Category Archives: Anti-estrogenic

A549, Akt, angiogenesis, Anti-angiogenic, Anti-cancer, Anti-estrogenic, anti-inflammatory, anti-lymphangiogenesis, anti-metastasis, Anti-metastatic, anti-tumor, anti-tumor activity, apoptosis, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Breast cancer, c-ErbB2, CAM, CD31, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemo-protective, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, ER, ER-negative, ER-positive, ERK1, G1, GBC-SD, HCT116, HeLa, Hep G2,Hep 3B and SK-Hep1, HIF, HT-29, hypoxia-induced drug resistance, IGF-1, IL-1, iNOS, LM8, Lung cancer, MCF-7, MCP-1, MDR, metastasis, Multi-Drug Resistance, Multi-drug resistance, neuro-protective, Osteosarcoma, p-Akt, p27, p53, PARP, PGE2, PI3K, PI3K/Akt, Pro-apoptotic, pro-oxidative, ROS, Sarcoma, T47D, MDA-MB-231, TNF, TRAIL, VEGF, VEGF, VEGFR

Wogonin

Cancer:
Breast, lung (NSCLC), gallbladder carcinoma, osteosarcoma, colon, cervical

Action: Neuro-protective, anti-lymphangiogenesis, anti-angiogenic, anti-estrogenic, chemo-sensitizer, pro-oxidative, hypoxia-induced drug resistance, anti-metastatic, anti-tumor, anti-inflammatory

Wogonin is a plant monoflavonoid isolated from Scutellaria rivularis (Benth.) and Scutellaria baicalensis (Georgi).

Breast Cancer; ER+ & ER-

Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell-cycle progression, and apoptosis. Cell growth was attenuated by wogonin (50-200 microM), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by up-regulation of PARP and Caspase 3 cleavages as well as pro-apoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3beta and p27, was observed. Suppression of Cyclin D1 expression suggested the down-regulation of the Akt-mediated canonical Wnt signaling pathway.

ER expression was down-regulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MDA-MB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemo-preventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types (Chung et al., 2008).

Neurotransmitter Action

Kim et al. (2011) found that baicalein and wogonin activated the TREK-2 current by increasing the opening frequency (channel activity: from 0.05 ± 0.01 to 0.17 ± 0.06 in baicalein treatment and from 0.03 ± 0.01 to 0.29 ± 0.09 in wogonin treatment), while leaving the single-channel conductance and mean open time unchanged. Baicalein continuously activated TREK-2, whereas wogonin transiently activated TREK-2. Application of baicalein and wogonin activated TREK-2 in both cell attached and excised patches, suggesting that baicalein and wogonin may modulate TREK-2 either directly or indirectly with different mechanisms. These results suggest that baicalein- and wogonin-induced TREK-2 activation help set the resting membrane potential of cells exposed to pathological conditions and thus may give beneficial effects in neuroprotection.

Anti-metastasic

The migration and invasion assay was used to evaluate the anti-metastasis effect of wogonin. Wogonin at the dose of 1–10 µM, which did not induce apoptosis, significantly inhibited the mobility and invasion activity of human gallbladder carcinoma GBC-SD cells. In addition, the expressions of matrix metalloproteinase (MMP)-2, MMP-9 and phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) but not phosphorylated Akt were dramatically suppressed by wogonin in a concentration-dependent manner. Furthermore, the metastasis suppressor maspin was confirmed as the downstream target of wogonin.

These findings suggest that wogonin inhibits cell mobility and invasion by up-regulating the metastasis suppressor maspin. Together, these data provide novel insights into the chemo-protective effect of wogonin, a main active ingredient of Chinese medicine Scutellaria baicalensis (Dong et al., 2011).

Anti-tumor and Anti-metastatic

Kimura & Sumiyoshi (2012) examined the effects of wogonin isolated from Scutellaria baicalensis roots on tumor growth and metastasis using a highly metastatic model in osteosarcoma LM8-bearing mice. Wogonin (25 and 50mg/kg, twice daily) reduced tumor growth and metastasis to the lung, liver and kidney, angiogenesis (CD31-positive cells), lymphangiogenesis (LYVE-1-positive cells), and TAM (F4/80-positive cell) numbers in the tumors of LM8-bearing mice. Wogonin (10–100µM) also inhibited increases in IL-1β production and cyclooxygenase (COX)-2 expression induced by lipopolysaccharide in THP-1 macrophages. The anti-tumor and anti-metastatic actions of wogonin may be associated with the inhibition of VEGF-C-induced lymphangiogenesis through a reduction in VEGF-C-induced VEGFR-3 phosphorylation by the inhibition of COX-2 expression and IL-1β production in Tumor-associated macrophages (TAMs).

Anti-inflammatory

Wogonin extracted from Scutellariae baicalensis and S. barbata is a cell-permeable and orally available flavonoid that displays anti-inflammatory properties. Wogonin is reported to suppress the release of NO by iNOS, PGE2 by COX-2, pro-inflammatory cytokines, and MCP-1 gene expression and NF-kB activation (Chen et al., 2008).

Hypoxia-Induced Drug Resistance (MDR)

Hypoxia-induced drug resistance is a major obstacle in the development of effective cancer therapy. The reversal abilities of wogonin on   hypoxia resistance were examined and the underlying mechanisms discovered. MTT assay revealed that hypoxia increased maximal 1.71-, 2.08-, and 2.15-fold of IC50 toward paclitaxel, ADM, and DDP in human colon cancer cell lines HCT116, respectively. Furthermore, wogonin showed strong reversal potency in HCT116 cells in hypoxia and the RF reached 2.05. Hypoxia-inducible factor-1α (HIF-1α) can activate the expression of target genes involved in glycolysis. Wogonin decreased the expression of glycolysis-related proteins (HKII, PDHK1, LDHA), glucose uptake, and lactate generation in a dose-dependent manner.

In summary, wogonin could be a good candidate for the development of a new multi-drug resistance (MDR) reversal agent and its reversal mechanism probably is due to the suppression of HIF-1α expression via inhibiting PI3K/Akt signaling pathway (Wang et al., 2013).

NSCLC

Wogonin, a flavonoid originated from Scutellaria baicalensis Georgi, has been shown to enhance TRAIL-induced apoptosis in malignant cells in in vitro studies. In this study, the effect of a combination of TRAIL and wogonin was tested in a non-small-cell lung cancer xenografted tumor model in nude mice. Consistent with the in vitro study showing that wogonin sensitized A549 cells to TRAIL-induced apoptosis, wogonin greatly enhanced TRAIL-induced suppression of tumor growth, accompanied with increased apoptosis in tumor tissues as determined by TUNEL assay.

The down-regulation of these antiapoptotic proteins was likely mediated by proteasomal degradation that involved intracellular reactive oxygen species (ROS), because wogonin robustly induced ROS accumulation and ROS scavengers butylated hydroxyanisole (BHA) and N-acetyl-L-cysteine (NAC) and the proteasome inhibitor MG132 restored the expression of these antiapoptotic proteins in cells co-treated with wogonin and TRAIL.

These results show for the first time that wogonin enhances TRAIL's anti-tumor activity in vivo, suggesting this strategy has an application potential for clinical anti-cancer therapy (Yang et al., 2013).

Colon Cancer

Following treatment with baicalein or wogonin, several apoptotic events were observed, including DNA fragmentation, chromatin condensation and increased cell-cycle arrest in the G1 phase. Baicalein and wogonin decreased Bcl-2 expression, whereas the expression of Bax was increased in a dose-dependent manner compared with the control. Furthermore, the induction of apoptosis was accompanied by an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt in a dose-dependent manner.

The administration of baicalein to mice resulted in the inhibition of the growth of HT-29 xenografts without any toxicity following 5 weeks of treatment. The results indicated that baicalein induced apoptosis via Akt activation in a p53-dependent manner in the HT-29 colon cancer cells and that it may serve as a chemo-preventive or therapeutic agent for HT-29 colon cancer (Kim et al., 2012).

Breast

The involvement of insulin-like growth factor-1 (IGF-1) and estrogen receptor α (ERα) in the inhibitory effect of wogonin on the breast adenocarcinoma growth was determined. Moreover, the effect of wogonin on the angiogenesis of chick chorioallantoic membrane (CAM) was also investigated. The results showed wogonin and ICI182780 both exhibited a potent ability to blunt IGF-1-stimulated MCF-7 cell growth. Either of wogonin and ICI182780 significantly inhibited ERα and p-Akt expressions in IGF-1-treated cells. The inhibitory effect of wogonin showed no difference from that of ICI182780 on IGF-1-stimulated expressions of ERα and p-Akt. Meanwhile, wogonin at different concentrations showed significant inhibitory effect on CAM angiogenesis.

These results suggest the inhibitory effect of wogonin on breast adenocarcinoma growth via inhibiting IGF-1-mediated PI3K-Akt pathway and regulating ERα expression. Furthermore, wogonin has a strong anti-angiogenic effect on CAM model (Ma et al., 2012).

Chemoresistance; Cervical Cancer, NSCLC

Chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic. The combination of cisplatin with other agents has been recognized as a promising strategy to overcome cisplatin resistance. Previous studies have shown that wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid isolated from the root of the medicinal herb Scutellaria baicalensis Georgi, sensitizes cancer cells to chemotheraputics such as etoposide, adriamycin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TNF.

In this study, the non-small-cell lung cancer cell line A549 and the cervical cancer cell line HeLa were treated with wogonin or cisplatin individually or in combination. It was found for the first time that wogonin is able to sensitize cisplatin-induced apoptosis in both A549 cells and HeLa cells as indicated by the potentiation of activation of caspase-3, and cleavage of the caspase-3 substrate PARP in wogonin and cisplatin co-treated cells.

Results provided important new evidence supporting the potential use of wogonin as a cisplatin sensitizer for cancer therapy (He et al., 2012).

References

Chen LG, Hung LY, Tsai KW, et al. (2008). Wogonin, a bioactive flavonoid in herbal tea, inhibits inflammatory cyclooxygenase-2 gene expression in human lung epithelial cancer cells. Mol Nutr Food Res. 52:1349-1357.


Chung H, Jung YM, Shin DH, et al. (2008). Anti-cancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts. Int J Cancer, 122(4):816-22.


Dong P, Zhang Y, Gu J, et al. (2011). Wogonin, an active ingredient of Chinese herb medicine Scutellaria baicalensis, inhibits the mobility and invasion of human gallbladder carcinoma GBC-SD cells by inducing the expression of maspin. J Ethnopharmacol, 137(3):1373-80. doi: 10.1016/j.jep.2011.08.005.


He F, Wang Q, Zheng XL, et al. (2012). Wogonin potentiates cisplatin-induced cancer cell apoptosis through accumulation of intracellular reactive oxygen species. Oncology Reports, 28(2), 601-605. doi: 10.3892/or.2012.1841.


Kim EJ, Kang D, Han J. (2011). Baicalein and wogonin are activators of rat TREK-2 two-pore domain K+ channel. Acta Physiologica, 202(2):185–192. doi: 10.1111/j.1748-1716.2011.02263.x.


Kim SJ, Kim HJ, Kim HR, et al. (2012). Anti-tumor actions of baicalein and wogonin in HT-29 human colorectal cancer cells. Mol Med Rep, 6(6):1443-9. doi: 10.3892/mmr.2012.1085.


Kimura Y & Sumiyoshi M. (2012). Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis. Phytomedicine, 20(3-4):328-336. doi:10.1016/j.phymed.2012.10.016


Ma X, Xie KP, Shang F, et al. (2012). Wogonin inhibits IGF-1-stimulated cell growth and estrogen receptor α expression in breast adenocarcinoma cell and angiogenesis of chick chorioallantoic membrane. Sheng Li Xue Bao, 64(2):207-12.


Wang H, Zhao L, Zhu LT, et al. (2013). Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via down-regulation of HIF-1α and glycolysis, by inhibiting PI3K/Akt signaling pathway. Mol Carcinog. doi: 10.1002/mc.22052.


Yang L, Wang Q, Li D, et al. (2013). Wogonin enhances anti-tumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated down-regulation of cFLIPL and IAP proteins. Apoptosis, 18(5):618-26. doi: 10.1007/s10495-013-0808-8.

Anti-estrogenic, Breast cancer, Chapter 7 Isolates and Cancer Research, Chemoprevention, ER, G1, G1/S, Glycine max, growth-inhibitory, LNCaP, Ovarian cancer, Prostate cancer, S

Glyceolins

Cancer: Prostate, breast, ovarian

Action: Anti-estrogenic

Glyceollins are soy-derived phytoalexins isolated from activated soy ( Glycine max [(L.) Merr.] that have been proposed to be candidates for cancer-preventive compounds.

Prostate cancer

It has been found that the glyceollins inhibited prostate cancer cell LNCaP growth similar to that of the soy isoflavone genistein. The growth-inhibitory effects of the glyceollins appeared to be due to an inhibition of G1/S progression and correlated with an up-regulation of cyclin-dependent kinase inhibitor 1 A and B mRNA and protein levels. By contrast, genistein only up-regulates cyclin-dependent kinase inhibitor 1A.

In addition, glyceollin treatments led to down-regulated mRNA levels for androgen responsive genes. In contrast to genistein, this effect of glyceollins on androgen responsive genes appeared to be mediated through modulation of an estrogen- but not androgen-mediated pathway.

Hence, the glyceollins exerted multiple effects on LNCaP cells that may be considered cancer-preventive and the mechanisms of action appeared to be different from other soy-derived phytochemicals (Payton-Stewart et al., 2009).

Anti-estrogenic Effects; Breast Cancer, Ovarian Cancer

The phytoalexin compounds glyceollins I, II, and III have been identified to exhibit marked anti-estrogenic effects on estrogen receptor function and estrogen-dependent tumor growth in vivo. The interactions among the induced soy phytoalexins glyceollins I, II, and III on the growth of estrogen-dependent MCF-7 breast cancer and BG-1 ovarian cancer cells were studied. Four treatment groups for each cell line were used: vehicle control, 20 mg/kg/mouse/d glyceollin mixture injection, 0.72 mg estradiol (E2) implant, and E2 implant + 20 mg/kg/mouse/d glyceollin injection.

Treatment with glyceollin suppressed E2-stimulated tumor growth of MCF-7 cells (-53.4%) and BG-1 cells (-73.1%) in ovariectomized athymic mice. These tumor-inhibiting effects corresponded with significantly lower E2-induced progesterone receptor expression in the tumors. In contrast to tamoxifen, the glyceollins had no estrogen-agonist effects on uterine morphology and partially antagonized the uterotropic effects of estrogen. These findings identify glyceollins as anti-estrogenic agents that may be useful in the prevention or treatment of breast and ovarian carcinoma (Salvo et al., 2006).

Anti-estrogenic Effects

The soybean plant under stress produces a mixture of glyceollins I, II, and III that bind to the estrogen receptor (ER) and inhibit estrogen-induced tumor progression. In further in vitro studies, the glyceollin mixture exhibits potential anti-estrogenic, therapeutic activity preventing estrogen-stimulated tumorigenesis and displaying a differential pattern of gene expression from tamoxifen.

Glyceollin I was identified as the active anti-estrogenic component of the mixture. Ligand-receptor modeling (docking) of the isomers within the ERα ligand binding cavity demonstrated a unique type II anti-estrogenic confirmation adopted by glyceollin I, but not isomers II and III. Glyceollin I treatment in 17β- estradiol-stimulated MCF-7 breast cancer cells and BG-1 ovarian cancer cells resulted in a novel inhibition of ER-mediated gene expression and cell proliferation/ survival.

Glyceollin I may represent an important component of a phytoalexin-enriched food (activated) diet in terms of chemoprevention as well as a novel therapeutic (Tilghman et al., 2010).

References

Payton-Stewart F, Schoene NW, Kim YS, et al. (2009). Molecular effects of soy phytoalexin glyceollins in human prostate cancer cells LNCaP. Molecular Carcinogenesis, 48(9):862–71. doi: 10.1002/mc.20532.


Salvo VA, BouŽ SM, Fonseca JP, et al. (2006). Antiestrogenic glyceollins suppress human breast and ovarian carcinoma tumorigenesis. Clin Cancer Res, 12(23):7159-64. doi: 10.1158/1078-0432.CCR-06-1426.


Tilghman SL, BouŽ SM, Burow ME. (2010). Glyceollins, a novel class of antiestrogenic phytoalexins. Molecular and Cellular Pharmacology, 2(4):155-60. doi: 10.4255/mcpharmacol.10.21

Anti-cancer, Anti-estrogenic, anti-oxidant, anti-proliferative, Breast cancer, Cachexia-inducing, cachexia-inhibiting, cancer stem cells, CCND2, Chapter 7 Isolates and Cancer Research, Endometrial cancer, ER, Hair Loss, inflammation, Lung cancer, MKN45cl85 and 85As2mLuc, pneumonitis, Prostate cancer, Radio-protective, radio-protective effect, Radio-sensitizer, radiotherapy, S, Weight Gain or Weight Loss

Isoflavones

Cancer: Prostate, breast, endometrial

Action: Anti-estrogenic effects, radio-protective effect, pneumonitis, cachexia-inhibiting

Prostate Cancer, Breast Cancer

Isoflavones have been investigated in detail for their role in the prevention and therapy of prostate cancer. This is primarily because of the overwhelming data connecting high dietary isoflavone intake with reduced risk of developing prostate cancer. A number of investigations have evaluated the mechanism(s) of anti-cancer action of isoflavones such as genistein, daidzein, biochanin A, equol, etc., in various prostate cancer models, both in vitro and in vivo.

Nuclear receptors are considered to be a central goal for maximizing treatment opportunities in breast cancer. Among natural ligands for estrogen receptors (ER and ERβ), which are members of the nuclear receptors super-family, are found isoflavones. These natural compounds have a similar structure to the main female hormone 17β-estradiol. A rich source of isoflavones is soy and its products. Three isoflavones of the aglycone form (genistein, daidzein, glycitein) are predominantly found in soybean and red clover. Other important isoflavones are biochanin A and formononetin (Bialešová et al., 2013).

Breast Cancer

Soy isoflavones do not function as an estrogen, but rather exhibit anti-estrogenic properties. However, their metabolism differs between humans and animals and therefore the outcomes of animal studies may not be applicable to humans. The majority of breast cancer cases are hormone-receptor-positive; therefore, soy isoflavones should be considered a potential anti-cancer therapeutic agent (Douglas et al., 2013).

Anti-cancer Effects

Use of soy isoflavone mixture has been advocated as an alternative, wherein daidzein can negate harmful effects of genistein. Recent research indicates the novel role of genistein and other isoflavones in the potentiation of radiation therapy, epigenetic regulation of key tumor suppressors and oncogenes, and the modulation of miRNAs, epithelial-to-mesenchymal transition, and cancer stem cells, which has renewed the interest of cancer researchers in this class of anti-cancer compounds (Ahmad et al. 2013).

Radiation-induced Pneumonitis, Radiation-induced Side-effects

Radiation-induced pneumonitis and fibrosis have restricted radiotherapy for lung cancer. In a preclinical lung tumor model, soy isoflavones showed the potential to enhance radiation damage in tumor nodules and simultaneously protect normal lung from radiation injury. Soy isoflavones given pre- and post-radiation protected the lungs against adverse effects of radiation including skin injury, hair loss, increased breathing rates, inflammation, pneumonitis and fibrosis, providing evidence for a radio-protective effect of soy (Hillman et al., 2013 a).

Radio-sensitizer

Combined soy and radiation caused a significantly stronger inhibition of tumor progression compared to each modality alone in contrast to large invasive tumor nodules seen in control mice. At the same time, soy reduced radiation injury in lung tissue by decreasing pneumonitis, fibrosis and protecting alveolar septa, bronchioles and vessels (Hillman et al., 2013 b).

Endometrial Cancer

Because of their anti-oxidant and anti-mutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have anti-estrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells. The intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins was measured and high consumption of selected proanthocyanidins may reduce endometrial cancer risk (Rossi et al., 2013).

Breast Cancer Protection

The evidence to date from observational epidemiologic studies, suggests that soy food intake, in the amount consumed in Asian populations (about 10 to 20 mg isoflavones per day), may be associated with a reduction of risk of breast cancer development as well as mortality and recurrence among women with breast cancer. The large number of clinical intervention studies on soy that have investigated intermediate biomarkers of breast cancer risk, including circulating estrogen levels, mammographic density, and breast tissue changes (cell proliferation), have not shown clear beneficial or deleterious effects (Wu et al., 2013).

Cachexia-Inhibiting

Isoflavones possess anti-proliferative effects of cachexia-inducing cells (MKN45cl85 and 85As2mLuc) cancer cell lines. Isoflavone treatment on the models induced tumor cytostasis, attenuation of cachexia, and prolonged survival whereas discontinuation of the treatment resulted in progressive tumor growth and weight loss (Yanagihara et al., 2013).

Methylation Effects

There is an inverse correlation between estrogenic marker complement (C)3 and genistein, which suggests an anti-estrogenic effect. Isoflavones induced dose-specific changes in RARβ2 and CCND2 gene methylation, which correlated with genistein levels. Research by Qin & Zhu (2009) provides novel insights into estrogenic and methylation effects of dietary isoflavones.

References

Ahmad A, Biersack B, Li Y, et al. (2013). Perspectives on the Role of Isoflavones in Prostate Cancer. AAPS J, 15(4):991-1000.


Bialešová L, Brtko J, Lenko V, Macejov‡ D. (2013). Nuclear receptors – target molecules for isoflavones in cancer chemoprevention. Gen Physiol Biophys.


Douglas CC, Johnson SA, Arjmandi BH. (2013). Soy and its isoflavones: the truth behind the science in breast cancer. Anti-cancer Agents Med Chem, 13(8):1178-87.


Hillman GG, Singh-Gupta V, Lonardo F, et al [a]. (2013). Radioprotection of Lung Tissue by Soy Isoflavones. J Thorac Oncol.


Hillman GG, Singh-Gupta V, Hoogstra DJ, et al [b]. (2013). Differential effect of soy isoflavones in enhancing high intensity radiotherapy and protecting lung tissue in a preclinical model of lung carcinoma. Radiother Oncol. doi: 10.1016/j.radonc.2013.08.015.


Rossi M, Edefonti V, Parpinel M, et al. (2013). Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case-control study in Italy. Br J Cancer, 109(7):1914-1920. doi: 10.1038/bjc.2013.447.


Wu AH, Lee E, Vigen C. (2013). Soy isoflavones and breast cancer. Am Soc Clin Oncol Educ Book, 2013:102-6. doi: E10.1200/EdBook_AM.2013.33.102.


Yanagihara K, Takigahira M, Mihara K, et al. (2013). Inhibitory effects of isoflavones on tumor growth and cachexia in newly established cachectic mouse models carrying human stomach cancers. Nutr Cancer, 65(4):578-89. doi: 10.1080/01635581.2013.776089.

Akt, angiogenesis, Anti-estrogenic, apoptosis, Apoptotic, Astragalus membranaceus, BAX, Breast cancer, Causes cell-cycle arrest, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, ER, ER-positive, ERK1, G0/G1, G1, growth-inhibitory, inhibits angiogenesis, MAPK, MCF-7, MCF-7 and T47D, MDR, PI3K, PI3K/Akt, Pro-apoptotic, Prostate cancer, ROS, VEGF, VEGF

Formononetin

Cancer: Prostate, colorectal., breast, cervical

Action: Cell-cycle arrest, MDR, growth-inhibitory

Estrogenic or Anti-estrogenic

Formononetin is one of the main active components of red clover plants, and considered as a phytoestrogen. Its pharmacological effects in vivo may be either estrogenic or anti-estrogenic, mainly depending upon the estrogen levels (Chen & Sun., 2012).

Cell-cycle Arrest, Prostate Cancer

Formononetin has been demonstrated to cause cell-cycle arrest at the G0/G1 phase by inactivating insulin-like growth factor 1(IGF1)/IGF1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in MCF-7 cells. The molecular mechanisms involved in the effect of formononetin on prostate cancer cells were hence investigated. These results suggest that higher concentrations of formononetin inhibit the proliferation of prostate cancer cells (LNCaP and PC-3), while the most striking effect was observed in LNCaP cells.

From these results, it was concluded that the induced apoptosis effect of formononetin on human prostate cancer cells was related to ERK1/2 MAPK-Bax pathway. Considering that red clover plants were widely used clinically, these results provided the foundation for future development of different concentrations of formononetin for treatment of prostate cancer (Ye et al., 2012).

Colon Cancer

Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses anti-tumorigenic properties. It has been demonstrated that formononetin initiates growth-inhibitory and pro-apoptotic activities in human colon cancer cells. The potential of formononetin in controlling angiogenesis and tumor cell invasiveness has further been examined in human colon cancer cells and tumor xenografts. The results showed that formononetin downregulated the expression of the key pro-angiogenic factors, including vascular endothelial growth factor (VEGF) and matrix metalloproteinases. The tumor size and the number of proliferating cells were reduced in the tumor tissues obtained from the formononetin-treated group.

The serum VEGF level was also reduced in the drug-treated animals when compared to the controls. These findings suggest that formononetin inhibits angiogenesis and tumor cell invasion, and thus support its use in the treatment of advanced and metastatic colon cancers (Auyeung et al., 2012).

Cervical Cancer

Formononetin may potentiate the cytotoxicity of epirubicin in HeLa cells through the ROS-mediated MRP inhibition and concurrent activation of the mitochondrial and death receptor pathways of apoptosis. Hence, the circumvention of pump and non-pump resistance using formononetin and epirubicin may pave the way for a powerful chemotherapeutic regimen for treating human cervical cancer (Lo et al., 2013).

Breast Cancer

Recent studies by Chen & Sun (2012) suggest that formononetin inactivated IGF1/IGF1R-PI3K/Akt pathways and decreased cyclin D1 mRNA and protein expression in human breast cancer cells in vitro and in vivo. In their present study, they further investigated the molecular mechanisms involved in the induced apoptosis effect of formononetin on breast cancer cells and formononetin inhibited the proliferation of ER-positive MCF-7 cells and T47D cells. The induced apoptosis effect of formononetin on human breast cancer cells was related to Ras-p38MAPK pathway.

Formononetin causes cell-cycle arrest at the G0/G1 phase by inactivating IGF1/IGF1R-PI3K/Akt pathways and decreasing cyclin D1 mRNA and protein expression, indicating the use of formononetin in the prevention of breast cancer carcinogenesis (Chen et al., 2011).

References

Auyeung KK, Law PC, Ko JK. (2012). Novel anti-angiogenic effects of formononetin in human colon cancer cells and tumor xenograft. Oncol Rep, 28(6):2188-94. doi: 10.3892/or.2012.2056.


Chen J, Zeng J, Xin M, Huang W, Chen X. (2011). Formononetin induces cell-cycle arrest of human breast cancer cells via IGF1/PI3K/Akt pathways in vitro and in vivo. Horm Metab Res, 43(10):681-6. doi: 10.1055/s-0031-1286306.


Chen J, Sun L. (2012). Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells. Horm Metab Res, 44(13):943-8. doi: 10.1055/s-0032-1321818.


Lo YL, Wang W. (2013). Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. Chem Biol Interact, 205(3):188-97. doi: 10.1016/j.cbi.2013.07.003.


Ye Y, Hou R, Chen J, et al. (2012). Formononetin-induced apoptosis of human prostate cancer cells through ERK1/2 mitogen-activated protein kinase inactivation. Horm Metab Res, 44(4):263-7. doi: 10.1055/s-0032-1301922.