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

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.
Authors	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
Journal	Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 128 Issue 1 Pg. 57-68 (Jul 2011) ISSN: 1573-7217 [Electronic] Netherlands
PMID	20665104 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents Apoptosis Regulatory Proteins Sesquiterpenes Sterol Regulatory Element Binding Proteins cacalol Cyclophosphamide Luciferases, Renilla Fatty Acid Synthases DAPK2 protein, human Death-Associated Protein Kinases Proto-Oncogene Proteins c-akt dapk2 protein, mouse Calcium-Calmodulin-Dependent Protein Kinases Caspase 3 Paclitaxel
Topics	Animals Antineoplastic Agents (adverse effects, pharmacology) Apoptosis (drug effects) Apoptosis Regulatory Proteins (genetics, metabolism) Breast Neoplasms Calcium-Calmodulin-Dependent Protein Kinases (genetics, metabolism) Caspase 3 (metabolism) Cell Line, Tumor Cyclophosphamide (pharmacology) Death-Associated Protein Kinases Drug Synergism Enzyme Activation Fatty Acid Synthases (genetics, metabolism) Female Genes, Reporter Humans Luciferases, Renilla (biosynthesis, genetics) Mice Mice, Nude Paclitaxel (pharmacology) Promoter Regions, Genetic Proto-Oncogene Proteins c-akt (metabolism) Sesquiterpenes (adverse effects, pharmacology) Signal Transduction Sterol Regulatory Element Binding Proteins (metabolism) Transcription, Genetic Tumor Burden (drug effects) Xenograft Model Antitumor Assays

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