Apigenin is a common dietary flavonoid that is abundantly present in many fruits, vegetables and Chinese medicinal herbs and serves multiple physiological functions, such as strong anti-inflammatory, antioxidant, antibacterial and antiviral activities and blood pressure reduction. Therefore, apigenin has been used as a traditional medicine for centuries. Recently, apigenin has been widely investigated for its anti-cancer activities and low toxicity. Apigenin was reported to suppress various human cancers in vitro and in vivo by multiple biological effects, such as triggering cell apoptosis and autophagy, inducing cell cycle arrest, suppressing cell migration and invasion, and stimulating an immune response. In this review, we focus on the most recent advances in the anti-cancer effects of apigenin and their underlying mechanisms, and we summarize the signaling pathways modulated by apigenin, including the PI3K/AKT, MAPK/ERK, JAK/STAT, NF-κB and Wnt/β-catenin pathways. We also discuss combinatorial strategies to enhance the anti-cancer effect of apigenin on various cancers and its use as an adjuvant chemotherapeutic agent to overcome cancer drug resistance or to alleviate other adverse effects of chemotherapy. The functions of apigenin against cancer stem cells are also summarized and discussed. These data demonstrate that apigenin is a promising reagent for cancer therapy. Apigenin appears to have the potential to be developed either as a dietary supplement or as an adjuvant chemotherapeutic agent for cancer therapy.

Mutated epidermal growth factor receptor (EGFR) is one of the most successful targets in cancer targeted therapy. While this treatment has benefited many patients with an activating EGFR mutation (EGFRm), almost all those who initially benefited will eventually develop acquired drug resistance (ADR) after a certain period of time. New therapeutic strategies need to be explored to treat EGFRm tumors and overcome or minimize this recurring ADR. Our data showed that apigenin alone has only mild inhibitory effects on EGFRm tumor cells. By drug screening, we found that ABT-263 can significantly enhance the antitumor activities of apigenin in tumor cells harbouring an activating EGFR mutation and AZD9291-resistant H1975 cells. Mechanistically, apigenin upregulated the expression of Noxa in EGFRm tumor cells by targeting the AKT-FoxO3a pathway, thereby synergizing with ABT-263 to suppress tumor cell growth and proliferation in vitro and in vivo. Our study provides a rationale for the clinical application of the combination treatment of apigenin and BH3 mimetics in the treatment of EGFRm tumors.