Breast Cancer Research and Treatment

, Volume 136, Issue 2, pp 429–441

Zerumbone causes Bax- and Bak-mediated apoptosis in human breast cancer cells and inhibits orthotopic xenograft growth in vivo

  • Anuradha Sehrawat
  • Julie A. Arlotti
  • Akira Murakami
  • Shivendra V. Singh
Preclinical study

DOI: 10.1007/s10549-012-2280-5

Cite this article as:
Sehrawat, A., Arlotti, J.A., Murakami, A. et al. Breast Cancer Res Treat (2012) 136: 429. doi:10.1007/s10549-012-2280-5

Abstract

The present study was undertaken to determine the anticancer efficacy of zerumbone (ZER), a sesquiterpene from subtropical ginger, against human breast cancer cells in vitro and in vivo. ZER treatment caused a dose-dependent decrease in viability of MCF-7 and MDA-MB-231 human breast cancer cells in association with G2/M phase cell cycle arrest and apoptosis induction. ZER-mediated cell cycle arrest was associated with downregulation of cyclin B1, cyclin-dependent kinase 1, Cdc25C, and Cdc25B. Even though ZER treatment caused stabilization of p53 and induction of PUMA, these proteins were dispensable for ZER-induced cell cycle arrest and/or apoptosis. Exposure of MDA-MB-231 and MCF-7 cells to ZER resulted in downregulation of Bcl-2 but its ectopic expression failed to confer protection against ZER-induced apoptosis. On the other hand, the SV40 immortalized mouse embryonic fibroblasts derived from Bax and Bak double knockout mice were significantly more resistant to ZER-induced apoptosis. ZER-treated MDA-MB-231 and MCF-7 cells exhibited a robust activation of both Bax and Bak. In vivo growth of orthotopic MDA-MB-231 xenografts was significantly retarded by ZER administration in association with apoptosis induction and suppression of cell proliferation (Ki-67 expression). These results indicate that ZER causes G2/M phase cell cycle arrest and Bax/Bak-mediated apoptosis in human breast cancer cells, and retards growth of MDA-MB-231 xenografts in vivo.

Keywords

Breast cancerZerumbonep53, PUMA, Bcl-2BaxBakApoptosis

Abbreviations

ZER

Zerumbone

DAPI

4′,6-Diamidino-2-phenylindole

PI

Propidium iodide

DMSO

Dimethyl sulfoxide

PUMA

p53 upregulated mediator of apoptosis

PARP

Poly-(ADP-ribose)-polymerase

PBS

Phosphate-buffered saline

siRNA

Small interfering RNA

JC-1

5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide

MEF

Mouse embryonic fibroblasts

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Anuradha Sehrawat
    • 1
  • Julie A. Arlotti
    • 2
  • Akira Murakami
    • 3
  • Shivendra V. Singh
    • 1
    • 2
  1. 1.Department of Pharmacology & Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.University of Pittsburgh Cancer InstituteUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Division of Food Science and Biotechnology, Graduate School of AgricultureKyoto UniversityKyotoJapan