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Pirarubicin combined with TLR3 or TLR4 agonists enhances anti-tumor efficiency
Ruobing Zhang1, Nai-Peng Cui2, Yanqiu He3
1Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, 071000 Hebei, China; Clinical Medical College, Hebei University, Baoding, 071000 Hebei, China; Department of Breast Surgery, Affiliated Hospital of Hebei University, Baoding, 071000 Hebei, China.
Background:
Triple-negative breast cancer (TNBC) is prone to relapse due to the lack of effective therapeutic targets. Macrophages are the most abundant immune cells in the tumor microenvironment (TME) of breast cancer. Targeting the cross-talk between macrophages and cancer cells provides a more efficient strategy for anti-tumor therapy. Toll-like receptors (TLRs) are important players involved in macrophage activation, and TLR agonists are known to play roles in cancer therapy. However, the combination strategy of TLR agonists with chemotherapy drugs is still not well characterized.
Methods:
RT-PCR and Western blot were used to detect the expression of TLRs. The communication between breast cancer cells and macrophages were determined by co-culture in vitro. Tumor cells proliferation and migration were investigated by MTT assay and scratch wound assay. The effects of drug combinations and toxic side effects were assessed by immunohistochemistry and Hematoxylin & Eosin staining.
Results:
Expression of TLR3 and TLR4 were lower in breast tumor tissues compared with adjacent normal tissues. Patients with higher TLR3 or TLR4 expression levels had a better prognosis than those with lower expression levels. TLR3/4 expression was significantly inhibited when breast cancer cells MDA-MB-231 and E0771 were conditioned-cultured with macrophages in vitro and was also inhibited by pirarubicin (THP). However, the combination of TLR agonists and THP could reverse this response and inhibit the proliferation and migration of breast cancer cells. Additionally, this combination significantly reduced the tumor volume and weight in the murine model, increased the expression of TLR3/4 in mouse breast tumors.
Conclusions:
Our results provide new ideas for the combination strategy of THP with TLR agonists which improves prognosis of breast cancer.
Insights
Combining Toll-like receptor (TLR) agonists with pirarubicin (THP) chemotherapy can overcome resistance in triple-negative breast cancer. This strategy reverses suppressed TLR expression, inhibits cancer cell growth and migration, and improves patient prognosis.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) often relapses due to limited therapeutic targets.
- Macrophages are key immune cells in the tumor microenvironment (TME), influencing cancer progression.
- Targeting macrophage-cancer cell communication offers a promising anti-tumor strategy.
Purpose of the Study:
- To investigate the role of Toll-like receptors (TLRs) in TNBC.
- To evaluate the efficacy of combining TLR agonists with chemotherapy (pirarubicin, THP).
- To understand the impact of this combination on the TME and cancer cell behavior.
Main Methods:
- Detected TLR3 and TLR4 expression using RT-PCR and Western blot.
- Assessed cancer cell-macrophage communication via in vitro co-culture.
- Evaluated tumor cell proliferation and migration using MTT and scratch wound assays.
- Analyzed drug combination effects and toxicity through immunohistochemistry and H&E staining.
Main Results:
- Lower TLR3/4 expression in TNBC tissues correlated with poorer prognosis.
- Macrophage co-culture and THP treatment inhibited TLR3/4 expression.
- The combination of TLR agonists and THP reversed this inhibition.
- This combination suppressed breast cancer cell proliferation and migration.
- In vivo studies showed reduced tumor volume/weight and increased TLR3/4 expression.
Conclusions:
- The combination of THP with TLR agonists offers a novel therapeutic strategy for TNBC.
- This approach can improve treatment outcomes and patient prognosis.
- Restoring TLR expression is a key mechanism in this combination therapy.
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