Epigenetic Targeting DNMT1 of Pancreatic Ductal Adenocarcinoma using interstitial control release biodegrading polymer reduced tumor growth through Hedgehog pathway inhibition

Publication date: Available online 29 October 2018Source: Pharmacological ResearchAuthor(s): Mao-Hsuan Huang, Yi-Wen Chou, Ming-Hsun Li, Tina E. Shih, Shinn-Zong Lin, Hong-Meng Chuang, Tzyy-Wen Chiou, Hong-Lin Su, Horng-Jyh HarnAbstractAnnually, 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 ...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research