The AAPS Journal

, 21:86 | Cite as

A Tangeretin Derivative Inhibits the Growth of Human Prostate Cancer LNCaP Cells by Epigenetically Restoring p21 Gene Expression and Inhibiting Cancer Stem-like Cell Proliferation

  • Guor-Jien Wei
  • Yen-Hsiang Chao
  • Yen-Chen Tung
  • Tien-Yuan Wu
  • Zheng-Yuan SuEmail author
Research Article Theme: Natural Products Drug Discovery in Cancer Prevention
Part of the following topical collections:
  1. Theme: Natural Products Drug Discovery in Cancer Prevention


Prostate cancer ranks the second in incidence and the fifth in mortality cancer in male globally. Citrus polymethoxyflavonoids (PMFs), such as tangeretin (PMF1), have been found to exhibit various biological activities. Here, we evaluated the inhibitory effects and mechanism of synthetic 5,4′-didemethyltangeretin (PMF2) on human prostate cancer LNCaP cells. We found that PMF2 inhibited the growth of LNCaP cells (GI50 14.6 μM) more strongly than PMF1, and it was less cytotoxic against the normal human prostate RWPE-1 cells. PMF2 upregulated Bad and Bax, downregulated Bcl-2, and activated caspase-3 and PARP in the LNCaP cells, thereby inducing apoptosis. PMF2 also suppressed the anchorage-independent growth of the LNCaP cells. It triggered p21 gene expression by demethylation of the p21 promoter region, and inhibited the protein expressions of DNMT 3B and HDACs 1, 2, and 4/5/9 by epigenetic regulations. We further found that PMF2 showed interactions with DNMTs 1, 2, and 3A ex vivo, which might inhibit DNMT activity. Additionally, PMF2 decreased the anchorage-independent growth of isolated LNCaP cancer stem-like cells (CSLCs) with high CD166 mRNA expression. These results indicated that PMF2 might inhibit the growth of human prostate cancer cells through different mechanisms, suggesting that PMF2 could be an innovative agent for prostate cancer therapy and prevention.


5,4′-didemethyltangeretin cancer stem-like cells epigenetics p21 prostate cancer 


Funding Information

This research is supported in part by institutional funds and by the MOST 105-2815-C-033-013-B and MOST 105-2320-B-033-001 from the Ministry of Science and Technology. We thank all the members of Dr. Su’s lab for their helpful discussion of this work.


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Institute of Food Safety and Health Risk AssessmentNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Department of Bioscience TechnologyChung Yuan Christian UniversityTaoyuan CityTaiwan
  3. 3.Institute of Food Science and TechnologyNational Taiwan UniversityTaipeiTaiwan
  4. 4.Department of Pharmacology, School of MedicineTzu Chi UniversityHualien CityTaiwan

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