Back to Search
Start Over
Epigenetic targeting DNMT1 of pancreatic ductal adenocarcinoma using interstitial control release biodegrading polymer reduced tumor growth through hedgehog pathway inhibition
- Source :
- Pharmacological Research. 139:50-61
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- Male
0301 basic medicine
Patched
Cell cycle checkpoint
Polymers
Mice, Nude
Biology
medicine.disease_cause
Epigenesis, Genetic
03 medical and health sciences
0302 clinical medicine
In vivo
Cell Line, Tumor
medicine
Animals
Humans
Gene silencing
Hedgehog Proteins
Epigenetics
RNA, Small Interfering
DNA Modification Methylases
Pharmacology
Mice, Inbred BALB C
Hedgehog signaling pathway
Pancreatic Neoplasms
Repressor Proteins
030104 developmental biology
Phthalic Anhydrides
030220 oncology & carcinogenesis
DNMT1
Cancer research
Carcinogenesis
Carcinoma, Pancreatic Ductal
Subjects
Details
- ISSN :
- 10436618
- Volume :
- 139
- Database :
- OpenAIRE
- Journal :
- Pharmacological Research
- Accession number :
- edsair.doi.dedup.....9dae2f0b2d57e26c9a3508e0f165dd49