Fluorinated thiazolidinol drives autophagic cell death in pancreatic cancer cells via AMPK activation and perturbation of critical sentinels of oncogenic signaling

Targeting Regulated Cell Death with Pharmacological Small Molecules: An Update on Autophagy-Dependent Cell Death, Ferroptosis, and Necroptosis in Cancer

“…15 Further, compound 3 can suppress migration, invasion, and angiogenesis of MIA PaCa-2 and PANC-1 cells and regress the development of the MIA PaCa-2 xenograft in a mice model. 15 N-Desmethyldauricine (Figure 1, compound 4) induces cytotoxicity that is associated with autophagic machinery and does not relate to the apoptotic pathways, which could trigger ADCD in a variety of types of cancer cells (e.g., A549, HeLa, Hep3B, HepG2, LLC-1, MCF-7, PC3 cells) and apoptosis-defective or -resistant cells (e.g., caspase-3/-7/-8/deficient mice embryonic fibroblasts (MEFs), caspase-3/-7 double knockout (DKO) MEFs and Bax-Bak DKO MEFs). 16 The compound 4-induced ADCD is mediated by mobilizing calcium release through inhibiting Sarco/endoplasmic reticulum calcium-ATPase (SERCA) to trigger the Ca 2+ /calmodulin-dependent kinase kinase-β (CaMKKβ)/AMPK/mTOR signaling pathways.…”

“…It is suggested that ADCD is the way by which compound 1 and compound 2 may cause their effects . Fluorinated thiazolidionol (Figure , compound 3 ) can induce AMPK activation and inhibit PI3K/AKT/mTORC1 and MEK/ERK pathways, triggering ADCD in pancreatic ductal adenocarcinoma MIA PaCa-2 and PANC-1 cells proved by increased cytoplasmic vacuoles formation and enhanced autophagic flux . Further, compound 3 can suppress migration, invasion, and angiogenesis of MIA PaCa-2 and PANC-1 cells and regress the development of the MIA PaCa-2 xenograft in a mice model …”

“…Fluorinated thiazolidionol (Figure , compound 3 ) can induce AMPK activation and inhibit PI3K/AKT/mTORC1 and MEK/ERK pathways, triggering ADCD in pancreatic ductal adenocarcinoma MIA PaCa-2 and PANC-1 cells proved by increased cytoplasmic vacuoles formation and enhanced autophagic flux . Further, compound 3 can suppress migration, invasion, and angiogenesis of MIA PaCa-2 and PANC-1 cells and regress the development of the MIA PaCa-2 xenograft in a mice model Figure , compound 4 ) induces cytotoxicity that is associated with autophagic machinery and does not relate to the apoptotic pathways, which could trigger ADCD in a variety of types of cancer cells (e.g., A549, HeLa, Hep3B, HepG2, LLC-1, MCF-7, PC3 cells) and apoptosis-defective or -resistant cells (e.g., caspase-3/-7/-8/deficient mice embryonic fibroblasts (MEFs), caspase-3/-7 double knockout (DKO) MEFs and Bax-Bak DKO MEFs) .…”

“…9 The vacuolar protein sorting 34 (VPS34)-beclin-1 complex is also the key regulator of autophagy, and the upregulation of beclin-1 expression promotes ADCD. 13 Further, prolonged activation of the protein kinases that cause cytoprotective autophagy can also induce ADCD, such as C-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK), 14,15 which can stimulate autophagy by modulating beclin-1 expression. Nevertheless, since autophagy is a doubleedged sword with both prosurvival and prodeath properties, 9 whether inducing hyperactivation of autophagy could evoke more complicated cellular responses beyond regulating cell death progress has yet to be established.…”

Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

“…This induces autophagy-dependent cell death, resulting in antiproliferative activity in MIA PaCa-2 and PANC-1 human pancreatic adenocarcinoma (PAAD) cells, with IC 50 values of 8 μmol/L. Additionally, fluorinated thiazolidionol demonstrates a promising anticancer effect in vivo , as it regresses tumors in the MIA PaCa-2 xenograft model 62 . Apigenin, present in numerous types of fruits, vegetables, and herbals, has been discovered to stimulate AMPK–ULK1 while inhibiting mTOR, leading to autophagy-dependent cell death in AGS and SNU-638 human gastric cancer (GC) cells 63 .…”