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Breast Cancer Research and Treatment

, Volume 128, Issue 1, pp 57–68 | Cite as

Cacalol, a natural sesquiterpene, induces apoptosis in breast cancer cells by modulating Akt-SREBP-FAS signaling pathway

  • Wen Liu
  • Eiji Furuta
  • Kazutoshi Shindo
  • Misako Watabe
  • Fei Xing
  • Puspa R. Pandey
  • Hiroshi Okuda
  • Sudha K. Pai
  • Laura L. Murphy
  • Deliang Cao
  • Yin-Yuan Mo
  • Aya Kobayashi
  • Megumi Iiizumi
  • Koji Fukuda
  • Bo Xia
  • Kounosuke Watabe
Preclinical study

Abstract

We previously isolated cacalol as a free radical-scavenging compound from Cacalia delphiniifolia which is a traditional Asian herbal plant and is believed to have medicinal effects on cancer. In this report, we demonstrated that cacalol has strong anti-proliferation effect on breast cancer cells and induces apoptosis by activating a pro-apoptotic pathway. We also found that a combination of cacalol and other chemotherapeutic drugs (Taxol and cyclophosphamide) synergistically induced apoptosis and partially overcame chemo-resistance. To further gain a mechanistic insight, we tested a potential inhibitory effect of cacalol on fatty acid synthase gene (FAS) in breast cancer cells, and found that cacalol significantly modulated the expression of the FAS gene, which resulted in apoptosis through activation of DAPK2 and caspase 3. We have also shown that cacalol significantly suppressed the Akt-sterol regulatory element-binding proteins (SREBP) signaling pathway and concomitant transcriptional activation of FAS. In a xenograft model of nude mouse, when cacalol was administered intraperitoneally, tumor growth was significantly suppressed. Importantly, oral administration of cacalol before implanting tumors showed significant preventive effect on tumor growth in the same animal model. Furthermore, the treatment of mice with a combination of low dose of Taxol and cacalol significantly suppressed the tumor growth. Taken together, our results indicate that cacalol induces apoptosis in breast cancer cells and impairs mammary tumor growth in vivo by blocking the expression of the FAS gene through modulation of Akt-SREBP pathway, suggesting that cacalol has potential utility as a chemopreventive and chemotherapeutic agent for breast cancer.

Keywords

Fatty acid synthase Breast cancer Herbal extract treatment Apoptosis Chemo-resistance 

Abbreviations

FAS

Fatty acid synthase.

ROS

Reactive oxygen species.

SREBP

Sterol regulatory element-binding protein

CPA

Cyclophosphamide

HIF1

Hypoxia-inducible factor-1

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Wen Liu
    • 1
  • Eiji Furuta
    • 1
  • Kazutoshi Shindo
    • 2
  • Misako Watabe
    • 1
  • Fei Xing
    • 1
  • Puspa R. Pandey
    • 1
  • Hiroshi Okuda
    • 1
  • Sudha K. Pai
    • 1
  • Laura L. Murphy
    • 3
  • Deliang Cao
    • 1
  • Yin-Yuan Mo
    • 1
  • Aya Kobayashi
    • 1
  • Megumi Iiizumi
    • 1
  • Koji Fukuda
    • 1
  • Bo Xia
    • 1
  • Kounosuke Watabe
    • 1
  1. 1.Department of Medical Microbiology, Immunology & Cell BiologySouthern Illinois University School of MedicineSpringfieldUSA
  2. 2.Department of Food and NutritionJapan Women’s UniversityTokyoJapan
  3. 3.Department of PhysiologySouthern Illinois University School of MedicineCarbondaleUSA

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