A new isoxazolyl-urea derivative induces apoptosis, paraptosis, and ferroptosis by modulating MAPKs in pancreatic cancer cells

• Published in: Biochimie 2024-12, Vol.227 (Pt A), p.262-272
• Main Authors: Jung, Young Yun, Suresh, Rajaghatta N., Mohan, Chakrabhavi Dhananjaya, Harsha, Kachigere B., Shivakumara, Chilkunda Sannaiah, Rangappa, Kanchugarakoppal S., Ahn, Kwang Seok
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Line, Tumor; Ferroptosis; Ferroptosis - drug effects; Human pancreatic cancer; Humans; MAP Kinase Signaling System - drug effects; MAPKs; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Paraptosis; Urea - analogs & derivatives; Urea - pharmacology
• ISSN: 0300-9084; 1638-6183; 1638-6183
• DOI: 10.1016/j.biochi.2024.08.001

MAPK pathway regulates the major events including cell division, cell death, migration, invasion, and angiogenesis. Small molecules that modulate the MAPK pathway have been demonstrated to impart cytotoxicity in cancer cells. Herein, the synthesis of a new isoxazolyl-urea derivative (QR-4) has been described and its effect on the growth of pancreatic cancer cells has been investigated. QR-4 reduced the cell viability in a panel of pancreatic cancer cells with minimal effect on normal hepatocytes. QR-4 induced the cleavage of PARP and procaspase-3, reduced the expression of antiapoptotic proteins, increased SubG1 cells, and annexin V/PI-stained cells indicating the induction of apoptosis. QR-4 also triggered paraptosis as witnessed by the reduction of mitochondrial membrane potential, decrease in the expression of Alix, increase in the levels of ATF4 and CHOP, and enhanced ER stress. QR-4 also modulated ferroptosis-related events such as elevation in iron levels, alteration in GSH/GSSG ratio, and increase in the expression of TFRC with a parallel decrease in the expression of GPX4 and SLC7A11. The mechanistic approach revealed that QR-4 increases the phosphorylation of all three forms of MAPKs (JNK, p38, and ERK). Independent application of specific inhibitors of these MAPKs resulted in a partial reversal of QR-4-induced effects. Overall, these reports suggest that a new isoxazolyl-urea imparts cell death via apoptosis, paraptosis, and ferroptosis by regulating the MAPK pathway in pancreatic cancer cells. •Pancreatic cancer is one of the fatal forms of cancers.•MAPK pathway regulates tumorigenesis in pancreatic cancer.•QR-4 can induce the apoptosis, paraptosis, and ferroptosis in MIA PaCa-2 and PANC-1 cells.•QR-4 triggers three cell deaths regulating the MAPK pathway.