Key Takeaways & Executive Findings
- •• PPT suppresses viability of paclitaxel-resistant breast cancer cells in a dose-dependent manner and enhances PTX efficacy when combined. • Combined PPT and PTX treatment induces apoptosis by increasing Bax/Bcl-2 ratio and cleaved caspase-3/PARP, while decreasing survivin. • PPT reduces inflammatory cytokines (IL-6, IL-8, CXCL1, CCL2) and cancer stem cell markers (OCT4, SOX2, NANOG, ALDH1, CD44), and inhibits NF-κB activity. • The combination therapy impairs tumor sphere formation, indicating potential to overcome drug resistance by targeting CSCs and inflammation.
Abstract
AIM: To investigate the effect of protopanaxatriol (PPT) on the drug resistance of paclitaxel (PTX)-resistant human breast cancer MDA-MB-231 cells (MB231-PR cells). METHODS: The MB231-PR cells were constructed as cell models. They were treated with PPT, and incubated for a certain period of time according to the experimental settings. CellTiter-Glo was used to determine the viability of MB231-PR cells and MDA-MB-231 parental cells (MB231-PT cells). The change of sub-G1 phase was detected by flow cytometry. Western blot was used to evaluate the apoptosis-related proteins, such as cleaved caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and survivin. The activity of nuclear factor-κB (NF-κB) was detected by luciferase reporter assay and immunofluorescence assay. The mRNA expression levels of interleukin-6 (IL-6), IL-8, chemokine CXC motif ligand 1 (CXCL1), chemokine CC motif ligand 2 (CCL2), CD44, NANOG, octamer-binding transcription factor 4 (OCT4), sex-determining region Y-box 2 (SOX2) and aldehyde dehydrogenase 1 (ALDH1) were detected by qPCR. The protein levels of IL-6 and IL-8 were measured by ELISA. Tumor sphere formation assay was used to evaluate the characteristics of stem cells. RESULTS: (1) The viability of MB231-PR cells was suppressed by PPT treatment in a dose-dependent manner compared with MB231-PT cells (P<0.01). Besides, the viability of MB231-PR cells was decreased after combined treatment with PPT and PTX (P<0.01), the accumulation of sub-G1 phase was induced (P<0.01), the ratio of Bax/Bcl-2 was elevated (P<0.01), and the protein levels of survivin, cleaved PARP and cleaved caspase-3 were increased (P<0.05). (2) After PPT treatment combined with PTX, the mRNA expression of inflammatory cytokines (IL-6, IL-8, CXCL1 and CCL2) and cancer stem cell-related markers (OCT4, SOX2, NANOG, ALDH1 and CD44) was reduced (P<0.05), and the protein levels of IL-6 and IL-8 were decreased (P<0.01). The activity of NF-κB in MB231-PR cells was suppressed (P<0.05), and the growth of tumor spheres from MB231-PR cells was damaged (P<0.05). (3) Immunofluorescence assay showed that PTX induced nuclear p-p65 expression, but this effect was attenuated by PPT. CONCLUSION: Combined treatment with PPT and PTX could attenuate PTX resistance of MB231-PR cells by inhibiting inflammatory cytokines and cancer stem cells.
1. Introduction
Breast cancer has become the most common cancer in females, accounting for 11.7% of all cancer cases. Triple-negative breast cancer (TNBC) is an aggressive, metastatic and highly drug-resistant subtype of breast cancer [1]. The TNBC patients typically have higher rates of recurrence and distant metastasis compared with other subtypes, and their overall survival rates are lower [2-3]. Due to the lack of hormone receptor targets, anthracycline- and paclitaxel (PTX)-based chemotherapy regimens are considered the mainstay of treatment for patients with TNBC [4]. However, the emergence of PTX resistance often limits the benefits of clinical treatment and has an adverse impact on patient prognosis.
Cancer stem cells (CSCs) are important in the process leading to chemotherapy resistance [5]. In breast cancer, we can identify the CSC population by cell surface markers, such as CD44 and aldehyde dehydrogenase (ALDH) enzyme activity [6]. Furthermore, the research has revealed that the unique metabolic characteristics and long-term self-renewal capability of CSCs are attributed to the expression of certain embryonic markers, such as CD44, NANOG, octamer-binding transcription factor 4 (OCT4), sex-determining region Y-box 2 (SOX2), and others [7]. Therefore, targeting CSCs for treatment is an effective approach to improve cancer therapy outcomes and prevent subsequent recurrence.
Ginsenosides are the main active constituents in ginseng, and protopanaxatriol (PPT) is one of important components of ginsenosides. Previous studies have shown that PPT have various effects, including anti-inflammatory, anti-liver fibrosis, improvement of cognitive function in Alzheimer disease, anti-aging, neuroprotection, anti-tumor, and attenuation of tumor... (text truncated)
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LI Lingyu, YE Qianyun, LI Yan, HAN Li, WANG Panpan, ZHANG Ronghua (2026). Mechanism of protopanaxatriol attenuating paclitaxel resistance in MDA-MB-231 cells. Chinese Journal of Pathophysiology. https://doi.org/10.3969/j.issn.1000-4718.2024.05.004
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that protopanaxatriol (PPT) attenuates paclitaxel resistance in MDA-MB-231 breast cancer cells by inhibiting inflammatory cytokines and cancer stem cell properties, thereby enhancing the efficacy of paclitaxel.
How does PPT overcome paclitaxel resistance?
PPT reduces the expression of inflammatory cytokines (IL-6, IL-8, CXCL1, CCL2) and cancer stem cell markers (OCT4, SOX2, NANOG, ALDH1, CD44), suppresses NF-κB activity, and impairs tumor sphere formation, collectively reversing drug resistance.
What experimental models were used?
The study used paclitaxel-resistant human breast cancer MDA-MB-231 cells (MB231-PR) compared to parental cells (MB231-PT), treated with PPT alone or in combination with paclitaxel.
What are the clinical implications?
The combination of PPT and paclitaxel may offer a novel therapeutic strategy to overcome drug resistance in triple-negative breast cancer, potentially improving patient outcomes.
What methods were employed to assess apoptosis and stemness?
Apoptosis was evaluated via flow cytometry (sub-G1 phase), Western blot for apoptosis-related proteins, and ELISA for cytokines. Stemness was assessed by qPCR for stem cell markers and tumor sphere formation assay.
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