Skip to main content
Log in

Growth Inhibitory Activity of Extracts and Purified Components of Black Cohosh on Human Breast Cancer Cells

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The purpose of this study was to determine whether black cohosh contains constituents that inhibit the growth of human breast cancer cells, and therefore might eventually be useful in the prevention or treatment of breast cancer. Black cohosh rhizomes were extracted with methanol/water and fractionated by solvent–solvent partitioning to yield three fractions: hexane, ethyl acetate and water. The ethyl acetate fraction displayed the highest potency in two cell-based assays, growth inhibition and cell cycle analysis. This fraction inhibited growth of both the ER+ MCF7 and ERMDA-MB-453 human breast cancer cell lines with IC50 values of about 20 and 10 µg/ml, respectively. It also induced cell cycle arrest at G1 when tested at 30 µg/ml and at G2/M at 60 µg/ml in MCF7 cells. This suggests that the extract contains a mixture of components with the more active (or more abundant) causing G1 arrest and the less active causing G2/M arrest. We then examined specific components in this extract. The triterpene glycoside fraction obtained by polyamide column chromatography, and the specific triterpene glycosides actein, 23-epi-26-deoxyactein and cimiracemoside A, inhibited growth of the MCF7 human breast cancer cells and induced cell cycle arrest at G1. The most potent compound, actein, decreased the level of cyclin D1, cdk4 and the hyperphosphorylated form of the pRb protein and increased the level of p21cip1 in MCF7 cells, changes that may contribute to the arrest in G1. Further studies are in progress to identify the mechanisms by which actein and related compounds present in black cohosh inhibit growth of human breast cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Sporn MB, Suh N: Chemoprevention of Cancer. Carcinogenesis 21: 525–530, 2000

    Google Scholar 

  2. McKenna DJ, Jones K, Humphrey S, Hughes K: Black cohosh: efficacy, safety, and use in clinical and preclinical applications. Altern Ther 7: 93–100, 2001

    Google Scholar 

  3. Foster S: Black cohosh: Cimicifuga racemosa. A literature review. HerbalGram 45: 35–49, 1999

    Google Scholar 

  4. Hsu H-Y, Chen Y-P, Hsu C-S, Shen S-J, Chen C-C, Chang H-C: Oriental Materia Medica: A Concise Guide. Keats Publishing, Inc., New Canaan, 1986

    Google Scholar 

  5. Upton R: Black cohosh rhizome. In: American Herbal Pharamacopoeia and Therapeutic Compendium. American Herbal Pharmacopoeia, Santa Cruz, 2002

    Google Scholar 

  6. Lehmann-Willenbrock E, Riedel HH: Clinical and endocrinological examinations concerning therapy of climacteric symptoms following hysterectomy with remaining ovaries. Zent Bl Gynakol 110: 611–618, 1998

    Google Scholar 

  7. Stoll W: Phytotherapy influences atrophic vaginal epithelium: Double-blind study-Cimicifuga vs. estrogenic substances. Therapeuticum 1: 23–31, 1997

    Google Scholar 

  8. Chen SN, Li W, Fabricant DS, Santarsiero BD, Mesecar A, Fitzloff JF, Fong HH, Farnsworth NR: Isolation, structure elucidation, and absolute configuration of 26-deoxyactein from Cimicifuga racemosa and clarification of nomenclature associated with 27-deoxyactein. J Natl Prod 65: 601–605, 2000

    Google Scholar 

  9. Zheng QY, He K, Pilkington L, Yu S, Zheng B: CimiPure (Cimicufuga racemosa): a standardized black cohosh extract with novel triterpene glycoside for menopausal women. In: Shahidi F, Ho C-T (eds) Phytochem Phytopharm. AOCS Press, Champagne, 2000, pp 360–370

    Google Scholar 

  10. Loser B, Kruse SO, Melzig MF, Nahrstedt A: Inhibition of neutrophil elastase activity by cinnamic acid derivatives from Cimicifuga racemosa. Planta Med 66: 751–753, 2000

    Google Scholar 

  11. Burdette JE, Chen SN, Lu ZZ, Xu H, White BE, Fabricant DS, Liu J, Fong HH, Farnsworth NR, Constantinou AI, Van Breemen RB, Pezzuto JM, Bolton JL: Black cohosh (Cimicifuga racemosa L.) protects against menadione-induced DNA damage through scavenging of reactive oxygen species: bioassay-directed isolation and characterization of active principles. J Agric Food Chem 50: 7022–7028, 2002

    Google Scholar 

  12. Dixon-Shanies D, Shaikh N: Growth inhibition of human breast cancer cells by herbs and phytoestrogens. Oncol Rep 6: 1383–1387, 1999

    Google Scholar 

  13. Nesselhut T, Schellhase C, Dietrich R, Kuhn W: Studies on mammary carcinoma cells regarding the proliferative potential of herbal medications with estrogen-like effects. Arch Gynecol Obstet 254: 817–818, 1993

    Google Scholar 

  14. Bodinet C, Freudenstein J: Influence of Cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells. Breast Cancer Res Treat 76: 1–10, 2002

    Google Scholar 

  15. Watanbe K, Mimaki Y, Sakagami H, Sashida Y: Cycloartane glycosides from the rhizomes of Cimicifuga racemosa and their cytotoxic activities. Chem Pharm Bull (Tokyo) 50: 121–125, 2002

    Google Scholar 

  16. Kennelly EJ, Gerhauser C, Song LL, Graham JG, Beecher CWW, Pezzuto JM, Kinghorn AD: Induction of quinone reductase by withanolides isolated from Physalis philadelphica (tomatillos). J Agric Food Chem 45: 3771–3777, 1997

    Google Scholar 

  17. Lim JTE, Piazza GA, Han K-H, Delohery TM, Li H, Finn TS, Buttyan R, Yamamoto H, Sperl GJ, Brendel K, Gross PH, Pamukcu R, Weinstein IB: Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines. Biochem Pharmacol 58: 1097–1107, 1999

    Google Scholar 

  18. Luo J, Soh J-W, Xing W-Q, Mao Y, Matsuno T, Weinstein IB: PM-3, a benzo-g-pyran derivative isolated from propolis, inhibits growth of MCF-7 human breast cancer cells. Anticancer Res 21: 1665–1672, 2001

    Google Scholar 

  19. Han EK, Sgambato A, Jiang W, Zhang YJ, Santella RM, Doki Y, Cacace AM, Schieren I: Stable overexpression of cyclin D1 in a human mammary epithelial cell line prolongs the S-phase and inhibits growth. Oncogene 10: 953–961, 1995

    Google Scholar 

  20. Sgambato A, Zhang Y-J, Ciaparrone M, Soh J-W, Cittadini A, Santella RM, Weinstein IB: Overexpression of p27(Kip1) inhibits the growth of both normal and transformed human mammary epithelial cells. Cancer Res 58: 3448–3454, 1998

    Google Scholar 

  21. Kruse SO, Löhning A, Pauli GF, Winterhoff H, Nahrstedt A: Fukiic and piscidic acid esters from the rhizome of Cimicifuga racemosa and the in vitro estrogenic activity of fukinolic acid. Planta Med 65: 763–764, 1999

    Google Scholar 

  22. Tsutsui S, Ohno S, Murakami S, Hachitanda Y, Oda S: Prognostic value of c-erbB2 expression in breast cancer. J Surg Oncol 79: 216–233, 2002

    Google Scholar 

  23. Weinstein IB: Disorders of cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis 21: 857–864, 2000

    Google Scholar 

  24. Joe AK, Arber N, Bose S, Heitjan D, Zhang Y, Weinstein IB, Hibshoosh H: Cyclin D1 overexpression is more prevalent in non-Caucasian breast cancer. Anticancer Res 21: 3535–3539, 2001

    Google Scholar 

  25. Han EK, Arber N, Yamamoto H, Lim JT, Delohery T, Pamukcu R, Piazza GA, Xing WQ, Weinstein IB: Effects of sulindac and its metabolites on growth and apoptosis in human mammary epithelial and breast carcinoma cell lines. Breast Cancer Res Treat 48: 195–203, 1998

    Google Scholar 

  26. Masuda M, Suzui M, Weinstein IB: Effects of epigallocatechin-3-gallate on growth, epidermal growth factor receptor signaling pathways, gene expression, and chemosensitivity in human head and neck squamous cell carcinoma cell lines. Clin Cancer Res: 4220–4229, 2001

  27. Meiers S, Kemeny M, Weyand U, Gastpar R, von Angerer E, Marko D: The anthocyanidins cyanidin and delphinidin are potent inhibitors of the epidermal growth-factor receptor. J Agric Food Chem 49: 958–962, 2001

    Google Scholar 

  28. Haridas V, Higuchi M, Jayatilake GS, Bailey D, Mujoo K, Blake ME, Arntzen CJ, Gutterman JU: Avicins: triterpenoid saponins from Acacia victoriae (Bentham) induce apoptosis by mitochondrial perturbation. Proc Natl Acad Sci USA 98: 5821–5826, 2001

    Google Scholar 

  29. Pisha E, Chai H, Lee IS, Chagwedera TE, Farnsworth NR, Cordell GA, Beecher CW, Fong HH, Kinghorn AD, Brown DM et al.: Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1: 1046–1051, 1995

    Google Scholar 

  30. Fulda S, Debatin KM: Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors. Med Pediatr Oncol 35: 616–618, 2000

    Google Scholar 

  31. Suh N, Honda T, Finlay H, Barchowsky A, Williams C, Benoit N, Xie OW, Nathan C, Gribble G, Sporn M: Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. Cancer Res 58: 717–723, 1998

    Google Scholar 

  32. Suh N, Wang Y, Honda T, Gribble GW, Dmitrovsky E, Hickey WF, Maue RA, Place AE, Porter DM, Spinella MJ, Williams CR, Wu G, Dannenberg AJ, Flanders KC, Letterio JJ, Mangelsdorf DJ, Nathan CF, Nguyen L, Porter WW, Ren RF, Roberts AB, Roche NS, Subbaramaiah K, Sporn MB: A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res 59: 336–341, 1999

    Google Scholar 

  33. Ito Y, Pandey P, Sporn MB, Datta R, Kharbanda S, Kufe D: The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism. Mol Pharmacol 5: 1094–1099, 2001

    Google Scholar 

  34. Pedersen IM, Kitada S, Schimmer A, Kim Y, Zapata JM, Charboneau L, Rassenti L, Andreeff M, Bennett F, Sporn MB, Liotta LD, Kipps TJ, Reed JC: The triterpenoid CDDO induces apoptosis in refractory CLL B cells. Blood 8: 2965–2972, 2002

    Google Scholar 

  35. Stadheim TA, Suh N, Ganju N, Sporn MB, Eastman A: The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) potently enhances apoptosis induced by tumor necrosis factor in human leukemia cells. J Biol Chem 19: 16448–16455, 2002

    Google Scholar 

  36. Wang Y, Porter WW, Suh N, Honda T, Gribble GW, Leesnitzer LM, Plunket KD, Mangelsdorf DJ, Blanchard SG, Willson TM, Sporn MB: A synthetic triterpenoid, 2-cyano-2,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor gamma. Mol Endocrinol 14: 1550–1556, 2000

    Google Scholar 

  37. Liske E: Therapeutic efficacy and safety of Cimicifuga racemosa for gynecologic disorders. Adv Nat Ther 15: 45–52, 1998

    Google Scholar 

  38. Dog TL: Black cohosh. 2000 In: 7th Annual Course Botanical Medicine in Modern Clinical Practice. New York, May 20-24, 2002, p 556

  39. Boik J: Natural Compounds in Cancer Therapy. Oregon Medical Press, Princeton, 2001, p 304

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Einbond, L.S., Shimizu, M., Xiao, D. et al. Growth Inhibitory Activity of Extracts and Purified Components of Black Cohosh on Human Breast Cancer Cells. Breast Cancer Res Treat 83, 221–231 (2004). https://doi.org/10.1023/B:BREA.0000014043.56230.a3

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:BREA.0000014043.56230.a3

Navigation