Endometrial Cancer In Herbs' Points of View

 Kyle J. Norton(Draft Article)

The incidence of endometrial cancer among white women are higher in comparison to black. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as  BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.
Depending to the stage and grade of the cancer, chemotherapy such as Doxorubicin, Cisplatin. Paclitaxel, Carboplatin, Topotecan may be necessary after surgery with certain side effects. Although epidemiological studies focusing the effective of vegetables and fruits in reduced risk and treatment of endometrial cancer with inconclusive results(1)(2)(3)(4), certain herbs, through clinical studies have found to be effective in reduced risk and treatment of endometrial cancer with little or no side effect.
Endometrium is the inner lining of the mammalian uterus and very susceptible hormone change, particular to menstrual cycle. Endometrial cancer is a late adulthood cancer defined as a condition of which the cells of the endometrial lining of uterus have growth uncontrollable or become cancerous as a result of the alternation of cells DNA. It's the fourth most common cancer among women overall, after breast cancer, lung cancer, and bowel cancer.

1. Licorice
Licorice (Glycyrrhiza Glabra) also known as sweetwood, is the genus Glycyrrhiza, belonging to the family Fabaceae, native to the Mediterranean and certain areas of Asia. The herb has been used in traditional medicine to treat skin diseases, coughs, constipation, bronchitis, inflammation, arthritis, etc. In mice study, licorice showed to inhibited the proliferation of endometrial carcinogenesis, through a significant decrease in the COX-2, IL-1alpha and TNF-alpha mRNA expressions(5). On estrogen-related endometrial carcinogenesis in mice, treatment after 2 weeks, licorice inhibited the E2-related endometrial carcinogenesis, through suppression of estrogen-induced c-fos/jun(a variety of physiological functions including cell proliferation and differentiation)-expressions(6).

2. Green tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Catechins. the major polyphenols in green tea, showed to reduced risk reduction of  endometrial cancer(7). Epigallocatechin-3-gallate, Another biological active component of green tea, also
inhibited endometrial cancer cell line (Ishikawa cells) proliferation, through cell cycle arrest, interfered with Akt(role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.) activation and MAPK(role in complex cellular programs like proliferation, differentiation, development, transformation, and apoptosis) signals, and increased apoptosis signals leading to a controlled caspases(mechanisms of apoptosis), Bcl-2(family of regulator proteins that regulate cell death), Bax(involved in p53-mediated apoptosis) genes and protein expression.(8). In a study of 152 patients with histopathologically diagnosed EEA(endometrial cancer), and 285 healthy women of the control who were matched for age and area of residence with individual cases, showed that green tea have an inverse association to endometrial cancer risk regardless of the presence or absence of factors such as obesity and menopause(9).
 
3. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in traditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
Curcumin, a major chemical constituent of turmeric, inhibited endometrial cancer proliferation through suppresses JAK-STAT(mechanisms of activation and regulation of this essential signaling cascade) signaling via activation of PIAS-3(Protein inhibitor of activated STAT3), thus attenuating STAT-3(signal transducer and activator of transcription-3 (STAT-3) is constitutively activated in ovarian and endometrial cancers) phosphorylation and tumor cell growth(10). In comparison of the effects of letrozole and curcumin in endometrial cancer in nude mice, treatment of curcumin or letrozole induced apoptosis in endometrial cancer and the composition further enhanced the inhibitory rate in tumor growth(11). In human endometrial carcinoma HEC-1-A cells, curcumin induced apoptosis through down-regulation of Ets-1 and Bcl-2 expression(12)

4. Garlic
Garlic (Allium sativum) is a species in the onion genus, belonging to family Amaryllidaceae, native to central Asia. It has been used popularly in traditional and Chinese medicine in treating common cold and flu to the Plague, blood pressure cholesterol levels, natural antibiotic, etc.
Allium vegetables have been found in many studies to have an inverse association between the frequency of use of and the risk of several common cancers(13). Purified allicin, a major ingredient of crushed garlic, showed to induced apoptosis through induction of activation of caspases-3, -8 and -9 and cleavage of poly(ADP-ribose) polymerase(14) A multi-centre case-control study of 454 endometrial cancer cases and 908 controls, allium vegetables, including garlic showed a moderate protective effect in reduced risk endometrial cancer(15). But according to the Korea Food and Drug Administration, there was no credible evidence to support a  garlic intake in reduced risk of endometrial cancer(16).

5. Ginger
Ginger (Zingiber officinale) or ginger root is the genus Zingiber, belonging to the family Zingiberaceae, native to Tamil. It has been used in traditional and Chinese medicine to treat dyspepsia, gastroparesis, constipation, edema, difficult urination, colic, etc.
A recent report identified a variety of terpenoids inhibited cancer cell proliferation and metastasis via various mechanisms(17), including inhibition of tumor-induced angiogenesis and of various oncogenic and anti-apoptotic signaling pathways and suppression or nuclear translocation of various transcription factors including nuclear factor kappa B (NF-κB)(18).Terpenoids, a chemical constituent found in the Steam Distilled Extract of Ginger (SDGE) induced apoptosis through activating p53(tumor antigen)(19).

6. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root). In the study of the effect of several fractions of 6-yr old fresh ginseng and red ginseng, four semi-synthetic ginsenoside Rh1, Rh2, Rg3 and Rg5, major saponin components in red ginseng,suggested that ginsenoside Rg3, Rg5 and Rh2 shwed anticarcinogensis actively. Rg3, Rg5 and Rh2 are active components in red ginseng prevent cancer either singularly or synergistically(20). Ginsenoside-Rb2 derived from ginseng inhibited proliferation of endometrial cancer cell lines  Ishikawa(21). In precancerous lesions of the esophagus and endometrium, Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs(22).

7. Red clover
Red Clover is a short-lived perennial plant, in the genus Trifolium, belonging to the family Fabaceae, native to to Europe, Western Asia and northwest Africa. The herb has been used in traditional medicine as diuretic and liver cleansing agent and to treat cancer, whooping cough, respiratory problems, and skin inflammations, etc.
Synthesized carbamate esters with long aliphatic chains without such atoms from Biochanin A (BCA), a major isoflavone in red clover, suppressed cell proliferation Ishikawa cell line(22). the University of Illinois at Chicago study indicated that the flower head and total above-ground parts extracts exhibited differential estrogenic activity in an Ishikawa (endometrial) cel line and autohydrolytic extracts of above-ground parts contained more isoflavones and had more estrogenic activity in Ishikawa endometrial cells as compared with extracts of flower heads(23) and red clover isoflavones had an antiproliferative effect in the endometrium(24).

7. Scutellaria baicalensis (Baikal Skullcap, Huang Qin)
Baikal Skullcap, also known as Huang Qin in traditional Chinese medicine, is a flower plant of the genus Scutellaria,  belonging to the family Lamiaceae, native to China. The herb has been used to treat jaundice,  hypertension ,
anxiety, headache due to cold or flu, prostate Cancer, breast cancer,  red eyes and sore throat, cough
and asthma.
In endometrial cancer cell lines, high does of Huang Qin significantly inhibition of cell growth but
while lower doses stimulated growth in endometrial cell lines(25). In an estrogen-responsive mouse
tumor cell line, the herb Scutellaria baicalensis, significantly inhibited the proliferation of B-1F
cells(estrogen-responsive mouse tumor cell line B-1F ) in vitro and in vivo, through induction of DNA
fragmentation and morphological changes(26).

8. Fritillaria cirrhose (Chuan Bei Mu)
Fritillaria cirrhose is a bulbous plants in the genus of Fritillaria belonging to the family Liliaceae, native to the Northern Hemisphere. The herb has been used in traditional Chinese medicine  as as antibiotic and to raise blood pressure, stop cough, , increased blood sugar,etc. as it transforms Phlegm, calms cough; clears Heat, dissolves nodules, etc. by enhancing the functions of heart and lung channels.
In the composition study of Scutellaria baicalensis (SB) and Fritillaria cirrhosa (FC), suggested that both herb inhibit the proliferation of endometrial cell line through activation of caspase-3(cell apoptosis) G₀ /G₁ phase cell cycle arrest, down regulation of cyclins D1 and D3(regulating cell cycle progression) and induction of p27(Cell cycle inhibition)(27)

9. Bufalin (Chan Su)
Bufalin is also known as toad venom. The acrid, warm, toxic herb has been used in TCM to food poisoning with stomach pain and bloating, vomiting, diarrhea, fainting, painful and swollen throat and certain types of cancer, including liver cancer, intestine cancer, leukemia, skin cancer etc. as it expels toxins, resolves oedema, calms pain, opens the orifices, etc. by enhancing the functions of heart, kidney and stomach channels. Bufalin, the cardioactive C-24 steroids was found to inhibit the growth of tumors of endometrium through cell cycle arrest, apoptosis, and expression of genes proliferation genes(28). The Oita University Faculty of Medicine study also showed that Cang Su indiced apoptosis through decreased the proportion of cells in the S-phase and increased the proportion in the G0/G1 phases of the cell cycle(29).

11. The compositions Shi-Quan-Da-Bu-Tang or Shimotsu-to
Shi-Quan-Da-Bu-Tang is a composition of RenShen, BaiZhu, FuLing, ShuDiHuang, DangQui, Chuan Xiong, HuanQi and RuGui commonly used in traditional Chinese medicine to treat qi and blood accompanied by yang deficiency and cold manifestations. In endometrial cell line, the composition induced apoptosis of the cancer cells through suppression of the suppression of The expression of ER-alpha mRNA, but not ER-beta mRNA(30). Juzen-taiho-to, consisting a mixture of Shimotsu-to and Shikunshi-to formulas, in mice study showed to exert protective effect against estrogen-related endometrial carcinogenesis(31) through suppression of estradiol-17 beta (E2)-induced expression of c-fos/jun(cell proliferation, differentiation and survival) in uterine corpus and inhibition of N-methyl-N-nitrosourea(a highly reliable carcinogen, mutagen, and teratogen) and E2-induced endometrial carcinogenesis(32).

 Taking altogether, without going into reviews, the above list are found ti be effective in reduced risk and treatnent of endometrial cancer through various expressions and mechanisms including cell cycle arrest, upregulation of induced apopticand  downregulation of proliferative expressions. Large sample size and muticenter studies are necessary with identification of the active principle in order to improve the validation of the clinical trial.


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