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Pharmacol Res. 2019 Jan;139:50-61. doi: 10.1016/j.phrs.2018.10.015. Epub 2018 Oct 29.

Epigenetic targeting DNMT1 of pancreatic ductal adenocarcinoma using interstitial control release biodegrading polymer reduced tumor growth through hedgehog pathway inhibition.

Author information

1
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan; Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
2
Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
3
Department of Pathology, Hualien Tzu Chi Hospital, Hualien, Taiwan.
4
Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Department of Neurosurgery, Hualien Tzu Chi Hospital, Hualien, Taiwan.
5
Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
6
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan. Electronic address: suhonglin@nchu.edu.tw.
7
Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Department of Pathology, Hualien Tzu Chi Hospital, Hualien, Taiwan; Department of Pathology, Tzu Chi University, Hualien, Taiwan. Electronic address: arthewduke@gmail.com.

Abstract

Annually, 48,000 people die from pancreatic ductal adenocarcinoma (PDAC), ranking it the fourth among cancer-related deaths in the United States. Currently, anti-cancer drugs are not effective against PDAC, and only extends survival by 3 months. Aberrant DNA methylation has been shown to play an important role during carcinogenesis in PDAC, with approximately 80% of tumor overexpressing the DNA methyltransferase 1 (DNMT1) protein. In the present study, we used DNMTs as a screening platform to find a new DNMT inhibitor, n-butylidenephthalide (n-BP), which is identified from a Chinese herbal drug. n-BP could inhibit DNMT1 expression in both dose-dependent and time-dependent manner. It also displays an effect in suppressing growth of PDAC cells and inducing cell cycle arrest at G0/G1 phase leading apoptosis. Growth suppression can be restored by the overexpression of DNMT1 in PDAC cells. Furthermore, we found n-BP-mediated DNMT1 suppression influenced the protein stability rather than changing the RNA expression. Through microarray studies, we found that the patched domain contained 4 (PTCHD4) is the potential downstream gene of DNMT1. Following silencing of PTCHD4 expression by siRNA, n-BP decreased tumor growth inhibition. Finally, in vivo, two animal models were used to evaluate the efficacy and survival after n-BP treatment by interstitial control release polymer delivery. The results show that n-BP could effectively inhibit PDAC tumor volume growth and extend animal survival. In summary, n-BP may inhibit the growth of human PDAC cells though reducing DNMT1 and increasing the expression of PTCHD4 both in vitro and in vivo.

KEYWORDS:

DNA methyltransferase 1; Hedgehog pathway; PTCHD4; Pancreatic ductal adenocarcinoma; n-Butylidenephthalide

PMID:
30385365
DOI:
10.1016/j.phrs.2018.10.015
[Indexed for MEDLINE]
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