Skip to main content

Advertisement

SpringerLink
Log in

Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Betulinic acid (BA) is a pentacyclic triterpene found in many plant species, among others in the bark of white birch Betula alba. BA was reported to display a wide range of biological effects, including antiviral, antiparasitic, antibacterial and anti-inflammatory activities, and in particular to inhibit growth of cancer cells. The aim of the study was further in vitro characterization of BA anticancer activity. In this study, we demonstrated a remarkable antiproliferative effect of BA in all tested tumor cell cultures including neuroblastoma, rabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukemia and multiple myeloma, as well as in primary cultures isolated from ovarian carcinoma, cervical carcinoma and glioblastoma multiforme. Furthermore, we have shown that BA decreased cancer cell motility and induced apoptotic cell death. We also observed decrease of bcl2 and cyclin D1 genes expression, and increase of bax gene expression after betulinic acid treatment. These findings demonstrate the anticancer potential of betulinic acid and suggest that it may be taken into account as a supportive agent in the treatment of cancers with different tissue origin.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326

    Article  PubMed  CAS  Google Scholar 

  • Basu S, Ma R, Boyle PJ, Mikulla B, Bradley M, Smith B, Basu M, Banerjee S (2004) Apoptosis of human carcinoma cells in the presence of potential anti-cancer drugs. III. Treatment of Colo-205 and SKBR3 cells with: cis-platin, tamoxifen, melphalan, betulinic acid, L-PDMP, L-PPMP, and GD3 ganglioside. Glycoconj J 20:563–577

    Article  PubMed  CAS  Google Scholar 

  • Bernard P, Scior T, Didier B, Hibert M, Berthon JY (2001) Etnopharmacology and bioinformatic combination for leads discovery: application to phospholipase A2 inhibitors. Phytochemistry 58:865–874

    Article  PubMed  CAS  Google Scholar 

  • Chan SL, Yu VC (2004) Proteins of the bcl-2 family in apoptosis signalling: from mechanistic insights to therapeutic opportunities. Clin Exp Pharmacol Physiol 31:119–128

    Article  PubMed  CAS  Google Scholar 

  • Eder-Czembirek C, Czembirek C, Erovic BM, Selzer E, Turhani D, Vormittag L, Thurnher D (2005) Combination of betulinic acid with cisplatin-different cytotoxic effects in two head and neck cancer cell lines. Oncol Rep 14:667–671

    PubMed  CAS  Google Scholar 

  • Ehrhardt H, Fulda S, Fuhrer M, Debatin KM, Jeremias I (2004) Betulinic acid-induced apoptosis in leukemia cells. Leukemia 8:1406–1412

    Article  Google Scholar 

  • Einzhammer DA, Xu ZQ (2004) Betulinic acid: a promising anticancer candidate. IDrugs 4:359–373

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Fulda S, Debatin KM (2005) Sensitization for anticancer drug-induced apoptosis by betulinic Acid. Neoplasia 7:162–170

    Article  PubMed  CAS  Google Scholar 

  • Fulda S, Friesen C, Los M, Scaffidi C, Mier W, Benedict M, Nunez G, Krammer PH, Peter ME, Debatin KM (1997) Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Res 57:4956–4964

    PubMed  CAS  Google Scholar 

  • Fulda S, Jeremias J, Steiner HH, Pietsch T, Debatin KM (1999) Betulinic acid: a new cytotoxic agent against malignant brain tumors. Int J Cancer 82:435–441

    Article  PubMed  CAS  Google Scholar 

  • Ji ZN, Ye WC, Liu GG, Hsiao WL (2002) 23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2 expression and telomerase activity in HL-60 Cells. Life Sci 72:1–9

    Article  PubMed  CAS  Google Scholar 

  • Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Poon KH, Zhang J, Wang C, Tse AK, Wang CK, Fong WF (2004) Betulinic acid enhances lalpha, 25-dihydroxyvitamin D3-induced differentiation in human HL-60 promyelocytic leukemia cells. Anticancer Drugs 15:619–624

    Article  PubMed  CAS  Google Scholar 

  • Raghuvar Gopal DV, Nakar AA, Badrinath Y, Mishra KP, Joshi DS (2005) Betulinic acid induces apoptosis in human chronic myelogenous leukemia (CML) cell line K-562 without altering the levels of Bcr-Abl. Toxicol Lett 15:343–351

    Article  Google Scholar 

  • Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos CE, Geilen CC (2001) The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol 117:333–340

    Article  PubMed  CAS  Google Scholar 

  • Sarek J, Klinot J, Dzubak P, Klinotova E, Noskova V, Krecek V, Korinkova G, Thomson JO, Janostakova A, Wang S, Parson S, Fischer PM, Zhelev NZ, Hajduch M (2003) New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure-activity relationships. J Med Chem 46:5402–5415

    Article  PubMed  CAS  Google Scholar 

  • Schmidt ML, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM (1997) Betulinic acid induces apoptosis in human neuroblastoma cell lines. Eur J Cancer 33:2007–2012

    Article  PubMed  CAS  Google Scholar 

  • Selzer E, Pimental E, Wacheck V, Schlegel W, Pehamberger H, Jansen B, Kodym R (2000) Effects of betulinic acid alone and in combination with irradiation in human melanoma cells. J Invest Dermatol 114:935–942

    Article  PubMed  CAS  Google Scholar 

  • Thurnher D, Turhani D, Pelzmann M, Wannemacher B, Knerer B, Formanek M, Wacheck V, Selzer E (2003) Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells. Head Neck 25:732–740

    Article  PubMed  Google Scholar 

  • Wick W, Grimmel C, Wagenknecht B, Dichgans J, Weller M (1999) Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing. J Pharmacol Exp Ther 289:1306–1312

    PubMed  CAS  Google Scholar 

  • Zuco V, Supino R, Righetti SC, Cleris L, Marchesi E, Gambacorti-Passerini C, Formelli F (2002) Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett 175:17–25

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland

    Wojciech Rzeski, Józef Kaczor, Katarzyna Wejksza, Barbara Zdzisińska & Martyna Kandefer-Szerszeń

  2. Department of Pediatric Neurology, Technical University, 01307, Dresden, Germany

    Andrzej Stepulak & Marco Sifringer

  3. Department of Obstetrics, Women’s Diseases and Oncological Gynecology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

    Marek Szymański

  4. Department of Toxicology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950, Lublin, Poland

    Wojciech Rzeski

  5. Department of Biochemistry and Molecular Biology, Medical University Lublin, 20-093, Lublin, Poland

    Andrzej Stepulak

Authors
  1. Wojciech Rzeski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrzej Stepulak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marek Szymański
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marco Sifringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Józef Kaczor
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katarzyna Wejksza
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Barbara Zdzisińska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martyna Kandefer-Szerszeń
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wojciech Rzeski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rzeski, W., Stepulak, A., Szymański, M. et al. Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. Naunyn-Schmied Arch Pharmacol 374, 11–20 (2006). https://doi.org/10.1007/s00210-006-0090-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-006-0090-1

Keywords

Search

Navigation