Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells

Abstract

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells.

Latest developments in coumarin-based anticancer agents: mechanism of action and structure–activity relationship studies

“…72 ) was found to selectively impede the proliferation of HER2-positive BC cells. 134 It induced DNA damage and apoptosis in HER-2-positive BC cells more effectively compared to HER-2 negative BC cells. In silico and theoretical calculations revealed that compound 75 could interact with c-Jun N-terminal kinase (JNK), and in vitro studies showed that it increased JNK phosphorylation through ROS generation.…”

Cannabidiol activates MAPK pathway to induce apoptosis, paraptosis, and autophagy in colorectal cancer cells

“…HT‐29, SW480, HCT‐116, and HCT‐15 cells (2 × 10 4 cells/well) were seeded onto the 8‐well slide chamber and they were exposed to 30 μM of CBD for 24 h. These cells were used to perform the live and dead assay as indicated before 34 …”

“…The four cell lines were treated with 30 μM of CBD for 24 h and then were stained with fluorescein isothiocyante‐tagged Annexin‐V antibodies and PI for 15 min. The rate of apoptotic cells was detected by BD Accuri TM C6 Plus Flow Cytometer (BD Biosciences) 34 …”

Euphorbiasteroid Induces Apoptosis as Well as Autophagy through Modulating SHP-1/STAT3 Pathway in Hepatocellular Carcinoma Cells

“…EPBS was treated for 12 h and the cells were collected. A total of 10 µM of DCFH-DA was treated for 30 min at 37 °C, and the samples were analyzed using a BD Accuri TM C6 Plus Flow Cytometer (BD Biosciences) [ 32 ].…”

“…It has been reported that NAC can prevent oxidative stress and promote the activity of antioxidant enzymes [ 31 ]. GSH is oxidized in the presence of ROS and converted to GSSG, which can prevent oxidative stress [ 32 ].…”