clinical application.

Finally, further development of novel delivery systems is warranted. In addition to the reported nanocellulose system, other nanocarriers (such as liposomes, polymer nanoparticles, etc.) could be explored for escin delivery to improve its targeting and therapeutic efficacy.

 Conclusion

  Escin, as a naturally derived compound, exerts antitumor effects through multiple mechanisms including induction of apoptosis, inhibition of migration and invasion, induction of ferroptosis, and cell cycle arrest. It shows significant activity in various tumor models including colorectal cancer, liver cancer, gastric cancer, and ovarian cancer. The development of nano-delivery systems provides new strategies for its targeted therapy.

Although escin antitumor research is still in its early stages, its multi-target mechanism of action and synergistic effects with existing chemotherapy drugs give it broad development prospects. With optimization of delivery technologies, in-depth structural modification, and advancement of clinical research, escin is expected to play an important role in future cancer treatment, particularly when combined with traditional chemotherapy drugs, potentially creating synergistic effects and providing new treatment options for cancer patients.

Future research should focus on overcoming the pharmaceutical limitations of escin, clarifying its in vivo targets, and systematically evaluating its safety and efficacy to accelerate the transformation of this natural active ingredient into a clinical antitumor drug.