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Monday, 17 March 2014

Ovarian Cancer in Herbs' Points of View

  Kyle J. Norton

Ovarian cancer is defined as a condition of  abnormal ovarian cells growth of ovaries.  It is one of most common cancer in US, according to the statistics adapted from the American Cancer Society's publication, Cancer Facts & Figures 2010, an estimated 21,880 women in the United States will be diagnosed with ovarian cancer and 13,850 deaths.
Depending to the stage and grade of the cancer, chemotherapy such as cisplatin, carboplatin, paclitaxel, liposomal doxorubicin may be necessary to prevent the spread and recurrence of the cancer. Epidemiological studies focusing in vegetables and fruits in reduced risk and treatment of ovarian cancer have not been conclusive(a)(b)(c)(d), but some herbs have showed to inhibit the progression of cancer with little or no side effects.

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. Isoliquiritigenin (ISL), a licorice chalconoid, induced apoptosis in ovarian carcinoma SKOV-3 cells and increased intracellular ROS levels through ER stress-triggered signaling pathways, according to Shihezi University(1). 18β-glycyrrhetinic acid, another compound found in the same herb, potentiated the effectiveness of Hsp90(heat shock protein 90) in induced apoptosis-related protein activation, nuclear damage, and cell death, through the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated cell death pathway(2). Licochalocone , a natural phenol licorice compounds, enhanced 3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a anticancer drugs, in exhibition of apoptosis in human epithelial ovarian carcinoma OVCAR-3 and SK-OV-3 cell lines, through decreased pro proliferative and increased apoptotic protein expression(3).

2. Cascara sagrada
Cascara sagrada is a species of buckthorn, genus Rhamnus, belonging to the family Rhamnaceae, native to western North America, it's bark has been used in traditional medicine for gastrointestinal support. and it is thought to have a laxative and natural cleansing, etc., effect.
Emodin, a chemical compound found in the herb, inhibited  drug resistant ovarian tumor growth through increasing cellular concentration of anti cancer drug paclitaxel and re-sensitizing the resistant cells to paclitaxel(4). The study of the effect of tamoxifen, emodin, and plumbagin in BRCA1(tumor suppressor genes)-blocked ER-positive BG-1 ovarian cancer cells inhibited ovarian cancer cell line through a induced loss of mitochondrial membrane potential (DeltaPsi(m)), nuclear condensation, DNA fragmentation, and morphological changes(5). In human ovarian carcinoma HO-8910PM cell lines, emodin and apigenin, induced cytotoxicity on HO-8910PM cells, through inhibition of tumor invasion and metastasis(6).

3. 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 compound of herbal Aloe Vera, in composition with Reih exhibited anti  human ovarian cancer SK-OV-3, effect in half inhibitory concentration (IC50)(7). Aloe-emodin (AE) alone, showed the effective in significant inhibition of  invasion, migration, and adhesion capacities of HO-8910PM cells(human ovarian cancer )(8). Aloin, a natural anthraquinone, extract from Aloe Vera, did not inhibit initiation of DNA synthesis and  cells replicated a full complement of DNA but had difficulty in M phase of cell cycle(9).

4. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties. 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(10). In Human epithelial ovarian cancer cell line A2780, S-allylcysteine (SAC), , an antioxidant and chemical compound extracted from garlic, SAC  induced apoptosis through G1/S phase arrest by decreased the proliferative expression and increased expression of active of pro apoptosis(11). In other human ovarian cancer cell lines, SAC and SAMC induced apoptosis through activation of E-cadherin(12).

5. 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). ginsenoside Rg3, a major chemical compound found in Ginseng, inhibited of SKOV-3 cell line through inhibition of tumor-induced angiogenesis and decrease of invasive ability and MMP-9(13).
Composition of ginsenoside Rg3 and cyclophosphamide CTX, significantly inhibited growth and angiogenesis of ovarian cancer(14). Ginsenoside Rh2, another chemical compound of the herb, inhibited the cancer cells through induction of apoptosis in addition to augmentation of the natural killer activity in spleen cells from tumor-hearing nude mice(15).  

6. Lingzhi (LZ)
Ling Zhi is also known as Lucid Ganoderma. The sweet and netral herb has been used in TCM to treat cough, asthma, tinnitus, deafness and lassitude of the loins and knees, palpitation, insomnia and amnesia, hepatitis B, etc. as it nourishes Yin and Blood, strengthens the Spleen tonifies Qi and Body Fluids, calms the Mind, strengthens the Stomach, etc., by enhancing the functions of Lung, Kidney, Liver, Heart, Spleen and Stomach channels.
Lingzhi (LZ),  also known as Ganoderma lucidum, inhibited the ovarian cancer cell line OVCAR-3, through  suppressing cell growth and inducing antioxidative/detoxification activity(16). Other study suggested that LingZhi also strongly decreased cell numbers in a dose-dependent manner. through inhibition of colony formation, cell migration and spheroid formation(17).

7. Cranberry
Cranberry is a evergreen dwarf shrubs, genus Vaccinium, belonging to the family  Ericaceae, native to Northern America and Southern Asia. Because of health benefits, it has been cultivated in some parts of the world forcommercial profits and used in traditional and herbal medicine to treat wounds,urinary disorders, diarrhea, diabetes, stomach ailments, and liver problems.
Proanthocyanidin (PAC)-rich isolate from cranberry (PAC-1), inhibited ovarian cancer SKOV-3 cell line through blocked cell cycle progression through the G2/M phase, increased the generation of reactive oxygen species (ROS), and induced apoptosis through activation of intrinsic and extrinsic pathway components(18). Treatment with Proanthocyanidin in SKOV-3 ovarian cancer cells  exhibited classic apoptotic changesnd pretreatment of SKOV-3 cells with PACs (106 microg/ml) resulted in a significant reduction of the paraplatin IC50 value(19).

8. Rosemary
Rosemaryis a perennial herb with fragrant, evergreen, needle-like leaves, the genus Rosmarinus, belonging to the family Lamiaceae. Its fresh and dried leaves has been used frequently in traditional Mediterranean cuisine and as flavor foods while barbecuing. Rosnary has been used in traditional medicine as an antiseptic, antioxidant, and antispasmodic agent to treat circulatory problem, eczema, rheumatism, muscle pain, etc.
Crude extracts of rosemary (Rosmarinus officinalis L), has been found to consist anti-proliferative property on several human cancer cell lines and antioxidant and anti-inflammatory properties(20).
Carnosol (CS), carnosic acid (CA) and rosmarinic acid (RA), the main ingredients in rosemary extract, exhibited the significant antiproliferation activity on human ovarian cancer A2780 and its CDDP resistant daughter cell line A2780CP70, with IC(50) (50% inhibitory concentration)(21).

9. Devil's Club 
Devil's Club is a large shrub, genus Oplopanax, belonging to the family Aralioideae, native to the cool moist forests of western North America. The herb has been used in traditional and herbal medicine as Adaptogen, Antipyretic, Pain Reliever, Antitussive, Antibacterial agent and to treat Arthritis, Diabetes, Colds, Cough, Sore throat, Chest congestion, Stomach pain, Constipation, Gall stones, Influenza, Cancer, etc.
Ethanolic extract of Devil club dry root bark powder, showed to inhibit the proliferation of some cancer cell lines including K562, HL60, MCF7 and MDA-MB-468 cell growth with the 50% inhibition (IC(50))(22). Water, 70% ethanol, 100% ethanol, and ethyl acetate extracts of OH exhibited significant anti-proliferation effect against both cisplatin sensitive and resistant human ovarian cell lines, including human ovarian cancer cell lines A2780, A2780CP70, OVCAR3, and OVCAR10, according the University of British Columbia(23). In comparison with stem and berry, researchers found that stem extract after administration of 72 h, increased cells apoptosis cells through cell cycle arrest and induction of apoptosis on different human cancer cell lines (SW-480, HCT-116, HT-29, MCF-7 and NSCLC)(24).

10. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It Has been used in traditional herbal medicine in treating impotence, memory loss,respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
Ginkgolide B (GB), a major component of Ginkgo biloba extracts, significantly inhibited SKOV3 and CAOV3 cell proliferation by 57.3% and 63.1% compared with control cells with treatment of with 100 µM GB for 3 days, through the upregulation of p21(promoted cell cycle arrest), p27(regulation of cell proliferation, cell motility and apoptosis), cleaved capase-3(activated antibody), and cleaved caspase-8(activation and cell death) and downregulation of cyclin D1(regulation of cell cycle progression)(25). In BRCA1 mutations risk of developing ovarian cancers, bioinformatics software analysis indicated that GB treatment involved multiple mechanisms and signal pathways in anticancer activities in BRCA1-mutant cells(26). According to Harvard Medical School, in vitro experiments, Ginkgo extract and its components, quercetin and ginkgolide A and B, have significant anti-proliferative effects ( approximately 40%) in normal and ovarian cancer cells(27).

11. Grape seed extract
Grape Seed Extract is the commercial extracts from whole grape seeds that contains many concentrations, including Resveratrol, 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.
Resveratrol, a major compound found in grape seed extract showed to prevent Cisplatin-induced EMT in ovarian cancer cells, through increased cell death, and reduced the risk of metastasis(28). The
University of Michigan, in the study of the effects of Resveratrol in response of ovarian cancer cells, indicated that Resveratrol inhibits the growth and induces death in a panel of five human ovarian carcinoma cell lines, associated with mitochondrial release of cytochrome c, formation of the apoptosome complex, and caspase activation(29). The Seoul National University suggested that Resveratrol retards the growth of PA-1 cell xenograft and the expression of eEF1A2 (the gene may be critical in the development of ovarian cancer) in athymic nude mice(30).

12. Valerian is a perennial flowering plant, in the genus Valeriana, belonging to the family Valerianaceae, native to Europe and parts of Asia. The herb has been used as a sedative and relaxing agent and to treat the liver, the urinary tract, the digestive tract problem, nerve conditions, etc.
IVHD-valtrate, one of the most active Valeriana jatamansi or Indian Valerian derivatives, inhibited the growth and proliferation of the A2780 and OVCAR-3 ovarian cancer cell lines, through  G2/M phase arrest and induced apoptosis, and significantly suppressed the growth of A2780 and OVCAR3 xenograft tumors in a dose-dependent manner(31). 

13. Phyllanthus niruri L. 
Phyllanthus niruri L., also known as stonebreaker or seed-under-leaf, is a widespread tropical plant the genus Phyllanthus, belonging to the family Phyllanthaceae, native to to China, India and South/Central America. The herb has been used in folk medicine to treat kidney stones and in Indian medicine which is for problems of the stomach, genitourinary system, liver, kidney and spleen(32).
Corilagin, a major chemical constituent from Phyllanthus niruri L., inhibited the growth of the ovarian cancer cell lines SKOv3ip and Hey associated with cell cycle arrest at the G2/M stage and enhanced apoptosis(33). Other researchers suggested that Corilagin inhibited into the culture supernatant of all tested ovarian cancer cell lines through blocking the secretion of TGF-β(involved in many cellular processes)(34).

15.
Thelypteris torresiana (Gaud) 
Thelypteris torresiana (Gaud)  is a species of fernin the genus of Thelypteris, belonging to the family Thelypteridaceae native to China. The herb has been used in traditional Chinese medicine for treatment of treatment of hydropsy and traumatic bleeding (Institute of Botany, 1976; Ding, 1982).
The total flavonoid fraction from the roots of M. torresiana shows significant antitumor activity(35).
Protoapigenone, a novel flavonoid isolated from the whole plant Thelypteris torresiana (Gaud), exhibited a significant cytotoxicity on human ovarian cancer cells MDAH-2774 and SKOV3 but not on the immortalized non-cancer ovarian epithelial cells HOSE 6-3 and HOSE 11-12, through S and G2/M phases arrest via decreasing the expression of p-Cdk2, Cdk2(the regulatory subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A) and p27Kip1 (CDKN1B).), p-Cyclin B1 and Cyclin B1(activity is restricted to the G1-S phase, and is essential for cell cycle G1/S phase transition). This protein associates with and is regulated by the regulatory subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A) and p27Kip1 (CDKN1B)(36)), as well as increasing the expression of inactive p-Cdc25C(antibody)(37).

Taking altogether, Certain herbs have been found effectively in reduced risk and treatment of ovarian cancer, through cell cycle arrest, up and down regulation of some mechanisms, but large sample size and multi centers studies are necessary to validate the effectiveness of principle ingredients. As always, All articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.

Ovarian Cysts And PCOS Elimination
Holistic System In Existence That Will Show You How To
Permanently Eliminate All Types of Ovarian Cysts Within 2 Months

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References
(a) Fruit and vegetable consumption and risk of epithelial ovarian cancer: the European Prospective Investigation into Cancer and Nutrition by Schulz M1, Lahmann PH, Boeing H, Hoffmann K, Allen N, Key TJ, Bingham S, Wirfält E, Berglund G, Lundin E, Hallmans G, Lukanova A, Martínez Garcia C, González CA, Tormo MJ, Quirós JR, Ardanaz E, Larrañaga N, Lund E, Gram IT, Skeie G, Peeters PH, van Gils CH, Bueno-de-Mesquita HB, Büchner FL, Pasanisi P, Galasso R, Palli D, Tumino R, Vineis P, Trichopoulou A, Kalapothaki V, Trichopoulos D, Chang-Claude J, Linseisen J, Boutron-Ruault MC, Touillaud M, Clavel-Chapelon F, Olsen A, Tjønneland A, Overvad K, Tetsche M, Jenab M, Norat T, Kaaks R, Riboli E.(PubMed)
(b) Fruits and vegetables and ovarian cancer risk in a pooled analysis of 12 cohort studies by Koushik A1, Hunter DJ, Spiegelman D, Anderson KE, Arslan AA, Beeson WL, van den Brandt PA, Buring JE, Cerhan JR, Colditz GA, Fraser GE, Freudenheim JL, Genkinger JM, Goldbohm RA, Hankinson SE, Koenig KL, Larsson SC, Leitzmann M, McCullough ML, Miller AB, Patel A, Rohan TE, Schatzkin A, Smit E, Willett WC, Wolk A, Zhang SM, Smith-Warner SA(PubMed).
(c) Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk by Riboli E1, Norat T.(PubMed)
(d) Risk of ovarian carcinoma and consumption of vitamins A, C, and E and specific carotenoids: a prospective analysis by Fairfield KM1, Hankinson SE, Rosner BA, Hunter DJ, Colditz GA, Willett WC.(PubMed)
(1) Involvement of endoplasmic reticulum stress in isoliquiritigenin-induced SKOV-3 cell apoptosis by Yuan X1, Yu B, Wang Y, Jiang J, Liu L, Zhao H, Qi W, Zheng Q.(PubMed)
(2) 18β-glycyrrhetinic acid potentiates Hsp90 inhibition-induced apoptosis in human epithelial ovarian carcinoma cells via activation of death receptor and mitochondrial pathway by Yang JC1, Myung SC, Kim W, Lee CS(PubMed)
(3) Guanylate cyclase activator YC-1 potentiates apoptotic effect of licochalcone A on human epithelial ovarian carcinoma cells via activation of death receptor and mitochondrial pathways by Lee CS1, Kwak SW, Kim YJ, Lee SA, Park ES, Myung SC, Kim W, Lee MS, Lee JJ.(PubMed)
(4) Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro by Li J1, Liu P, Mao H, Wanga A, Zhang X.(PubMed)
(5) Antisense blocking of BRCA1 enhances sensitivity to plumbagin but not tamoxifen in BG-1 ovarian cancer cells by Srinivas G1, Annab LA, Gopinath G, Banerji A, Srinivas P.(PubMed)
(6) [Effect of emodin and apigenin on invasion of human ovarian carcinoma HO-8910PM cells in vitro].[Article in Chinese] by Zhu F1, Liu XG, Liang NC.(PubMed)
(7) Synthesis and anti-tumor activity evaluation of rhein-aloe emodin hybrid molecule by Yuan YF1, Hu XY, He Y, Deng JG.(PubMed)
(8) Inhibitory effect of aloe-emodin on metastasis potential in HO-8910PM cell line by He TP1, Yan WH, Mo LE, Liang NC.(PubMed)
(9) DNA ploidy and S phase fraction of breast and ovarian tumor cells treated with a natural anthracycline analog (aloin) by Esmat AY1, El-Gerzawy SM, Rafaat A.(PubMed)
(10) Onion and garlic use and human cancer by Galeone C, Pelucchi C, Levi F, Negri E, Franceschi S, Talamini R, Giacosa A, La Vecchia C.(PubMed)
(11) S-allylcysteine, a garlic derivative, suppresses proliferation and induces apoptosis in human ovarian cancer cells in vitro by Xu YS1, Feng JG2, Zhang D3, Zhang B4, Luo M3, Su D5, Lin NM(PubMed)
(11) A novel anticancer effect of garlic derivatives: inhibition of cancer cell invasion through restoration of E-cadherin expression by Chu Q1, Ling MT, Feng H, Cheung HW, Tsao SW, Wang X, Wong YC.(PubMed)
(12) Cytotoxic components from the dried rhizomes of Zingiber officinale Roscoe by Kim JS1, Lee SI, Park HW, Yang JH, Shin TY, Kim YC, Baek NI, Kim SH, Choi SU, Kwon BM, Leem KH, Jung MY, Kim DK.(PubMed)
(13) Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis by Xu TM1, Cui MH, Xin Y, Gu LP, Jiang X, Su MM, Wang DD, Wang WJ.(PubMed)
(14) Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer by Xu TM1, Xin Y, Cui MH, Jiang X, Gu LP.(PubMed)
(15) Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells by Nakata H1, Kikuchi Y, Tode T, Hirata J, Kita T, Ishii K, Kudoh K, Nagata I, Shinomiya N.(PubMed)
(16) Suppression of proliferation and oxidative stress by extracts of Ganoderma lucidum in the ovarian cancer cell line OVCAR-3 by Hsieh TC1, Wu JM.(PubMed)
(17) Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin by Zhao S1, Ye G, Fu G, Cheng JX, Yang BB, Peng C.(PubMed)
(18) Anti-angiogenic activity of cranberry proanthocyanidins and cytotoxic properties in ovarian cancer cells by Kim KK1, Singh AP, Singh RK, Demartino A, Brard L, Vorsa N, Lange TS, Moore RG.(PubMed)
(19) Cranberry proanthocyanidins are cytotoxic to human cancer cells and sensitize platinum-resistant ovarian cancer cells to paraplatin by Singh AP1, Singh RK, Kim KK, Satyan KS, Nussbaum R, Torres M, Brard L, Vorsa N.(PubMed)
(20) Anti-proliferative and antioxidant properties of rosemary Rosmarinus officinalis.by Cheung S1, Tai J.(PubMed)
(21) Antiproliferation effect of Rosemary (Rosmarinus officinalis) on human ovarian cancer cells in vitro by Tai J1, Cheung S, Wu M, Hasman D.(PubMed)
(22) In vitro anti-proliferative and antioxidant studies on Devil's Club Oplopanax horridus by Tai J1, Cheung S, Cheah S, Chan E, Hasman D.(PubMed)
(23) Inhibition of human ovarian cancer cell lines by devil's club Oplopanax horridus by Tai J1, Cheung S, Chan E, Hasman D.(PubMed)
(24) High performance liquid chromatographic analysis and anticancer potential of Oplopanax horridus: comparison of stem and berry extracts by Wang CZ1, Aung HH, Mehendale SR, Shoyama Y, Yuan CS.(PubMed)
(25) Ginkgo May Sensitize Ovarian Cancer Cells to Cisplatin: Antiproliferative and Apoptosis-Inducing Effects of Ginkgolide B on Ovarian Cancer Cells by Jiang W1, Cong Q, Wang Y, Ye B, Xu C.(PubMed)
(26) Ginkgo may prevent genetic-associated ovarian cancer risk: multiple biomarkers and anticancer pathways induced by ginkgolide B in BRCA1-mutant ovarian epithelial cells by Jiang W1, Qiu W, Wang Y, Cong Q, Edwards D, Ye B, Xu C.(PubMed)
(27) Ginkgo biloba and ovarian cancer prevention: epidemiological and biological evidence by Ye B1, Aponte M, Dai Y, Li L, Ho MC, Vitonis A, Edwards D, Huang TN, Cramer DW.(PubMed)
(28) Resveratrol Inhibits Cisplatin-Induced Epithelial-to-Mesenchymal Transition in Ovarian Cancer Cell Lines by Baribeau S, Chaudhry P, Parent S, Asselin E.(PubMed)
(29) Resveratrol-induced autophagocytosis in ovarian cancer cells by Opipari AW Jr1, Tan L, Boitano AE, Sorenson DR, Aurora A, Liu JR.(PubMed)
(30) Resveratrol suppresses growth of human ovarian cancer cells in culture and in a murine xenograft model: eukaryotic elongation factor 1A2 as a potential target by Lee MH1, Choi BY, Kundu JK, Shin YK, Na HK, Surh YJ.(PubMed)
(31) Valeriana jatamansi constituent IVHD-valtrate as a novel therapeutic agent to human ovarian cancer: in vitro and in vivo activities and mechanisms.

(32) "Keelanelli". Tamilnadu.com. 21 January 2013.
(33) A potential anti-tumor herbal medicine, Corilagin, inhibits ovarian cancer cell growth through blocking the TGF-β signaling pathways by Jia L1, Jin H, Zhou J, Chen L, Lu Y, Ming Y, Yu Y.(PubMed)
(34) A potential anti-tumor herbal medicine, Corilagin, inhibits ovarian cancer cell growth through blocking the TGF-β signaling pathways by Jia L1, Jin H, Zhou J, Chen L, Lu Y, Ming Y, Yu Y.(PubMed
(35) In vitro and in vivo antitumor activity of Macrothelypteris torresiana and its acute/subacute oral toxicity by Huang XH1, Xiong PC, Xiong CM, Cai YL, Wei AH, Wang JP, Liang XF, Ruan JL(PubMed
(36) Bioworld
(37) Protoapigenone, a novel flavonoid, inhibits ovarian cancer cell growth in vitro and in vivo by Chang HL1, Su JH, Yeh YT, Lee YC, Chen HM, Wu YC, Yuan SS.(PubMed)