Apigenin
| Cancer types mentioned | Food it is found in | |
| Breast, Colorectal, Liver, Lung, Prostate, Skin, Gastric, Bone (Osteosarcoma), Sarcoma | Parsley, celery, chamomile, citrus fruits |
Summary, apigenin exerts multi-target anti-cancer effects by modulating immune components, reversing multidrug resistance, regulating autophagy and ferroptosis, and inducing cell cycle arrest and apoptosis.
Because of its poor solubility, advanced drug delivery systems like liposomes and nanoparticles are needed to boost its therapeutic potential for different cancer types. These methods help improve solubility, control the release, and target specific cancers more effectively, making apigenin a promising option for cancer treatment.
It’s a flavonoid mainly found in chamomile (Matricaria chamomilla), has gained a lot of attention lately for its wide range of health benefits, including anti-inflammatory, antioxidant, antidepressant effects, and heart protection.
Impressively, it’s also shown potential in fighting various types of cancer, such as lung, breast, colon, bladder, head and neck, melanoma, prostate, kidney, cervical, thyroid, oral, pancreatic, and leukemia.
It slows cancer progression through several pathways, like boosting tumor immunity, reversing drug resistance, encouraging autophagy and ferroptosis, triggering apoptosis, and stopping invasion and metastasis.
The in silico model uses advanced computational methods like molecular docking, dynamic simulations, QSAR analysis, and quantum calculations to assess apigenin derivatives as potential inhibitors of HPV-related cervical cancer and DNA polymerase theta.
Apigenin is classified as a BCS class II compound, meaning it has low solubility but high permeability. Recent advances in drug delivery, like self-micro emulsifying drug delivery systems (SMEDDS) and microwave solid dispersion techniques, have significantly boosted its bioavailability.
There is also increasing evidence that combining this with other drugs can create synergistic effects, improving therapeutic results. To guide future research and clinical applications, the following sections will give a brief overview of the mechanisms, delivery routes, and molecular targets involved in Apigenin’s anti-cancer activity.
It boosts tumor immunity by showing strong immunomodulatory effects in different cancer types. It works through interactions with various immune cells, such as dendritic cells (DCs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and T lymphocytes.
Some recent studies show that high doses of apigenin can inhibit the proliferation of DCs, and can also reduce the protein expression of programmed death-ligand 1 (PD-L1) in DCs by inhibiting the phosphorylation of STAT1, thus inducing anti-cancer immunity.
Apigenin helps by boosting NK-92 cell growth and has been shown to lower M2-like macrophage levels while encouraging M1 macrophage activity in mouse models, possibly through increased Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) expression. It also appears to reduce C–C motif chemokine ligand 2 (CCL2) secretion, which limits MDSC infiltration into pancreatic tumors. This anti-invasive action may be linked to reduced nuclear factor kappa-B (NF-κB) signaling.
It shows great promise as an immunotherapy option for cancer, thanks to its ability to target multiple immune components. It works by inhibiting PD-L1 expression and modulating the NF-κB/SHIP-1 signaling pathway, boosting the effectiveness of cancer immunotherapy. Beyond that, apigenin can help reverse drug resistance in various cancers through different molecular pathways. For example, in nasopharyngeal carcinoma (HONE1 and CNE2) cells, it tackles drug resistance by blocking epidermal growth factor receptor (EGFR) signaling.
In head and neck squamous cell carcinoma (HNSCC), Apigenin reverses resistance to cetuximab by inhibiting extracellular signal-regulated kinase 1/2 (ERK1/2) and blocking RAS-Mitogen-activated protein kinase (MAPK) pathway. Apigenin’s role in modulating drug resistance is further supported by its interaction with key pathways such as GLUT-1 and PI3K/AKT. Overexpression of GLUT-1, a marker for hypoxia, and the hyperphosphorylation of AKT are critical contributors to cisplatin resistance in laryngeal cancer cells, including HEp-2 cells.
It is thought to boost cisplatin sensitivity in certain cells by lowering GLUT-1 protein levels and AKT phosphorylation. In ovarian cancer cells (SK-OV-3 and SK-OV-3/DDP), it decreases myeloid cell leukemia-1 (Mcl-1) mRNA and protein, an anti-apoptotic Bcl-2 family member, helping to reverse cisplatin resistance.
In doxorubicin-resistant liver cancer cells (BEL-7402/ADM), apigenin restores drug sensitivity by reducing nuclear factor erythroid 2-related factor 2 (NRF2) at both RNA and protein levels through PI3K/AKT pathway inhibition, which increases intracellular doxorubicin. In doxorubicin-resistant human uterine sarcoma (MES-SA/Dx5), it lowers intracellular glutathione (GSH) by inhibiting ATP-binding cassette subfamily B member 1ABCB1), while in prostate cancer, it counters doxorubicin resistance by reducing ABCB1 protein expression.
It can help re-sensitize Adriamycin-resistant breast cancer (MCF-7/ADR) cells by blocking the STAT3 pathway. In hypoxic tumor models, it also tackles paclitaxel resistance by suppressing AKT and HSP90 signaling, which slows the production of HIF-1α. These results show apigenin’s versatile ability to fight drug resistance by interacting with drug efflux transporters and important signaling pathways.
It helps slow cancer growth by influencing the processes of autophagy and ferroptosis. Autophagy is how cells move macromolecules and organelles to lysosomes for breakdown and recycling. This process is strongly tied to many proteins produced by autophagy-related genes (ATGs) and is also regulated by mTOR.
For example, activating the mammalian target of rapamycin complex 1 (mTORC1) can slow down the autophagy process. Apigenin blocks mTOR and p70S6K, boosting LC3-II conversion and GFP-LC3 puncta formation, which are key signs of autophagy. It also shuts down the mTOR/PI3K/AKT pathway, helping trigger autophagy in erythroid subtype leukemia (TF-1), liver cancer (Hep G2), and colon cancer (HT-29) cells. In low-oxygen conditions, apigenin treatment in gastric cancer (AGS and SNU-638) cells ramps up phosphorylation of ATG5, LC3-II, AMP-activated protein kinase (AMPK), and unc-51 like autophagy activating kinase 1 (ULK1), while lowering p62 levels, together pushing cells toward autophagy-driven death.
Ferroptosis, marked by the buildup of iron-dependent lipid reactive oxygen species (ROS), is another way apigenin works against cancer. It triggers ferroptosis in multiple myeloma (NCI-H929) cells, reduces myeloperoxidase (MPO)-driven oxidative stress, and prevents ferroptotic death in neurons while boosting glutathione peroxidase 4 (GPX4) activity. Through its control of both autophagy and ferroptosis, apigenin slows cancer growth. By blocking the mTOR signaling pathway, it encourages autophagy-driven cell death, making it harder for cancer cells to survive under metabolic or oxidative stress.
Its ability to trigger ferroptosis in cancer cells further boosts its potential as an anti-cancer agent. These findings highlight apigenin’s versatile role in targeting various cellular processes, making it a strong candidate for cancer therapy.
Apigenin slows cancer progression through well-known mechanisms. It affects multiple stages of the cell cycle in cancers such as skin, liver, breast, and colon, mainly by causing G0/G1 phase arrest, blocking the shift from G0/G1 to S phase, and interrupting movement through the G2/M phase, which curbs cell growth. In colon cancer (HCT 116), it induces G0/G1 arrest by increasing miR-215-5p, which influences E2F transcription factors—key players in cell cycle control. In prostate cancer (22Rv1 and PC-3), it causes G0/G1 arrest in a dose-dependent manner. In breast cancer (MDA-MB-468), it slightly prolongs the S phase. Apigenin also promotes cancer cell death through several pro-apoptotic routes, including the mitochondrial pathway, Caspase activation, and oxidative stress. In cervical cancer (HeLa), it triggers apoptosis via two routes: reducing Bcl-2 protein levels and activating p53, which then boosts p21 and fatty acid synthase (Fas) expression, leading to cell death.
In lung cancer (A549) cells, apigenin increases cytochrome C levels, which in turn inhibits mitochondrial function, thereby leading to Caspase-9 and Caspase-3 activation and subsequent apoptosis. Moreover, apigenin also inhibits tumor by modulating EMT and related protein expression. In human liver cancer (BEL-7402) cells, apigenin decreases Snail1 and NF-κB protein levels while influencing cancer cell EMT.
In human melanoma (A375) cells, apigenin down-regulates STAT3 target genes matrix metalloproteinase 2 (MMP-2) and MMP-9, thereby suppressing tumor growth and invasion. Collectivelly, apigenin suppresses cancer progression through a multifaceted mechanisms that includes cell cycle regulation, apoptosis induction, and metastasis inhibition. Apigenin arrests cancer cells in the G2/M phase or the G0/G1 phase, thereby halting their proliferation. It also modulates critical proteins like Bcl-2 and p53 to induce apoptosis, promoting cell death in various cancer types.
Additionally, it inhibits metastasis by down-regulating proteins involved in EMT and tumor cell invasion, such as Snail1, MMP-2, and MMP-9. Investigating apigenin anti-cancer effects through drug delivery system.
Despite its promising anti-cancer effects, apigenin’s clinical application is limited by its poor water solubility. To address this challenge, advanced DDS have been developed to enhance its bioavailability, stability, and therapeutic efficacy. Emulsions, such as W/O/W formulations (water-in-oil-in-water), has been shown to significantly improve the oral bioavailability of apigenin. Moreover, the development of liposomal delivery systems presents a promising approach for the efficient administration of apigenin. The cytotoxicity of apigenin nanoliposomes in colon cancer (HCT-15 and HT-29) cells is stronger than that of free apigenin.
Apigenin and tocopherol derivative-containing D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) liposomes shows inhibitory effects in A549 tumor-bearing nude mice. This combination leverages the unique properties of TPGS, which not only enhances the solubility and stability of apigenin but also prolongs its circulation half-life, thereby improving its bioavailability and therapeutic efficacy. The apigenin-loaded lipid nanocapsules (AP-LNC) are prepared using a phase transformation method, demonstrating a significant enhancement in the inhibition rate of Hep G2 and MCF-7 cells. Poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) have been extensively utilized as polymeric carriers for DDS due to their biocompatibility, biodegradability, and ability to enhance drug solubility and stability. In melanoma (A375) cells, PLGA NPs prepared via the solvent replacement method exhibit a concentration-dependent inhibitory effect on tumor growth. Similarly, PLGA NPs prepared through nanoprecipitation have been shown to effectively block p53 production in ovarian cancer (OVCAR4) cells, thereby exerting a more potent anti-tumor effect compared to free apigenin.
Additionally, multi-emulsion solvent evaporation technique has been use to create nanoparticles that effectively maintain hepatocyte structure and restore normal cellular function in Hep G2 cells.