Plant-derived substances with anti-cancer activity

Lukasz

Jedi Master
I stumbled upon a book in which plant-derived substances with anti-cancer activity are summed up nicely, and it inspired me to start this thread. Some of the substances, like apigenin, seem to be especially interesting and I'll try to present them here. The book is only available in Polish - Roślinne terapie antynowotworowe w praktyce terapeutycznej by Lidia Wincek.


Apigenin

Apigenin blocks the development of cancer at various stages. It is considered to be one of the most active substances of the flavonoid group, which inhibits the multiplication of breast cancer cells.

Apigenin becomes particularly interesting in the case of hormonally dependent cancers. Research indicates that this compound may block estrogen receptors, which in turn results in the inhibition of cancer cell proliferation. Another mechanism, which has a beneficial effect on hormonal management in oncological patients, is blocking the aromatase enzyme that affects estrogen levels in the body.

Furthermore, studies have shown that apigenin:
  • inhibits the growth of leukemia cells
  • plays an important role in the process of repair of DNA oxidative damage
  • influences the inhibition of epidermal growth factor and tyrosine kinase, which confirms its anti-cancer and anti-metastatic properties
  • has a beneficial effect on the gene of the tumor suppressor - p53 protein and inhibition of neoangiogenesis, i.e. formation of new blood vessels within the tumor
  • has a strong antiproliferative function and ability to induce apoptosis of cancer cells

Apigenin is found among others in camomile, celery leaves, parsley leaves, and St. John's wort.

There are various supplements and medications containing apigenin available on the market such as: capsules, tinctures and intravenous solutions. The dosage depends on the patient's weight and condition. The most common dose is about 100-150 mg of apigenin per day.


Related research:

Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor-α-dependent and estrogen receptor-α-independent mechanisms
An exciting aspect of this study is that apigenin has the potential to inhibit both ERα-dependent pathway and protein kinase–mediated growth factor signaling pathways. As both pathways are commonly altered in antiestrogen-resistant breast cancer, these broad effects of apigenin may be synergistic in combination with antiestrogens in growth inhibition of antiestrogen-resistant breast cancer cells.


Signal pathways involved in apigenin inhibition of growth and induction of apoptosis of human anaplastic thyroid cancer cells (ARO)
In summary, apigenin is a promising inhibitor of signal transduction pathways that regulate the growth (anchorage-dependent and independent) and survival of human anaplastic thyroid cancer cells. Apigenin may provide a new approach for the treatment of human anaplastic thyroid carcinoma for which no effective therapy is presently available.


Inhibition of aromatase activity by flavonoids
28 randomly selected flavonoids were screened for inhibitory effects against partially purified aromatase prepared from human placenta. Over 50% of the flavonoids significantly inhibited aromatase activity, with greatest activity being demonstrated with apigenin (IC50: 0.9 microg/mL), chrysin (IC50: 1.1 microg/mL), and hesperetin (IC50: 1.0 microg/mL).


Apigenin Inhibits Growth of Breast Cancer Cells: The Role of ERα and HER2/neu
It was shown that high doses of apigenin (50 μM) do not display estrogen-like activity and can suppress ER activation by 17β-estradiol.

Apigenin was found to be the most effective phytoestrogen that strongly inhibits the growth of breast cancer cells, including HER2-positive ones.


Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest
Apigenin inhibits growth of pancreatic cancer cells through suppression of cyclin B-associated cdc2 activity and G2/M arrest, and may be a valuable drug for the treatment or prevention of pancreatic cancer.


Structure-activity relationships of flavonoids and the induction of granulocytic- or monocytic-differentiation in HL60 human myeloid leukemia cells
The flavones apigenin and luteolin strongly inhibited the growth of HL60 cells and induced morphological differentiation into granulocytes.


Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway
Data demonstrated that flavone, apigenin and luteolin induced cell cycle arrest and apoptosis in breast cancer cells through inhibiting PI3K/Akt activation and increasing FOXO3a activation, which suggest that flavone, apigenin and luteolin will be the potential leads for the preventing and treating of breast cancer.


Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFκB signaling in HER2-overexpressing breast cancer cells
Our study indicates that apigenin could be a potential useful compound to prevent or treat HER2-overexpressing breast cancer.


Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: In vitro and in vivo study
Apigenin (4′,5,7,-trihydroxyflavone), an anticancer agent, selectively toxic to cancer cells induces cell cycle arrest and apoptosis through mechanisms that have not been fully elucidated. Our studies indicate that apigenin-mediated growth inhibitory responses are due to inhibition of class I histone deacetylases (HDACs) in prostate cancer cells.

Our findings confirm for the first time that apigenin inhibits class I HDACs, particularly HDAC1 and HDAC3 and its exposure results in reversal of aberrant epigenetic events that promote malignancy.
 
Wogonin

Wogonin is a monoflavonoid found in the roots of the Baikal skullcap (Scutellaria baicalensis).

It has been reported to induce apoptosis of cancer cells and show an inhibitory effect on cancer cell growth. What most important, wogonin acts selectively, which means that healthy cells are not damaged. It is COX-2 inhibitor therefore it has an anti-inflammatory effect. It also has antiviral and anticoagulant properties.

Due to the effect of wogonin, increased amounts of hydrogen peroxide are formed in cancer cells, which initiates a cascade of apoptotic reactions dependent on calcium ions. However, this is only one of many anti-cancer properties of this flavonoid.

Wogonin administered orally showed promising therapeutic results in hormone-dependent as well as hormone-independent breast cancer cells.

Related research:

Advances of wogonin, an extract from Scutellaria baicalensis, for the treatment of multiple tumors
Wogonin (WG) showed potent and promising antitumor effects both in vitro and in vivo. It has been proved that WG has the ability to inhibit the growth of tumor cells, induce apoptosis, and suppress angiogenesis. The molecular mechanisms involve reactive oxygen species, Ca2+, NF-κB, tumor necrosis factor-related apoptosis-inducing ligand, and tumor necrosis factor-alpha.

In the past few years, research on WG has improved dramatically. Currently, almost all types of cancer have been investigated to explore the effect of WG, especially in HCC and leukemia. Accumulating evidence shows that WG not only targets the key molecules, which play an important role in the development of tumors, but also enhances the anticancer effect of chemotherapeutic drugs. What is more, based on the explorations both in vitro and in vivo, WG has been approved for Phase I trials in the People’s Republic of China, which is a milestone for its clinical use in the future.


Wogonin suppresses tumor growth in vivo and VEGF-induced angiogenesis through inhibiting tyrosine phosphorylation of VEGFR2
In this study, we found for the first time that wogonin inhibited the growth and tumor angiogenesis of human gastric carcinoma in nude mice. We explored the inhibitory effect of wogonin on angiogenesis stimulated by vascular endothelial growth factor (VEGF) in vitro. Wogonin suppressed the VEGF-stimulated migration and tube formation of human umbilical vein endothelial cells (HUVECs). It also restrained VEGF-induced tyrosine phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). This inhibition of receptor phosphorylation was correlated with a significant decrease in VEGF-triggered phosphorylated forms of ERK, AKT and p38. Taken together, these findings strongly suggest that wogonin might be a promising antitumor drug.


Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1
Wogonin has been shown to induce apoptosis in different cancer cells and to suppress growth of human cancer xenografts in vivo.
Several independent research groups have demonstrated that at a dose of 10–20 mg/kg wogonin efficiently inhibited tumor growth in vivo in several mouse tumor models although higher concentrations of wogonin (25–200 μM) were needed to achieve the same effects in cell culture experiments.2, 4, 5 The mouse data demonstrate that the amount of wogonin required to achieve anti-cancer effects in vivo is in a suitable range. Toxicological studies in experimental animals (rat and dog) showed that up to 60 mg/kg/day wogonin had no organ toxicity when intravenously administered for 90 days.30, 31 Thus, wogonin may be an attractive new anti-cancer compound that offers relative safety for long term therapies.
Taken together, our results demonstrate that wogonin and related natural flavones are CDK9 inhibitors. The current knowledge about the biology of CDK9 strongly suggests that targeting CDK9 is a promising therapeutic strategy in oncology and virology.


Anticancer effects of wogonin in both estrogen receptor‐positive and ‐negative human breast cancer cell lines in vitro and in nude mice xenografts
We report that wogonin was effective on both ER‐positive and ‐negative breast cancer cell lines, both in vitro and in vivo, by affecting various signaling pathways. It is of significance that wogonin was effective in ER‐negative, EGFR or c‐ErbB2‐overexpressing breast cancer cells, because this type of breast cancer is resistant to hormonal therapies and tends to have a more aggressive phenotype.


Wogonin affects proliferation and the energy metabolism of SGC‑7901 and A549 cells
The differential regulatory roles of wogonin in metabolism‑associated enzymes in human gastric cancer and lung adenocarcinoma cells indicated its various antitumor mechanisms. The different metabolic regulatory mechanisms exhibited by wogonin in different tumor tissues should therefore be considered for antitumor therapy.
In summary, the findings of the present study indicated that wogonin may affect the energy metabolism and the acidic microenvironment in SGC-7901 cells by decreasing HIF-1α and MCT-4 expressions.
While inhibiting cell proliferation, wogonin interferes with changes in certain proteins and key enzymes during cellular energy metabolism. The current study hypothesizes that the combination of wogonin and certain enzyme inhibitors in energy metabolism may prevent the supply of energy to tumor cells and therefore inhibit tumor cell proliferation.


Therapy Effects of Wogonin on Ovarian Cancer Cells
Our present data show that wogonin inhibits cancer cell proliferation and reduces clonogenic survival ability of ovarian cancer cells. Treatment with wogonin also decreases the percentage of G0/G1 subpopulation. Of interest, we observed downregulated expression of ER-α in A2780 cells when cells were exposed to wogonin, suggesting that the antitumor activity of wogonin may interact with ER-α signaling. In clinical practice, estrogen receptor is recognized as a prognostic factor for breast cancer and a critical reference for clinical management of breast cancer. Although no prognostic value for ER expression has been suggested for ovarian cancers, up to 60% of ovarian epithelial tumors were reported to have ER overexpression, suggesting a potential of regulatory effects of estrogen signaling for deployment and progression of ovarian cancer, and thus targeting ER-α signaling may benefit ovarian cancer patients. To this setting, our results suggest wogonin may act on estrogen signaling as a novel therapeutic agent for ovarian tumor treatment.


Wogonin induces apoptosis and down-regulates survivin in human breast cancer MCF-7 cells by modulating PI3K–AKT pathway
Wogonin can induce apoptosis in human breast cancer MCF-7 cells. Wogonin induces apoptosis via regulating the expression of bcl-2,Bax, P53 and survivin. Both PI3K–AKT and MAPK/ERK pathways play a key role on wogonin induces apoptosis. Wogonin down-regulates survivin,a downstream target of the PI3K/AKT pathway. The activation of caspase-3 play a important role on wogonin-induced -apoptosis.


Wogonin induces apoptosis in RPMI 8226, a human myeloma cell line, by downregulating phospho-Akt and overexpressing Bax
As wogonin was effective in vitro in promotion of apoptosis of myeloma cell by Akt-modulated, Bax and Bcl-2 related intrinsic apoptotic pathway, wogonin may be a potential therapeutic agent against multiple myeloma.
 
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