Ruthenium red, inhibitor of mitochondrial Ca2+ uniporter, inhibits curcumin-induced apoptosis via the prevention of intracellular Ca2+ depletion and cytochrome c release.
Curcumin, a natural, biologically active compound extracted from rhizomes of Curcuma species, has been shown to possess potent anti-inflammatory, anti-tumor, and anti-oxidative properties. The mechanism by which curcumin initiates apoptosis remains poorly understood. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human leukemia U937 cells. Curcumin induces apoptosis in U937 cells via a mechanism that appears to involve down-regulation of the anti-apoptotic Bcl-xL, and IAP proteins, release of cytochrome c, and activation of caspase 3. Ruthenium red, an inhibitor of mitochondrial uniporter, specifically inhibits curcumin-induced apoptosis in U937 cells. Cotreatment with ruthenium red markedly prevented the activation of caspase 3, cytochrome c release, and cell death, suggesting a role for intracellular Ca(2+) in this process. Curcumin induced a marked depletion of [Ca(2+)](i) in Caki cells bathed with both Ca(2+)-containing and -free solutions. Thapsigargin (TG), cyclopiazonic acid (CPA), and dantolene (DAN) had no effect. Ruthenium red, an inhibitor of mitochondrial uniporter, only attenuated the curcumin-induced [Ca(2+)](i) depletion in a dose-dependent manner. These data indicate that curcumin acts as a stimulator of intracellular Ca(2+) uptake into mitochondria via uniporter pathway and may involve in the execution of apoptosis.
Bae
Jae Hoon
JH
Department of Physiology, School of Medicine, Keimyung University, 194 DongSan-Dong, Jung-Gu, Taegu 700-712, Republic of Korea.
Park
Jong-Wook
JW
Kwon
Taeg Kyu
TK
D017209:Apoptosis; D002118:Calcium / Q000032:analysis; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry; D019610:Cytoprotection; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008928:Mitochondria / Q000187:drug effects; D051966:Phospholipase C gamma; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012430:Ruthenium Red / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D020298:U937 Cells
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D003574:Cytochrome c Group; D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C034703:mitochondrial calcium uniporter; D012430:Ruthenium Red; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003474:Curcumin; D002118:Calcium