Reactivation of Tumor Suppressor Genes in Breast Cancer by Dietary Supplements as

Summary

Principal Investigator: Zhongfa Liu
Abstract: DESCRIPTION (provided by applicant): Reactivation of Tumor Suppressor Genes in Breast Cancer by Dietary Supplements Hypermethylation-silenced tumor suppressor gene (TSG) is a hallmark of most cancers, including breast cancer and has been detected in pre-invasive lesions and/or high-risk tissues. In contrast to genetic mutation, DNA methylation is susceptible to change and reversible;therefore, it represents an excellent target to develop DNA methylation inhibitors for chemotherapy and chemoprevention. Reactivation of TSGs by azanucleoside DNA methylation inhibitors, such as decitabine and 5-azacitidine will result in restoration of their biological functions and represents a novel, superior chemotherapeutic strategy for treatment of various leukemia, including myelodysplastic syndrome (MDS) compared to cytotoxic agents. However, there are limitations in developing azanucleosides as cancer prevention agents because of their chemical instability and high toxicity. Therefore, there is a surging interest to identify DNA methylation inhibitors from dietary supplements, e.g. EGCG to reactivate TSGs in cancers as chemopreventive agents because of their pharmacological safety in long-term use. Using an integrated platform consisting of the DNMT1 homology modeling, in-vitro cell-free M. SssI assay and a rapid, robust, specific and sensitive LC-MS/MS method for determination of both global and specific promoter DNA methylation levels established on our group, parthenolide and curcumin have been found to possess DNA hypomethylation activity. Curcumin, the active constituent of turmeric and wide-consumed dietary additives, is significantly more potent (>100 fold) than parthenolide as a DNA methylation inhibitor with an IC50 of 30 nM on M. SssI and 35-40% global DNA hypomethylation at 0.1 5M in MCF-7 cells. This data suggests that curcumin may be a potent and safe DNA methylation inhibitor. Curcumin has been shown strong antiproliferation effects on lung, breast, prostate and colon cancers through multiple molecular targets and signaling pathways and extensively tested as a cancer chemoprotective agent. Therefore, two tightly associated aims are pursued in this proposal to elucidate the underlying molecular mechanism of its hypomethylation activity and test our hypothesis whether curcumin can hypomethylate and reactivate TSGs involved in initiation, propagation, and metastasis of breast cancer. The first aim is to further evaluate the hypomethylation activity of curcumin in-vitro and in- vivo for induction of promoter hypomethylation of specific TSGs e.g. RASSF1A and their reactivation in breast cancer cell lines at its attainable in-vivo concentration. The second aim is to elucidate the other underlying molecular mechanism of the hypomethylating activity of curcumin in breast cancer cell lines. The proposed studies will yield data which will steer the future development of curcumin as a chemopreventive agent in breast cancer. PUBLIC HEALTH RELEVANCE: The project will establish curcumin as an effective DNA methylation inhibitor to reactivate several tumor suppressor genes involved in cancer cell apoptosis, cell cycle control and metastasis in vitro and in vivo and elucidate its underlying molecular mechanism. It is expected that the result will provide a direct molecular mechanism of curcumin and steer its future use as a chemopreventive agent on breast cancer and potentially for other prevalent cancers e.g. colon cancers.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc A liquid chromatography-tandem mass spectrometric method for quantification of curcumin-O-glucuronide and curcumin in human plasma
    Wei Chen
    Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province 310022, China
    J Chromatogr B Analyt Technol Biomed Life Sci 900:89-93. 2012
  2. ncbi Reactivation of RASSF1A in breast cancer cells by curcumin
    Liping Du
    College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA
    Nutr Cancer 64:1228-35. 2012
  3. pmc Curcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia
    Jianhua Yu
    Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
    PLoS ONE 8:e55934. 2013
  4. pmc A high-throughput quantification method of curcuminoids and curcumin metabolites in human plasma via high-performance liquid chromatography/tandem mass spectrometry
    Yu Cao
    College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 949:70-8. 2014
  5. pmc A liquid chromatography-tandem mass spectrometric method for quantification of curcuminoids in cell medium and mouse plasma
    U V R Vijaya Saradhi
    College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 878:3045-51. 2010
  6. pmc Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice
    Liu Zhongfa
    College of Pharmacy, The Ohio State University, Room 152, Riffe Building, 500 W 12th Avenue, Columbus, OH 43210, USA
    Cancer Chemother Pharmacol 69:679-89. 2012

Scientific Experts

  • Zhongfa Liu
  • Kenneth K Chan
  • Ming Chiu
  • Yu Cao
  • Wei Chen
  • Jianhua Yu
  • Zhiliang Xie
  • Lai Chu Wu
  • Shujun Liu
  • Liu Zhongfa
  • Patty Fan-Havard
  • Liping Du
  • Lisa D Yee
  • Jiang Wang
  • U V R Vijaya Saradhi
  • Ronald X Xu
  • Qi En Wang
  • Xiaoming He
  • Youcai Deng
  • Yong Peng
  • Michael R Grever
  • Xiaokui Mo
  • Tiffany Hughes
  • Shun He
  • Winston Yen
  • Gary D Stoner
  • Jiayuh Lin
  • James R Fuchs
  • Yonghua Ling
  • Eric B Schwartz

Detail Information

Publications6

  1. pmc A liquid chromatography-tandem mass spectrometric method for quantification of curcumin-O-glucuronide and curcumin in human plasma
    Wei Chen
    Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province 310022, China
    J Chromatogr B Analyt Technol Biomed Life Sci 900:89-93. 2012
    ..2% and their co-efficiency of variations were in the range of 3.5-12.7% and 3.1-11.3%, respectively. This method was capable of detecting only COG in human plasma samples from two healthy volunteers after an oral ingestion of curcumin...
  2. ncbi Reactivation of RASSF1A in breast cancer cells by curcumin
    Liping Du
    College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA
    Nutr Cancer 64:1228-35. 2012
    ..Altogether, this study reveals a novel molecular mechanism of curcumin as a chemo-preventive agent for breast cancer through hypomethylation reactivation of RASSF1A...
  3. pmc Curcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia
    Jianhua Yu
    Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
    PLoS ONE 8:e55934. 2013
    ....
  4. pmc A high-throughput quantification method of curcuminoids and curcumin metabolites in human plasma via high-performance liquid chromatography/tandem mass spectrometry
    Yu Cao
    College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 949:70-8. 2014
    ..This method was validated according to the US FDA GLP analytic criteria and applied to characterize the pharmacokinetics of curcumin, COG, and COS in human plasma after an oral dose of bioavailable curcumin (nanoemulsion curcumin). ..
  5. pmc A liquid chromatography-tandem mass spectrometric method for quantification of curcuminoids in cell medium and mouse plasma
    U V R Vijaya Saradhi
    College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 878:3045-51. 2010
    ..0, 1.0 h, respectively vs 0.4h for curcumin) and an increased drug exposure as described by the area under the curve (0.64, 0.98 μM h, respectively vs 0.4 μM h for curcumin)...
  6. pmc Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice
    Liu Zhongfa
    College of Pharmacy, The Ohio State University, Room 152, Riffe Building, 500 W 12th Avenue, Columbus, OH 43210, USA
    Cancer Chemother Pharmacol 69:679-89. 2012
    ..Here, we established a practical nano-emulsion curcumin (NEC) containing up to 20% curcumin (w/w) and conducted the pharmacokinetics of curcuminoids and curcumin metabolites in mice...