Halogenated anthraquinones in breast cancer therapy: Structural modifications targeting VEGF-related angiogenesis pathways

Halogenated anthraquinone derivatives have good potential in addressing the major clinical challenges associated with anthracyclines for breast cancer, including high toxicity, low selectivity, and drug resistance issues. By analyzing the structure-activity relationships of these compounds, the review highlights how specific structural modifications may enhance therapeutic efficacy. A comprehensive overview is also provided to categorize breast cancer progression across stages 0 to IV, along with therapeutic approaches for each of the three basic molecular subtypes, with placing particular focus on triple-negative breast cancer. This review details how anthraquinone derivatives modulate the vascular endothelial growth factor (VEGF)-related signaling pathways and regulate the expression of key proteins and chemokines, thereby inhibiting endothelial cell function during tumor angiogenesis, suppressing cancer cell migration and immune evasion in breast cancer. Studies on halogenated anthraquinone derivatives in anticancer applications between 2013 and 2025 are summarized, and the cutting-edge therapeutic strategies that have contributed to the development of anthraquinone derivatives are highlighted. The high approval rate of halogen-containing drugs released by the U.S. Food and Drug Administration in 2024, alongside their promising therapeutic efficacy in oncology, has once again drawn the attention of researchers. Overall, the contributions of halogen substitution to molecular stability, target specificity, and resistance to metabolic degradation highlight the significant potential of halogenated anthraquinone derivatives in the development of novel therapeutics for breast cancer. • Structure-activity relationship (SAR) analysis reveals that halogen substitutions significantly improve molecular stability and selectivity of anthraquinone and its derivatives. • Halogenated anthraquinones exhibit enhanced anti-angiogenic activity by modulating VEGF signaling axis, especially in triple-negative breast cancer (TNBC). • Reactive oxygen species (ROS) induced by anthraquinone derivatives exert dual effects, triggering cancer cell apoptosis or promoting host toxicity depending on the dosage.