Astragaloside IV overcoming cancer cell drug resistance

Beat Cancer Cell Resistance: How Astragaloside IV Could Be a Game-Changer

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Lena Kashyap in Health & Wellness November 2026 • 4 min read.

"New research highlights Astragaloside IV's potential to combat drug resistance in liver cancer by targeting a key signaling pathway."


Chemotherapy remains a vital tool in cancer treatment, but its effectiveness is often hampered by the development of drug resistance. Cancer cells can become resistant to multiple antineoplastic drugs, a phenomenon known as multidrug resistance (MDR). One major player in MDR is P-glycoprotein (P-gp), a protein that pumps drugs out of cells, reducing their effectiveness. Overcoming MDR is a crucial challenge in improving cancer treatment outcomes.

Astragaloside IV (ASIV), a natural compound extracted from the herb Radix Astragali, has shown promise in reversing MDR. Previous studies suggest that ASIV can downregulate the expression of genes responsible for drug resistance, making cancer cells more susceptible to chemotherapy. However, the precise mechanisms by which ASIV achieves this effect are still being investigated.

A recent study delved deeper into ASIV's mechanism of action, focusing on the JNK/c-Jun/AP-1 signaling pathway. This pathway is known to play a role in MDR, and researchers hypothesized that ASIV might exert its effects by interfering with this pathway. The study used a liver cancer cell line resistant to the drug 5-fluorouracil (Bel-7402/FU) to explore ASIV's potential.

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Cancer Resistance and AS-IV

Cancer remains a global intractable disease, with morbidity and mortality increasing year by year in developing countries. The Frontiers review and its PubMed record report that surgery and chemotherapy can produce severe side effects and drug resistance. A 2023 review further reports that astragaloside IV can enhance sensitivity to antitumor drugs or reverse tumor-cell resistance, suggesting that it may act through multiple antitumor pathways.

From Traditional Medicine to Oncology

Astragaloside IV is one of the major compounds isolated from Astragalus membranaceus Bunge. A technical guide describes it as a primary active saponin extracted from the dried root of Astragalus membranaceus, a perennial plant used for centuries in traditional Chinese medicine. Modern research has reported antitumor effects involving inhibition of cancer-cell proliferation, invasion, and metastasis across various cancer types.

Unlocking ASIV's Potential: Targeting the JNK/c-Jun/AP-1 Pathway

Astragaloside IV overcoming cancer cell drug resistance

The study's findings revealed that ASIV significantly impacts the JNK/c-Jun/AP-1 signaling pathway in Bel-7402/FU cells. Researchers observed that ASIV treatment led to a decrease in the protein expression of phosphorylated JNK (p-JNK) and phosphorylated c-Jun (p-c-Jun). Phosphorylation is a crucial step in activating these proteins, so ASIV appears to be effectively dampening the activity of this signaling cascade.

To further confirm the role of the JNK pathway, the researchers used a specific JNK inhibitor called SP600125. They found that SP600125, like ASIV, reduced the mRNA expression levels of MDR1 and P-gp. This indicates that inhibiting the JNK pathway, either through ASIV or a direct inhibitor, can effectively reduce the production of proteins responsible for drug resistance.

  • Reduced Protein Expression: ASIV decreases the levels of key proteins (p-JNK and p-c-Jun) in the JNK/c-Jun/AP-1 pathway.
  • mRNA Reduction: Both ASIV and a JNK inhibitor (SP600125) lower the mRNA expression of MDR1 and P-gp.
  • DNA Binding Activity: ASIV and SP600125 reduce the DNA-binding activity of activator protein-1 (AP-1).
  • Increased Accumulation: ASIV and SP600125 boost the intracellular accumulation of fluorescent P-gp substrates, enhancing drug effectiveness inside cells.
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Expanding Mechanistic Evidence

A 2025 review synthesized more than 41 peer-reviewed studies on astragaloside IV and astragalus polysaccharide in digestive-system cancers. Its coverage includes hepatocellular carcinoma, colorectal cancer, gastric cancer, and other digestive-system malignancies. Another 2025 systematic review focuses specifically on the molecular mechanisms of astragaloside IV in hepatocellular carcinoma therapy, while a 2026 report describes astragaloside IV-loaded zeolitic imidazolate framework-8 being investigated to improve bioavailability and antitumor activity against non-small cell lung cancer.

An Unresolved Resistance Mechanism

Evidence on astragaloside IV-related resistance reversal remains incomplete. The cited report states that AS-IV-induced downregulation of mdr1 was observed, but the signaling pathway responsible for that change remained to be elucidated. This unresolved mechanism limits how confidently the resistance-reversal process can be explained.

Resistance Across Cancer Models

The cited retinoblastoma study examined the multidrug-resistance reversal activity of FG020318 in the SO-Rb50/VCR subline, which was resistant to 200 μg/L vincristine. The leukemia minireview reports that cell lines expressing mdr1 resist several structurally unrelated lipophilic drugs, including anthracyclines, vinca alkaloids, and epopodophyllotoxins. Together, these sources illustrate that resistance can be studied both in a defined drug-selected model and across multiple drug classes.

The study also investigated the effect of ASIV on the DNA-binding activity of activator protein-1 (AP-1), a transcription factor downstream of the JNK pathway. Using electrophoretic mobility shift assays, they discovered that ASIV reduced the DNA-binding activity of AP-1. This suggests that ASIV not only inhibits the activation of JNK and c-Jun but also reduces the ability of AP-1 to promote the expression of genes involved in drug resistance. Further flow cytometric analysis showed that ASIV increased the intracellular accumulation of fluorescent P-gp substrates, meaning that more drugs are able to stay inside the cancer cells, thus further killing them.

Future Directions: Towards More Effective Cancer Therapies

This research provides valuable insights into the mechanisms by which ASIV can overcome drug resistance in liver cancer cells. By targeting the JNK/c-Jun/AP-1 signaling pathway, ASIV offers a potential strategy for improving the effectiveness of chemotherapy. Further research is needed to explore whether ASIV also affects other MAPK signaling pathways and to evaluate its efficacy in combination with other anticancer drugs. These findings pave the way for the development of novel therapeutic approaches to combat MDR and improve outcomes for cancer patients.

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Targeting the JNK/c-Jun/AP-1 Pathway

The cited article presents astragaloside IV as a natural compound that might help overcome drug resistance in liver cancer cells. It identifies the JNK/c-Jun/AP-1 pathway as the proposed therapeutic target. The article frames this approach as a potential route toward more effective cancer therapies, but the wording indicates that this remains an emerging possibility rather than an established clinical outcome.

The tested concentrations behind the pathway result

  • 11 µM and 0.1 mM treatment concentrationsThe study tested the JNK inhibitor SP600125 at 11 µM, while the ASIV experiments measuring pathway proteins and AP-1 activity used 0.1 mM ASIV.[1]

Reading the findings in resistant liver-cancer cells

The results connect ASIV's effect on drug resistance with a signaling sequence that includes JNK, c-Jun, and AP-1, rather than showing only a change in the resistance marker itself.[1]

Because the evidence comes from 5-fluorouracil-resistant Bel-7402/FU cells, it shows a laboratory mechanism in this model; it does not establish that the same effect occurs in people or in other cancers.[1]

Limits identified around the ASIV mechanism

  • The study did not resolve whether ERK or p38 MAPK also contribute to ASIV-related mdr1 downregulation.[2]

ASIV and signaling in 5-fluorouracil-resistant liver-cancer cells

Population5‑fluorouracil‑resistant Bel‑7402/FU human hepatic cancer cells[1]
ComparisonJNK pathway inhibitor SP600125[1]
Main outcomemdr1 expression and drug resistance[1]
Times cited28[1]

How this cell study fits the resistance literature

A later review also characterizes ASIV as a proposed P-glycoprotein-mediated resistance agent whose mechanism was explored in hepatic cancer cells, which is consistent with this study's laboratory focus.[3]

What remains unresolved about ASIV and resistance

  • Do ERK or p38 MAPK participate in the same ASIV-related mdr1 response?[2]
  • Would the pathway findings remain consistent in other resistant cancer-cell models or with different anticancer drugs?[1] [4] [5]
  • How closely does reduced mdr1 expression correspond to functional resistance reversal beyond the tested cell model?[1] [5]

Terms used in the resistance study

P-glycoprotein
A protein encoded by the mdr1 gene[5]

Sources

  1. Astragaloside IV downregulates the expression of MDR1 in Bel-7402/FU human hepatic cancer cells by inhibiting the JNK/c-Jun/AP-1 signaling pathway (Spandidos Publications, 2017)
  2. www.spandidos-publications.com (www.spandidos-publications.com, 2017)
  3. Chemical diversity and biological activities of the saponins isolated from Astragalus genus: focus on Astragaloside IV (2019)
  4. Reversal effect of FG020318 on multidrug resistance in retinoblastoma cell line SO-Rb50 (Zhongguo bingli shengli zazhi, 2007)
  5. The multidrug resistance in human leukemias. Minireview. (PubMed, 1998)

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.3892/mmr.2017.6924, Alternate LINK

Title: Astragaloside Iv Downregulates The Expression Of Mdr1 In Bel-7402/Fu Human Hepatic Cancer Cells By Inhibiting The Jnk/C-Jun/Ap-1 Signaling Pathway

Subject: Cancer Research

Journal: Molecular Medicine Reports

Publisher: Spandidos Publications

Authors: Pei-Pei Wang, Jia-Jie Luan, Wen-Ke Xu, Lin Wang, Du-Juan Xu, Chun-Yan Yang, Yan-Hong Zhu, Ya-Qin Wang

Published: 2017-03-01

Everything You Need To Know

1

What is Astragaloside IV, and why is it relevant to this research?

Astragaloside IV (ASIV) is a natural compound extracted from the herb Radix Astragali. In this context, it is highlighted for its potential to combat drug resistance in liver cancer cells. ASIV is being investigated for its ability to reverse multidrug resistance (MDR), a phenomenon where cancer cells become resistant to multiple chemotherapy drugs. Its significance lies in its potential to improve the effectiveness of chemotherapy treatments by making cancer cells more susceptible to the drugs.

2

What is the JNK/c-Jun/AP-1 signaling pathway, and why is it important in this context?

The JNK/c-Jun/AP-1 signaling pathway is a key pathway involved in drug resistance in cancer cells. In this context, ASIV has been shown to target this pathway. The pathway's importance lies in its role in promoting the expression of genes that contribute to drug resistance, such as P-glycoprotein (P-gp). By interfering with this pathway, ASIV can reduce the production of these resistance-related proteins, thus enhancing the effectiveness of chemotherapy. The implications are that by targeting the JNK/c-Jun/AP-1 pathway, ASIV could make cancer cells more vulnerable to chemotherapy.

3

What is P-glycoprotein (P-gp), and what role does it play in this research?

P-glycoprotein (P-gp) is a protein that plays a significant role in multidrug resistance (MDR) in cancer cells. It functions as an efflux pump, pushing chemotherapy drugs out of the cancer cells, thereby reducing the drugs' effectiveness. The significance of P-gp is that it directly contributes to the failure of chemotherapy. In this context, ASIV has been shown to reduce the expression of P-gp, leading to an increased accumulation of chemotherapy drugs inside the cancer cells. This implies that by inhibiting P-gp, ASIV can help overcome drug resistance and improve the efficacy of chemotherapy.

4

What is multidrug resistance (MDR), and why is it a problem in cancer treatment?

Multidrug resistance (MDR) is the phenomenon where cancer cells develop resistance to multiple chemotherapy drugs. It is a significant challenge in cancer treatment because it limits the effectiveness of chemotherapy, a vital tool in fighting cancer. In the context of this research, MDR is overcome by Astragaloside IV. Cancer cells become resistant through mechanisms like increased expression of P-glycoprotein (P-gp), which pumps drugs out of the cell. The implications of MDR are that treatment can fail due to cancer cells developing this resistance.

5

What is the role of activator protein-1 (AP-1), and why is it important?

The role of activator protein-1 (AP-1) is as a transcription factor downstream of the JNK pathway, involved in drug resistance. AP-1 binds to DNA and promotes the expression of genes involved in drug resistance. Its significance here is that it directly influences the expression of genes that contribute to drug resistance. By reducing the DNA-binding activity of AP-1, ASIV helps to reduce the expression of genes that cause drug resistance, and ultimately improves chemotherapy effectiveness. The implications are that by inhibiting AP-1, ASIV reduces the cancer cell's ability to resist chemotherapy.

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