The Role of Nonapoptotic Programmed Cell Death — Ferroptosis, Necroptosis, and Pyroptosis — in Pancreatic Ductal Adenocarcinoma Treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer, with a dismal 5-year survival rate of less than 10%. It is estimated that approximately 80% of pancreatic ductal carcinoma (PDAC) patients are diagnosed at an advanced or metastatic stage. Hence, most patients are not appropriate candidates for surgical resection and therefore require systemic chemotherapy. However, it has been reported that most patients develop chemoresistance within several months, partly because of antiapoptotic mechanisms. Hence, inducing alternative programmed cell death (PCD), including ferroptosis, necroptosis or pyroptosis, seems to be a promising strategy to overcome antiapoptosis-mediated chemoresistance. In this review, we shed light on the molecular mechanisms of ferroptosis, necroptosis and pyroptosis and suggest several potential strategies (e.g., compounds and nanoparticles [NPs]) that are capable of triggering nonapoptotic PCD to suppress PDAC progression. In conclusion, these strategies might serve as adjuvants in combination with clinical first-line chemotherapies to improve patient survival rates.

Development of ZD2767P–carboxypeptidase G2–ultrasound therapy against cisplatin-resistant cancer

“…Ferroptosis in ZD2767P-CPG2-US therapy suggested a strategy against resistant cancers, since inducing nonapoptotic cell death can combat chemoresistance (25). A cancer is heterogeneous with multiple cell subpopulations with distinct features (26)(27)(28).…”

New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer

“…For example, combination therapies of chelators or chelators with other anticancer agents could be used in initiating ferroptosis in relation to drug resistance to established therapies. In these cases, the regulation of ferroptosis appears to offer therapeutic solutions for refractory and recurring tumors in almost all types of cancer, metastasis and drug resistance [143][144][145][146][147][148][149][150][151]. In other cases, such as in therapeutic combination with immunotherapy, ferroptosis can be enhanced and improve the efficacy of immunotherapy [152][153][154].…”

A high-throughput Gaussia luciferase reporter assay for screening potential gasdermin E activators against pancreatic cancer

“…Moreover, the capacity of PDAC cells to evade death also plays a vital role in this process 6 , 7 . As resistance to apoptosis is a general hallmark of cancer, non-apoptotic cell death, like pyroptosis, provide alternative strategies for killing PDAC cells 8 , 9 , 10 .…”