Apigenin and its dimeric derivatives in lung cancer therapy: a review of their biological activities and molecular mechanisms

Phytomedicine Plus · Published 2026-06-19 · DOI 10.1016/j.phyplu.2026.101018

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Authors (2)

Mohammad-Sadegh Lotfi, Majid Jafari-Sabet

Abstract

Background and objectives: Late diagnosis, metastasis and drug resistance drive the high mortality rate of lung cancer worldwide. Apigenin is a natural flavonoid with low toxicity and multi‑target anticancer properties, naturally present in fruits and vegetables. This review critically analyzes the molecular mechanisms of apigenin and its dimers (amentoflavone and hinokiflavone) against lung cancer. We also discuss nano-delivery systems and chemosensitization strategies. Methods: PubMed, Scopus, Web of Science, and Google Scholar were searched for ''Apigenin AND Lung Cancer'', ''Amentoflavone AND Lung Cancer'', and ''Hinokiflavone AND Lung Cancer'' without date restrictions. After screening, 56 (apigenin), 10 (amentoflavone), and 2 (hinokiflavone) original articles on molecular mechanisms, efficacy, pharmacokinetics, or nano-delivery were included. Results: Apigenin induces apoptosis through mitochondrial (Bax/Bcl-2, cytochrome c) and death receptor (DR4/DR5) pathways to induce apoptosis. It exerts anti‑proliferative effects by inducing G1/S and G2/M phase arrest and downregulating the PI3K/Akt/mTOR, MAPK/ERK pathways, as well as decreasing c-Myc/Sp1 expression. Apigenin inhibits glycolysis, induces ferroptosis, suppresses PD-L1, sensitizes TRAIL, inhibits angiogenesis via VEGF/HIF-1, and reverses EMT, in addition to targeting CD26/DPPIV and Axl. Bioavailability is enhanced by nano-delivery systems. Apigenin chemosensitizes by inhibiting P-gp, HDAC, and cancer stem cells. Amentoflavone inhibits PARP-1, while both amentoflavone and hinokiflavone inhibit ERK2, demonstrating complementary mechanisms. Conclusion: Preclinical evidence supports apigenin as an adjunctive agent despite translational limitations (low oral bioavailability, lack of clinical trials, heterogeneous data). Optimized nanoformulations and rigorous testing are needed. This is the first comparative review of apigenin and its dimers.

Abstract from DOAJ. Public domain (CC0 1.0).

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Publication details

Year
2026

Citation

Lotfi, M., Jafari-Sabet, M. (2026). Apigenin and its dimeric derivatives in lung cancer therapy: a review of their biological activities and molecular mechanisms. Phytomedicine Plus. https://doi.org/10.1016/j.phyplu.2026.101018

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