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Synergistic effects of anlotinib and DDP on breast cancer: targeting the VEGF/JAK2/STAT3 axis
Hongmei Zhang1,2, Chunling Liu3, Ye Jin2
1Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China.
Background:
Anlotinib, a highly selective inhibitor of VEGFR2, has demonstrated significant anti-tumor effects in various cancers. However, its potential synergistic effects with DDP (cisplatin) in breast cancer (BRCA) remain to be fully elucidated. This study aims to discover the therapeutic efficacy of anlotinib on BRCA, specifically the synergistic effects with DDP, and to elucidate the underlying molecular mechanisms.
Methods:
BRCA cells were treated with anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, cell cycle distribution, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by flow cytometry technique and Hoechst33342 fluorescence staining. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR, immunofuorescence and western blot. The anti-breast cancer efficacy of anlotinib was evaluated in vivo using a xenograft tumor model.
Results:
Our findings reveal that increased VEGFA expression in BRCA patients is associated with poorer prognosis, underscoring the need for targeted therapeutic strategies. We also demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion, while their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident through the induction of apoptosis and autophagy in BRCA cells. Mechanistically, anlotinib's effectiveness is linked to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. In vivo study further support these results, showing that anlotinib markedly inhibits tumor growth in xenografted mice.
Conclusion:
This study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib's effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway.
Insights
Anlotinib and cisplatin show synergistic effects against breast cancer by inhibiting the JAK2/STAT3 pathway. This combination therapy effectively reduces tumor growth and improves patient prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) inhibitor anlotinib shows anti-tumor effects.
- The synergistic potential of anlotinib with cisplatin (DDP) in breast cancer (BRCA) requires further investigation.
- VEGFA overexpression in BRCA correlates with poor prognosis, necessitating targeted therapies.
Purpose of the Study:
- To evaluate the therapeutic efficacy of anlotinib in breast cancer.
- To investigate the synergistic effects of anlotinib in combination with DDP against BRCA.
- To elucidate the molecular mechanisms underlying anlotinib's action in BRCA.
Main Methods:
- Cell-based assays (CCK-8, cell cycle, clone formation, wound healing, Transwell, flow cytometry, Hoechst staining) were used to assess BRCA cell proliferation, migration, invasion, and apoptosis.
- Bioinformatics analysis predicted mechanisms, with subsequent validation via qPCR, immunofluorescence, and Western blot.
- An in vivo xenograft tumor model evaluated anlotinib's anti-cancer efficacy.
Main Results:
- Anlotinib and DDP synergistically inhibited BRCA cell growth, migration, and invasion, inducing apoptosis and autophagy.
- Anlotinib's efficacy is attributed to the inhibition of the JAK2/STAT3 signaling pathway.
- In vivo studies confirmed that anlotinib significantly inhibits tumor growth in a xenograft model.
Conclusions:
- Anlotinib demonstrates efficacy as a monotherapy and in combination with DDP for breast cancer treatment.
- The study elucidates anlotinib's mechanism of action, emphasizing its role in JAK2/STAT3 pathway inhibition.
- Combination therapy with anlotinib and DDP offers a promising strategy for breast cancer management.
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