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Pharmaceutical Research

, Volume 32, Issue 3, pp 863–875 | Cite as

Curcumin and Dimethoxycurcumin Induced Epigenetic Changes in Leukemia Cells

  • Hazem E. Hassan
  • Samuel Carlson
  • Inas Abdallah
  • Thomm Buttolph
  • Karen C. Glass
  • Tamer E. Fandy
Research Paper

Abstract

Purpose

Curcumin is an ideal chemopreventive and antitumor agent characterized by poor bioavailability and low stability. The development of synthetic structural analogues like dimethoxycurcumin (DMC) could overcome these drawbacks. In this study we compared the cytotoxicity, metabolism and the epigenetic changes induced by both drugs in leukemia cells.

Methods

Apoptosis and cell cycle analysis were analyzed by flow cytometry. Real-time PCR was used for gene expression analysis. DNA methylation was analyzed by DNA pyrosequencing. The metabolic stability was determined using human pooled liver microsomes. Chromatin Immunoprecipitation was used to quantify histone methylation.

Results

Clinically relevant concentration of curcumin and DMC were not cytotoxic to leukemia cells and induced G2/M cell cycle arrest. DMC was more metabolically stable than curcumin. Curcumin and DMC were devoid of DNA hypomethylating activity. DMC induced the expression of promoter methylated genes without reversing DNA methylation and increased H3K36me3 mark near the promoter region of hypermethylated genes.

Conclusion

DMC is a more stable analogue of curcumin that can induce epigenetic changes not induced by curcumin. DMC induced the expression of promoter methylated genes. The combination of DMC with DNA methyltransferase inhibitors could harness their combined induced epigenetic changes for optimal re-expression of epigenetically silenced genes.

KEY WORDS

curcumin dimethoxycurcumin DNA methylation DNA pyrosequencing histone methylation 

Abbreviations

5 AC

5-azacytidine

7-AAD

7-aminoactinomycin D

Annexin V-PE

Annexin V-phosphatidylethanolamine

ChIP

Chromatin immunoprecipitation

DMC

Dimethoxycurcumin

DNMT

DNA methyltransferase

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

TET

Ten Eleven Translocation

UDPGA

Uridine 5′-diphosphoglucuronic acid

Notes

Acknowledgments & Disclosures

This work was supported by the Scholarship of Discovery Intramural Research Grant Program (SDIRGP) from Albany College of Pharmacy to TEF and University of Maryland intramural research grant to HH. The work was also supported by NIH Grant Numbers NIGMS R15GM104865 to KCG, 5 P30 RR032135 from the COBRE Program of the National Center for Research Resources and 8 P30 GM 103498 from the National Institute of General Medical Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

Conflicts of Interest

The authors have no financial disclosures or conflicts of interest to declare.

Supplementary material

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Table I (DOCX 18 kb)
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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Hazem E. Hassan
    • 1
  • Samuel Carlson
    • 2
  • Inas Abdallah
    • 1
  • Thomm Buttolph
    • 3
  • Karen C. Glass
    • 2
  • Tamer E. Fandy
    • 2
  1. 1.Department of Pharmaceutical SciencesUniversity of MarylandBaltimoreUSA
  2. 2.Department of Pharmaceutical SciencesAlbany College of Pharmacy (Vermont Campus)ColchesterUSA
  3. 3.Department of Neurological SciencesUniversity of VermontBurlingtonUSA

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