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Ursolic acid triggers nonprogrammed death (necrosis) in human glioblastoma multiforme DBTRG-05MG cells through MPT pore opening and ATP decline.

SCOPE
Ursolic acid, a natural pentacyclic triterpenic acid, possesses anticancer potential and diverse biological effects, but its correlation with glioblastoma multiforme cells and different modes of cell death is unclear. We studied the cellular actions of human glioblastoma multiforme DBTRG-05MG cells after ursolic acid treatment and explored cell-selective killing effect of necrotic death as a cell fate.


METHODS AND RESULTS
Ursolic acid effectively reversed temozolomide resistance and reduced DBTRG-05MG cell viability. Surprisingly, ursolic acid failed to stimulate the apoptosis- and autophagy-related signaling networks. The necrotic death was characterized by annexin V/propidium iodide double-positive detection and release of high-mobility group protein B1 and lactate dehydrogenase. These ursolic acid elicited responses were accompanied by reactive oxygen species generation and glutathione depletion. Rapid mitochondrial dysfunction was paralleled by the preferential induction of necrosis, rather than apoptotic death. Mitochondrial permeability transition (MPT) is a phenomenon to provide the onset of mitochondrial depolarization during cellular necrosis. The opening of MPT pores that were mechanistically regulated by cyclophilin D, and adenosine triphosphate decline occurred in treated necrotic DBTRG-05MG cells. Cyclosporine A (an MPT pore inhibitor) prevented ursolic acid-provoked necrotic death and the acid-involved key regulators.


CONCLUSION
Our study is the first to report that ursolic acid-modified mitochondrial function triggers defective death by necrosis in DBTRG-05MG cells rather than augmenting programmed death.