Apigenin is a bioactive flavonoid with anti-inflammatory, antioxidant and anticancer properties which is found in common fruits and vegetables.

In epidemiologic studies, a diet rich in flavones has possibly been shown to be related to a decreased risk of breast, digestive tract, skin, prostate and certain hematological cancers.

Most of the benefits are related to apoptosis – normal, programmed cell death which is part of the natural renewal and replacement of cells in our body. We want to encourage apoptosis in cancer cells.

In relation to prostate cancer the following has been found:

Androgen-independent human prostate cancer PC-3 cells show complete growth retardation after apigenin exposure. Source: [Source]

Long term treatment of human prostate carcinoma cells with low concentrations of quercetin, apigenin and kaempferol induced a process called tyrosine dephosphorylation. This in turn inactivated an cancer causing substance called PDPK FA. [Source].

Apigenin has the capability to significantly reduce cell number and induce cell death in the following cancer cell types:

  • PWR-1E
  • LNCaP
  • PC-3
  • DU145

The PC-3 and DU145 cells were less susceptible to apigenin induced cell death than LNCaP and PWR-1E cells. This was dependent on caspases which are chemicals found in cells and which have a role in apoptosis.

In cancer cells Apigenin has a positive role in the following processes:

  • Generates a type of free radical called reactive oxygen species. Elevated levels of this are found in all cancer types yet they are implicated in cancer cell death. [Source]
  • Reduces expression of mitochondrial Bcl-2. This is an anti-apoptotic protein and its over-expression in LNCaP B10 cells reduces the positive effects of apigenin. [Source]
  • Increases mitochondrial permeability in cancer cells, which generally precedes cell death. [Source]
  • Causes cytochrome C release which is an important factor in cell death. [Source]
  • Induces cleavage of caspase 3, 7, 8, and 9. Caspase is an important factor in cell death and cleavage is part of the process of activating them. [Source]

Apigenin treatment to NHPE and PZ-HPV-7 resulted in growth inhibitory responses of low magnitude but significant decrease in cell viability was observed in CA-HPV-10 cells. [Source]

But most importantly…

A major benefit of Apigenin is that it helps to achieve a significant decrease in Androgen Receptor (AR) protein expression. In so doing it decreases sensitivity to androgens. In some cancers increased AR expression can make cells more sensitive to androgens even when they are relatively absent. Anyone going through Androgen Deprivation Therapy will understand and appreciate the possible role of Apigenin in improving and extending the effectiveness of this treatment

The inhibitory effects of apigenin on androgen-refractory human prostate carcinoma DU145 cells were studied. These types of cell no longer respond to Androgen Deprivation Therapy and have mutations in the tumor suppressor gene p53 and pRb. Exposure of DU145 cells to Apigenin resulted in inhibition of growth and colony formation as well as interruption of the cell cycle.

Apigenin exposure also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1 (Apaf-1). This effect was found to result in a significant increase in cleaved fragments of caspase-9, -3, and poly (ADP-ribose) polymerase (PARP).

Apigenin exposure also resulted in down modulation of the expression of NF-κB/p65 and NF-κB/p50. NF-κB is a gene that regulates several cell survival and anti-apoptotic genes.

Exposure of PC-3 cells to apigenin inhibited DNA binding and reduced nuclear levels of the p65 and p50 subunits of NF-κB with concomitant decrease in IκBα degradation, IκB-α phosphorylation and IKKα kinase activity.

In addition, apigenin exposure inhibited TNFα-induced activation of NF-κB via the IκBα pathway, thereby sensitizing the cells to TNFα-induced apoptosis. The inhibition of NF-κB activation correlated with a decreased expression of NF-κB-dependent reporter gene and suppressed expression of NF-κB-regulated genes, specifically, Bcl2, cyclin D1, cyclooxygenase-2, matrix metalloproteinase 9, nitric oxide synthase-2, and VEGF. Furthermore, Shukla et al (66) investigated the in vivo growth inhibitory effects of apigenin on androgen-sensitive human prostate carcinoma 22Rv1 tumor xenografts subcutaneously implanted in athymic male nude mice. Apigenin feeding resulted in dose-dependent inhibition of tumor growth which was associated with increased accumulation of human IGFBP-3 in mouse serum. Apigenin consumption by these mice also resulted in simultaneous decrease in serum IGF-I levels and induction of apoptosis in tumor xenografts, evidence favoring the concept that the growth inhibitory effects of apigenin involve modulation of IGF-axis signaling in prostate cancer. Further studies with pharmacologic intervention of apigenin have a direct growth inhibitory effect on human prostate tumors implanted in athymic nude mice. Oral feeding of apigenin resulted in dose-dependent (i) increase in the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18; (ii) down-modulation of the protein expression of cyclins D1, D2, and E; and cyclin-dependent kinases (cdk), cdk2, cdk4, and cdk6; (iii) decrease in retinoblastoma phosphorylation at serine 780; (iv) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27; and (v) decrease in the binding of cyclin E toward cdk2 in both types of tumors (128). More recent studies with apigenin in LNCaP and PC-3 cells causes G0-G1 phase arrest, decrease in total retinoblastoma (Rb) protein and its phosphorylation at Ser780 and Ser807/811 in dose- and time-dependent fashion. Apigenin treatment caused increased phosphorylation of ERK1/2 and JNK1/2 and this sustained activation resulted in decreased ELK-1 phosphorylation and c-FOS expression thereby inhibiting cell survival. Interestingly, apigenin caused a marked reduction in cyclin D1, D2 and E and their regulatory partners CDK 2, 4 and 6, operative in G0-G1 phase of the cell cycle. This was accompanied by a loss of RNA polymerase II phosphorylation, suggesting the effectiveness of apigenin in inhibiting transcription of these proteins (46). In another study using TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, Shukla et al (67) demonstrated that oral administration of apigenin at doses of 20 and 50 μg/mouse/day, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver. Administration of apigenin resulted in increased levels of E-cadherin and decreased levels of nuclear β-catenin, c-Myc, and cyclin D1 in the dorso-lateral prostates of TRAMP mice. These studies indicate that apigenin is effective in suppressing the prostate carcinogenesis in in vivo model, at least in part, by blocking β-catenin signaling. Furthermore, Shukla & Gupta, (129) demonstrated that apigenin at different doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis in human prostate cancer 22Rv1 cells. There was accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment. In vivo, 22Rv1 xenograft studies confirmed that apigenin administration resulted in p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicated that apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways.

The mechanism(s) of apigenin action on the IGF/IGF-IR (insulin-like growth factor receptor 1 protein) signaling pathway in human prostate cancer DU145 cells markedly reduced IGF-I-stimulated cell proliferation and induced apoptosis (130). This effect of apigenin was might be partially due to reduced auto-phosphorylation of IGF-IR. Inhibition of p-Akt by apigenin resulted in decreased phosphorylation of GSK-3beta. In another study, Kaur et al (131) using human prostate cancer PC-3 cells demonstrated that apigenin-mediated dephosphorylation of Akt resulted in inhibition of its kinase activity, which was confirmed by reduced phosphorylation of pro-apoptotic proteins BAD and glycogen synthase kinase-3, essential downstream targets of Akt. These results suggest that Akt inactivation and dephosphorylation of BAD is a critical event, at least in part, in apigenin-induced decreased cell survival and apoptosis. Mirzoeva et al (132) reported that hypoxia induced a time-dependent increase in the level of HIF-1alpha subunit protein in PC3-M cells, and treatment with apigenin markedly decreased HIF-1alpha expression under both normoxic and hypoxic conditions. Apigenin prevented the activation of the HIF-1 and its downstream target gene vascular endothelial growth factor (VEGF). Recent studies from the same group observed that apigenin inhibited the focal adhesion kinase (FAK)/Src, motility and invasion in the metastatic prostate carcinoma PC-3M cells (133).


Apigenin: A Promising Molecule for Cancer Prevention

Flavonoids suppress androgen-independent human prostate tumor proliferation.

Inhibition of CK2 activity provokes different responses in hormone-sensitive and hormone-refractory prostate cancer cells.

Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells.

Apigenin drives the production of reactive oxygen species and initiates a mitochondrial mediated cell death pathway in prostate epithelial cells

Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells.

Androgen receptor gene amplification and protein expression in recurrent prostate cancer.

Apigenin suppresses insulin-like growth factor I receptor signaling in human prostate cancer: an in vitro and in vivo study.

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