Cervical cancer in Herbs' Points of View

 Kyle J. Norton(Draft Article)

Cervical cancer is malignant neoplasm of the cervix uteri or cervical area caused by abnormal cells growth with alternation of cells DNA. According to the American Cancer Society's, in 2014, 12,360 new cases of invasive cervical cancer will be diagnosed with the death of  4,020 patients. The risk of cervical cancer is higher in Hispanic women followed by African-Americans, Asians and Pacific Islanders, and whites(a).
Depending to the stage and grade of the cancer, if the cancer is found in the early stahe, hysterectomy may not be needed. Other while  after sugery, chemotherapy including Cisplatin, Fluorouracil (5-FU), Mitomycin, Paclitaxel, Ifosfamide, Carboplatin, Bevacizumab and radiotherapy may be necesary, but with certain side effects. Rmerging suggestion of a healthy and balanced diet to improve high serum levels of antioxidants may reduce cervical neoplasia risk(b)(c)  but other suggested that the role of diet and nutrition in the etiology of cervical cancer is not yet resolved(d) and Catalan Institute of Oncology study showed statistically nonsignificant inverse associations were also observed for leafy vegetables, root vegetables, garlic and onions, citrus fruits, vitamin C, vitamin E and retinol for invasive squamous cervical cancer (ISC)(e).
Epidemiological studies, linking herbal medicine in reduced risk of cervical cancer have not been consistent. But certain herbs and spice may be effective in  treating cervical caner(1) with little or no side effects.
1. Peony root
Bai Shao also known as White Peony Root, the bitter sour and cool herb has been used in TCM as anti-spastic, anticonvulsant, analgesic, sedative, antipyretic, anti-inflammatory, antibiotic agent and to owers blood pressure, dilates peripheral blood vessels etc., as it nourishes Blood and liver, preserves the Yin, clams pain;, etc., by promoting the function of liver and spleen channels.
Chi Shao or Chi Shao Yao is also known as Red Peony Root, the bitter, sour and cool herb has been used in TCM to anti-spastic, antipyretic, anti-inflammatory, antibiotic, anticonvulsant, analgesic, sedative agnet and to lower blood pressure, dilate peripheral blood vessels, coronary arteries, treat viral hepatitis, chronic constipation, asthma, whooping coughs, diabetes, etc., as it clears Heat, cools Blood, eliminates Blood accumulation, calms paindilates, etc., by enhancing the functions of liver and spleen channels. 
Paeoniflorin (PF), the principal bioactive chemical coonhound from the peony root, inhibited human cervical cancer cell line (HeLa) cells, through a decrease in the expression of Bcl-2 and increase the expression of Bax and caspase-3 genes(2)(3).

2. Dang Qui (Angelica sinensis)
Dang Qui (Angelica sinensis)  is a herb of Genus Angelica from the family Apiaceae, indigenous to China. The herb has been used as a Queen herb in traditional Chinese medicine antispasmodic and vasodilatory agent, and to balance the hormones in women for a normal menstrual cycle and menstruation and strengthen heart, spleen, kidneys, and liver for both men and women, etc. In other words, it is used to treat gynecological ailments, fatigue, mild anemia and high blood pressure. It has analgesic, anti-inflammatory, etc.
Polysaccharide(APS-1d) isolated from Angelica sinensis, induced -induced apoptosis of human cervical cancer cell line through regulation of Bcl-2 family protein expression, a decrease in the mitochondrial membrane potential, and an increase in the cytosolic cytochrome c levels(4).

3. Asparagus
Asparagus is a flowering plant belong to species the genus Asparagus, native to the western coasts of northern Spain, north to Ireland, Great Britain, and northwest Germany, northern Africa and western Asia. Asparagus has been used from early times as a vegetable and medicine, because of its delicate.
Formononetin, as an O-methylated isoflavone found in Astragalus, in doses depending mummer induced the apoptosis of CC cell line HeLa through inhibited the phosphorylation of AKT(5).

4. 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 cervical cancer Ca Ski cells, Isoliquiritigenin, a constituent of licorice induced apoptosis of the cancer cell line through down regulation of HPV(Human papillomavirus) 16 E6 expression associated with an increase of p53(tumor suppressor) and p21(cyclin-dependent kinase inhibitor) levels, enhanced expression of Bax and decreased expression of Bcl-2 and Bid proform triggering dissipation of the mitochondrial membrane potential, released cytochrome c to the cytosol followed by activation of caspase cascade with cleavage of caspase-9, caspase-3, and PARP. Caspase-8.(6) or through G2/M phase arrest was also associated with decreases in the amounts of cyclin B, cyclin A, cdc2, and cdc25C, and increases in the phosphorylation of Chk2, cdc25C, and cdc2.(7). Other chemical constituent Liquiritigenin (LQ), inhibited the growth of tumors xenografted in nude mice from human cervical cancer cell line HeLa cells, in a dose dependent manner(8).

5. 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 polyphenol extracted from turmeric, decreased survival after IR in HeLa cells via induced increased reactive oxygen species (ROS), sustained activation of ERK1/2(9). Human MDR-1 gene expression in multidrug resistant human cervical carcinoma cell line was inhibited by bisdemethoxycurcumin  isolated from turmeric(10). Other extract NBFR-03, from Curcuma longa Linn extract, exhibited a arrest low-grade squamous intraepithelial neoplasia (LSIL) a 12 week(11). according to the effect of curcumin on HPV-positive and negative cervical cancer cell lines HeLa, SiHa, CaSki, and C33A pretreated with estradio, conducted by All India Institute of Medical Science, showed a positive effects of curcumin in counteracted the proliferative response of estradiol, and induce apoptosis(12).

6. Aloe vera
Aloe Vera is species of succulent plant in the genus Aloe, belonging to the Family Xanthorrhoeaceae, native to Sudan. It has become very popular for commercial cultivation due to its health benefits. Aloe vera has been used in herbal medicine in treating many kinds of disease, including wound, burn healing, minor skin infections, sebaceous cysts, diabetes, and elevated of cholesterol, etc. It is also one of many popular herb studied in scientific ways with some conflicted results.
Aloe emodin, a major chemical constituent of Aloe vera, inhibited the growth of human cervical cancer cell line, HeLa cells in a dose-dependent manner, through cycle arrest and the decrease in cyclin A and CDK2, and the increase in cyclin B1 and CDK1expression(13). Aloin, another chemical compound from the herb, exerted a pronounced antiproliferative effect through cell cycle arrest in the S phase and induced increased HeLaS3 cell apoptosis(14). Rhein-aloe-emodin hybrid molecule (RH-AE), a synthetic version of from rhein and aloe-emodin, inhibited the human ovarian cancer SK-OV-3 in lesser effective than those of rhein and aloe-emodin(15).

8. Rhubarb (Rheum palmatum L.)
Rhubarb is a small flower grouped with large compound leafy in the the genus Rheum, belonging to the family Polygonaceae. The herb has been used in traditional medicine as laxative agent, reduce inflammation and treat diarrhea, dysentery blood clots, tumor red and painful eyes abdominal-distention and/or pain blood in stool hemorrhoidal bleeding urination: burning sensation, absence of menses, etc.
Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a chemical compound isolated from Rhubarb, induced apoptosis of human cervical cancer cells through the mitochondrial pathway, via activation of caspases-3, -9 and cleavage of poly(ADP-ribose) polymerase(16) or through the intrinsic mitochondrial and extrinsic death receptor pathways(17).

10. Grape Seed Extract
Grape Seed Extract is the commercial extracts from whole grape seeds that contains many concentrations, including vitamin E, flavonoids, linoleic acid, oligomeric proanthocyanidins(OPCs), etc..The herb has been used in traditional medicine as antioxidant, anti-inflammatory agents and to treat skin wounds with less scarring, allergies, macular degeneration, arthritis, enhance circulation of blood vessels, lower cholesterol, etc.
Grape Seed Proanthocyanidins (GSPs) in comparison of the effects in 3 cancer cell lines showed to inhibited the human cervical cancer cell line Hela weaker than those of human leukemia K562 cells(18). Gallic acid (GA) , a major chemical compound of grape seed extract, induced HeLa cell death in relation to reactive oxygen species (ROS) and glutathione (GSH) levels(19)(20).

11. 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.
Diallyl sulfide (DAS), a chemical component of garlic induced mitochondrial dysfunction, leading to the release of cytochrome c for causing apoptosis in human cervical cancer Ca Ski cells(21) and cell cycle arrest and apoptosis through the p53, caspase- and mitochondria-dependent pathways in in HeLa human cervical cancer cells(22). The Defense Food Research Laboratory study indicated that Garlic exerted its anticarcinogenic effect(including cervical cancer) through a number of mechanisms, including scavenging of radicals, increasing gluathione levels, increasing the activities of enzymes(23). In 3-methylcholanthrene (MCA)-induced carcinogenesis in the uterine cervix of virgin young adult Swiss albino mice study, found a sginificant decline in the incidence of carcinoma witjh oral administration of garlic at the dose level of 400 mg/kg body wt./day for 2 weeks before and 4 weeks following carcinogen thread insertion(24).

12. 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).
Ginsenosides, the major chemical composition of Panax ginseng inhibited 74%  human cervical cancer cells (Hela) after 72 h exposure(25). Saponin ginsenoside Rd (1), isolated from Panax notoginseng inhibited HeLa cell proliferation, and induced cell apoptosis through down-regulating Bcl-2 expression, up-regulating Bax expression, lowering the mitochondrial transmembrane potential, and activating the caspase-3 pathway(26).

13. Milk Thistle
Milk Thistle is a flowering plant, in the genus Silybum Adans, belonging to the family Asteraceae, native to the Mediterranean. The herb has been used in traditional medicine in treating liver, kidney, gall bladder problems, etc.
Silibinin, an active constituent extracted from milk thistle (Silybum marianum), exhibited the cytotoxicity of NO in HeLa cells, through induced GSH depletion mediated by p53(27). In cervical cancer cells (C-33A), silymarin inhibited cancer cell viability and induced apoptosis through the modulation of Bcl-2 family proteins and activation of caspase 3(28). Other study found that the chemicanl compound also exerted its anti proliferative effect of human cervical cell line (HeLa) through inhibition of hypoxia-induced HIF-1alpha accumulation and HIF-1 transcriptional activity in human cervical (HeLa)(29)

14. Cat's claw
Cat's claw found in in the tropical jungles of South and Central America, is a genus Uncaria, belonging to the family Rubiaceae. It has been used in traditional medicine over two thousand years as a tonic, contraceptive, anti-inflammatory and infectious agent, and to treat diarrhea, rheumatic disorders, acne, diabetes, cancer and diseases of the urinary tract, etc..
According to the study at Polish Academy of Sciences, extract of Uncaria tomentosa in doses dependent manner, inhibited the proliferation of cervical carcinoma(30).

Taking altogether, without going into reviews, the list of herbal medicines above has showed effectively in reduced risk and treatment of cervical cancer. But larger sample size and multi centers studies to validate the effectiveness through identification of the principle ingredients are necessary. As always, all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying

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References
(a) Cerical cancer (Amerrican cancer society)
(b) Diet and serum micronutrients in relation to cervical neoplasia and cancer among low-income Brazilian women by Tomita LY¹, Longatto Filho A, Costa MC, Andreoli MA, Villa LL, Franco EL, Cardoso MA; Brazilian Investigation into Nutrition and Cervical Cancer Prevention (BRINCA) Study Team.(PubMed)
(c) Associations of dietary dark-green and deep-yellow vegetables and fruits with cervical intraepithelial neoplasia: modification by smoking by Tomita LY¹, Roteli-Martins CM, Villa LL, Franco EL, Cardoso MA; BRINCA Study Team.(PubMed)
(d) Diet and the risk of in situ cervical cancer among white women in the United States by Ziegler RG¹, Jones CJ, Brinton LA, Norman SA, Mallin K, Levine RS, Lehman HF, Hamman RF, Trumble AC, Rosenthal JF, et al.(PubMed)
(e) Dietary factors and in situ and invasive cervical cancer risk in the European prospective investigation into cancer and nutrition study by González CA¹, Travier N, Luján-Barroso L, Castellsagué X, Bosch FX, Roura E, Bueno-de-Mesquita HB, Palli D, Boeing H, Pala V, Sacerdote C, Tumino R, Panico S, Manjer J, Dillner J, Hallmans G, Kjellberg L, Sanchez MJ, Altzibar JM, Barricarte A, Navarro C, Rodriguez L, Allen N, Key TJ, Kaaks R, Rohrmann S, Overvad K, Olsen A, Tjønneland A, Munk C, Kjaer SK, Peeters PH, van Duijnhoven FJ, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Benetou V, Naska A, Lund E, Engeset D, Skeie G, Franceschi S, Slimani N, Rinaldi S, Riboli E.(PubMed)
(1) Anticancer Activity of Certain Herbs and Spices on the Cervical Epithelial Carcinoma (HeLa) Cell Line by Berrington D¹, Lall N.(PubMed)
(2) Modulating Bcl-2 family proteins and caspase-3 in induction of apoptosis by paeoniflorin in human cervical cancer cells by Zhang L¹, Zhang S.(PubMed)
(3) [Relevant study on apoptosis of cervical cancer HeLa cells induced by paeoniflorin].

[Article in Chinese] by Zhang LL¹, Zhang SL, Wang SZ.(PubMed)

(4) A novel polysaccharide, isolated from Angelica sinensis (Oliv.) Diels induces the apoptosis of cervical cancer HeLa cells through an intrinsic apoptotic pathway by Cao W¹, Li XQ, Wang X, Fan HT, Zhang XN, Hou Y, Liu SB, Mei QB.(PubMed) 

(5) In vitro and in vivo anti-cancer activity of formononetin on human cervical cancer cell line HeLa by Jin YM¹, Xu TM, Zhao YH, Wang YC, Cui MH.(PubMed) 

(6) Isoliquiritigenin induces caspase-dependent apoptosis via downregulation of HPV16 E6 expression in cervical cancer Ca Ski cells by Hirchaud F¹, Hermetet F, Ablise M, Fauconnet S, Vuitton DA, Prétet JL, Mougin C.(PubMed) 

(7)Shallot and licorice constituent isoliquiritigenin arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and initiation of the mitochondrial system in human cervical carcinoma HeLa cells by Hsu YL¹, Chia CC, Chen PJ, Huang SE, Huang SC, Kuo PL.(PubMed)

(8) Liquiritigenin inhibits tumor growth and vascularization in a mouse model of HeLa cells by Liu Y¹, Xie S, Wang Y, Luo K, Wang Y, Cai Y.(PubMed) 

(9) The chemopreventive agent curcumin is a potent radiosensitizer of human cervical tumor cells via increased reactive oxygen species production and overactivation of the mitogen-activated protein kinase pathway by Javvadi P¹, Segan AT, Tuttle SW, Koumenis C(PubMed) 

(10) Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids by Limtrakul P¹, Anuchapreeda S, Buddhasukh D.(PubMed) 

(11) Chemopreventive potential and safety profile of a Curcuma longa extract in women with cervical low-grade squamous intraepithelial neoplasia by Joshi JV¹, Paradkar PH, Jagtap SS, Agashe SV, Soman G, Vaidya AB.(PubMed) 

(12) Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells by Singh M¹, Singh N.(PubMed)
(13) Anticancer effect of aloe-emodin on cervical cancer cells involves G2/M arrest and induction of differentiation by Guo JM¹, Xiao BX, Liu Q, Zhang S, Liu DH, Gong ZH.(PubMed)
(14) Antitumor effects of a natural anthracycline analog (Aloin) involve altered activity of antioxidant enzymes in HeLaS3 cells by Nićiforović A¹, Adzić M, Spasić SD, Radojcić MB.(PubMed)
(15) Synthesis and anti-tumor activity evaluation of rhein-aloe emodin hybrid molecule by Yuan YF¹, Hu XY, He Y, Deng JG.(PubMed)
(16) Emodin induces apoptosis of human cervical cancer cells through poly(ADP-ribose) polymerase cleavage and activation of caspase-9 by Srinivas G¹, Anto RJ, Srinivas P, Vidhyalakshmi S, Senan VP, Karunagaran D.(PubMed)
(17) Emodin induces apoptosis of human cervical cancer hela cells via intrinsic mitochondrial and extrinsic death receptor pathway by Yaoxian W¹, Hui Y, Yunyan Z, Yanqin L, Xin G, Xiaoke W.(PubMed)
(18) [Study on the effect of grape seed proanthocyanidins on increasing the radiosensitivity for X-ray].[Article in Chinese] by Pan XJ¹, Wang M, Wang XX, Liu B, Zhang H.(PubMed)
(19) The effects of mitogen-activated protein kinase inhibitors or small interfering RNAs on gallic acid-induced HeLa cell death in relation to reactive oxygen species and glutathione by You BR¹, Park WH.(PubMed)
(20) Gallic acid inhibits the growth of HeLa cervical cancer cells via apoptosis and/or necrosis by You BR¹, Moon HJ, Han YH, Park WH.(PubMed)
(21) Diallyl sulfide promotes cell-cycle arrest through the p53 expression and triggers induction of apoptosis via caspase- and mitochondria-dependent signaling pathways in human cervical cancer Ca Ski cells by Chiu TH¹, Lan KY, Yang MD, Lin JJ, Hsia TC, Wu CT, Yang JS, Chueh FS, Chung JG.(PubMed)
(22) Diallyl sulfide induces cell cycle arrest and apoptosis in HeLa human cervical cancer cells through the p53, caspase- and mitochondria-dependent pathways by Wu PP¹, Chung HW, Liu KC, Wu RS, Yang JS, Tang NY, Lo C, Hsia TC, Yu CC, Chueh FS, Lin SS, Chung JG.(PubMed)
(23) Anticarcinogenic properties of garlic: a review by Khanum F¹, Anilakumar KR, Viswanathan KR.(PubMed)
(24) Chemopreventive action of garlic on methylcholanthrene-induced carcinogenesis in the uterine cervix of mice by Hussain SP¹, Jannu LN, Rao AR.(PubMed)
(25) Ginsenosides extracted from nanoscale Chinese white ginseng enhances anticancer effect by Ji Y¹, Rao Z, Cui J, Bao H, Chen C, Shu C, Gong JR(PubMed)
(26) Ginsenoside Rd from Panax notoginseng is cytotoxic towards HeLa cancer cells and induces apoptosis by Yang ZG¹, Sun HX, Ye YP.(PubMed)
(27) P53-mediated GSH depletion enhanced the cytotoxicity of NO in silibinin-treated human cervical carcinoma HeLa cells by Fan S¹, Yu Y, Qi M, Sun Z, Li L, Yao G, Tashiro S, Onodera S, Ikejima T.(PubMed)
(28) Silymarin inhibits cervical cancer cell through an increase of phosphatase and tensin homolog by Yu HC¹, Chen LJ, Cheng KC, Li YX, Yeh CH, Cheng JT.(PubMed)
(29) Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy by García-Maceira P¹, Mateo J.(PubMed)
(30) Anticancer activity of the Uncaria tomentosa (Willd.) DC. preparations with different oxindole alkaloid composition by Pilarski R¹, Filip B, Wietrzyk J, Kuraś M, Gulewicz K.(PubMed)