Skip to main content
SpringerLink
Log in

Perillyl Alcohol Inhibits Human Breast Cancer Cell Growth in vitro and in vivo

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

Abstract

The effect of monoterpene perillyl alcohol (POH) on cell growth, cell cycle progression, and expression of cell cycle-regulatory proteins in estrogen receptor (ER)-positive (KPL-1 and MCF-7) and ER-negative (MKL-F and MDA-MB-231) human breast cancer cell lines was examined. POH inhibited cell proliferation in a dose-dependent manner in all cell lines tested. POH at a dose of 500 µM had a cytostatic effect, in which growth inhibition was due to accumulation of cells in G1-phase. Cell cycle progression was preceded by a decrease in G1 cyclins (cyclin D1 and E), followed by an increase in p21Cip1/Waf1 and a decrease in proliferating cell nuclear antigen level. Levels of p53 and cyclin A were unchanged. POH at a dose of 75 mg/kg administered intraperitoneally three times a week throughout the entire 6-week experimental period suppressed orthotopically transplanted KPL-1 tumor cell growth and regional lymph node metastasis in a nude mouse system. POH inhibited both ER-positive and -negative human breast cancer cell growth in vitro, and suppressed growth and metastasis in vivo.

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

Similar content being viewed by others

References

  1. Crowell PL, Siar Ayoubi A, Burke YD: Antitumorigenic effects of limonene and perillyl alcohol against pancreatic and breast cancer. Adv Exp Med Biol 401: 131–136, 1996

    Google Scholar 

  2. Elegbede JA, Elson CE, Qureshi A, Tanner MA, Gould MN: Inhibition of DMBA-induced mammary cancer by the monoterpene d-limonene. Carcinogenesis 5: 661–664, 1984

    Google Scholar 

  3. Elson CE, Maltzman TH, Boston JL, Tanner MA, Gould MN: Anti-carcinogenic activity of d-limonene during the initiation and promotion/progression stages of DMBA-induced rat mammary carcinogenesis. Carcinogenesis 9: 331–332, 1988

    Google Scholar 

  4. Maltzman TH, Hurt LH, Elson CE, Tanner MA, Gould MN: The prevention of nitrosomethylurea-induced mammary tumors by d-limonene and orange oil. Carcinogenesis 10: 781–783, 1989

    Google Scholar 

  5. Gould MN: Prevention and therapy of mammary cancer by monoterpenes. J Cell Biochem Suppl 22: 139–144, 1995

    Google Scholar 

  6. Haag JD, Lindstrom MJ, Gould MN: Limonene-induced regression of mammary carcinomas. Cancer Res 52: 4021–4026, 1992

    Google Scholar 

  7. Simonsen JL, Owen LN: The Terpenes. Vol. 1, Cambridge University Press, London, 1953

    Google Scholar 

  8. Haag JD, Gould MN: Mammary carcinoma regression induced by perillyl alcohol, a hydroxylated analog of limonene. Cancer Chemother Pharmacol 34: 477–483, 1994

    Google Scholar 

  9. Crowell PL: Monoterpenes in breast cancer chemoprevention. Breast Cancer Res Treat 46: 191–197, 1997

    Google Scholar 

  10. Lantry LE, Zhang Z, Gao F, Crist KA, Wang Y, Kelloff GJ, Lubet RA, You M: Chemopreventive effect of perillyl alcohol on 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone induced tumorigenesis in (C3H/HeJ X A/J)F1 mouse lung. J Cell Biochem Suppl 27: 20–25, 1997

    Google Scholar 

  11. Reddy BS, Wang CX, Samaha H, Lubet R, Steele VE, Kelloff GJ, Rao CV: Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 57: 420–425, 1997

    Google Scholar 

  12. Mills JJ, Chari RS, Boyer IJ, Gould MN, Jirtle RL: Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. Cancer Res 55: 979–983, 1995

    Google Scholar 

  13. Stark MJ, Burke YD, McKinzie JH, Ayoubi AS, Crowell PL: Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol. Cancer Lett 96: 15–21, 1995

    Google Scholar 

  14. Belanger JT: Perillyl alcohol: applications in oncology. Altern Med Rev 3: 448–457, 1998

    Google Scholar 

  15. Shi W, Gould MN: Induction of cytostasis in mammary carcinoma cells treated with the anticancer agent perillyl alcohol. Carcinogenesis 23: 131–142, 2002

    Google Scholar 

  16. Bardon S, Picard K, Martel P: Monoterpenes inhibit cell growth, cell cycle progression, and cyclin D1 expression in human breast cancer cell lines. Nutr Cancer 32: 1–7, 1998

    Google Scholar 

  17. Ariazi EA, Satomi Y, Ellis MJ, Haag JD, Shi W, Sattler CA, Gould MN: Activation of the transforming growth factor â signaling pathway and induction of cytostasis and apoptosis in mammary carcinomas treated with the anticancer agent perillyl alcohol. Cancer Res 59: 1917–1928, 1999

    Google Scholar 

  18. Crowell PL, Chang RR, Ren Z, Elson CE, Gould MN: Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites. J Biol Chem 266: 17679–17685, 1991

    Google Scholar 

  19. Kurebayashi J, Kurosumi M, Sonoo H: A new human breast cancer cell line, KPL-1, secretes tumor-associated antigens and grows rapidly in female athymic nude mice. Br J Cancer 71: 845–853, 1995

    Google Scholar 

  20. Soule HD, Vazguez J, Long A, Albert S, Brennan M: A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51: 1409–1416, 1973

    Google Scholar 

  21. McLeskey SW, Zhang L, Kharbanda S, Kurebayashi J, Lippma ME, Dickson RB, Kern FG: Fibroblast growth factor overexpressing breast carcinoma cells as models of angiogenesis and metastasis. Breast Cancer Res Treat 39: 103–117, 1996

    Google Scholar 

  22. Cailleau R, Young R, Olive M, Reeves Jr WJ: Breast tumor cell lines from pleural effusions. J Natl Cancer Inst 53: 661–674, 1974

    Google Scholar 

  23. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB: Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47: 936–942, 1987

    Google Scholar 

  24. Geran RI, Greenberg NH, MacDonald MM, Schumacher AM, Abbott BJ: Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother Rep 3: 1–103, 1972

    Google Scholar 

  25. Labat-Moleur F, Guillermet C, Lorimier P, Robert C, Lantuejoul S, Brambilla E, Negoescu A: TUNEL apoptotic cell detection in tissue sections: critical evaluation and improvement. J Histochem Cytochem 46: 327–334, 1998

    Google Scholar 

  26. Ripple GH, Gould MN, Arzoomanian RZ, Alberti D, Feierabend C, Simon K, Binger K, Tutsch KD, Pomplun M, Wahamaki A, Marnocha R, Wilding G, Bailey HH: Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day. Clin Cancer Res 6: 390–396, 2000

    Google Scholar 

  27. Sherr CJ: G1 phase progression: cyclin on cue. Cell 79: 551–555, 1994

    Google Scholar 

  28. Jacks T, Weinberg RA: Cell-cycle control and its watchman. Nature 381: 643–644, 1996

    Google Scholar 

  29. Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501–1512, 1999

    Google Scholar 

  30. Cayrol C, Knibiehler M, Ducommun B: p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. Oncogene 16: 311–320, 1998

    Google Scholar 

  31. Pagano M, Pepperkok R, Verde F, AnsorgeW, Draetta G: Cyclin A is required at two points in the human cell cycle. EMBO J 11: 961–971, 1992

    Google Scholar 

  32. Bardon S, Foussard V, Fournel S, Loubat A: Monoterpenes inhibit proliferation of human colon cancer cells by modulating cell cycle-related protein expression. Cancer Lett 181: 187–194, 2002

    Google Scholar 

  33. Lluria-Prevatt M, Morreale J, Gregus J, Alberts DS, Kaper F, Giaccia A, Powell MB: Effects of perillyl alcohol on melanoma in the TPras mouse model. Cancer Epidemiol Biomarkers Prev 11: 573–579, 2002

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology II, Kansai Medical University, Moriguchi, Osaka, Japan

    Takashi Yuri, Naoyuki Danbara, Miki Tsujita-Kyutoku, Yasuhiko Kiyozuka, Hideto Senzaki, Nobuaki Shikata & Airo Tsubura

  2. Department of Obsterics and Gynecology, Kansai Medical University, Moriguchi, Osaka, Japan

    Takashi Yuri & Hideharu Kanzaki

Authors
  1. Takashi Yuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoyuki Danbara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miki Tsujita-Kyutoku
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhiko Kiyozuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hideto Senzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuaki Shikata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hideharu Kanzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Airo Tsubura
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuri, T., Danbara, N., Tsujita-Kyutoku, M. et al. Perillyl Alcohol Inhibits Human Breast Cancer Cell Growth in vitro and in vivo . Breast Cancer Res Treat 84, 251–260 (2004). https://doi.org/10.1023/B:BREA.0000019966.97011.4d

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:BREA.0000019966.97011.4d

Search

Navigation