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

Breast Cancer Res Treat. 2012 Nov;136(2):429-41. doi: 10.1007/s10549-012-2280-5. Epub 2012 Oct 6.


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 G(2)/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 G(2)/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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis* / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Proto-Oncogene Proteins / metabolism
  • Sesquiterpenes / administration & dosage
  • Sesquiterpenes / pharmacology*
  • Transcriptional Activation / drug effects
  • Tumor Burden / drug effects
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays
  • bcl-2 Homologous Antagonist-Killer Protein / genetics*
  • bcl-2-Associated X Protein / genetics*


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • Proto-Oncogene Proteins
  • Sesquiterpenes
  • Tumor Suppressor Protein p53
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • zerumbone