Tocotrienols induce apoptosis and autophagy in rat pancreatic stellate cells through the mitochondrial death pathway.
OBJECTIVE
Selective removal of activated pancreatic stellate cells (PSCs) through induction of their own programmed death is a goal of therapeutic interest in patients with chronic pancreatitis. Here, we investigated the effects of tocotrienols on PSC death outcomes.


METHODS
Activated and quiescent PSCs and acinar cells from rat pancreas were treated with vitamin E derivatives alpha-tocopherol; individual alpha-, beta-, gamma-, and delta-tocotrienols; and a tocotrienol rich fraction (TRF) from palm oil.


RESULTS
TRF, but not alpha-tocopherol, reduced viability of activated PSC by setting up a full death program, independent of cell cycle regulation. Activated PSCs died both through apoptosis, as indicated by increased DNA fragmentation and caspase activation, and through autophagy, as denoted by the formation of autophagic vacuoles and LC3-II accumulation. In contrast to alpha-tocopherol, TRF caused an intense and sustained mitochondrial membrane depolarization and extensive cytochrome c release. Caspase inhibition with zVAD-fmk suppressed TRF-induced apoptosis but enhanced autophagy. However, mitochondrial permeability transition pore blockade with cyclosporin A completely abolished the deadly effects of TRF. beta-, gamma-, and delta-tocotrienol, but not alpha-tocotrienol nor alpha-tocopherol, reproduced TRF actions on activated PSCs. TRF death induction was restricted to activated PSCs because it did not cause apoptosis either in quiescent PSCs or in acinar cells.


CONCLUSIONS
Tocotrienols selectively trigger activated pancreatic stellate cell death by targeting the mitochondrial permeability transition pore. Our findings unveil a novel potential for tocotrienols to ameliorate the fibrogenesis associated with chronic pancreatitis.
Rickmann
Mariana
M
Digestive System Research Unit, Institut de Recerca Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Vaquero
Eva C
EC
Malagelada
Juan Ramón
JR
Molero
Xavier
X
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007536:Isomerism; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010179:Pancreas / Q000166:cytology / Q000502:physiology*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D024508:Tocotrienols / Q000008:administration & dosage / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024508:Tocotrienols; D014815:Vitamins