Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells
Journal
Journal of Agricultural and Food Chemistry
Journal Volume
49
Journal Issue
3
Pages
1464-1474
Date Issued
2001
Author(s)
Abstract
Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC50 values of 9.42 and 19.5 μM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 μM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action.
Subjects
Apoptosis; Caspase-2; Caspase-3; Caspase-9; Caspase-activated deoxyribonuclease; Curcumin; Cytochrome c; DNA fragmentation factor; Garcinol; Poly-(ADP-ribose) polymerase
SDGs
Other Subjects
benzophenone; caspase; caspase 3; curcumin; cytochrome c; DNA fragment; garcinol; interleukin 1beta converting enzyme; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein BAD; protein Bax; protein bcl 2; unclassified drug; apoptosis; article; cell viability; enzyme activation; enzyme activity; enzyme degradation; enzyme release; human; human cell; leukemia cell; membrane potential; protein expression; Antineoplastic Agents; Apoptosis; Caspase 3; Caspases; Cell Survival; Curcumin; Cysteine Proteinase Inhibitors; Cytochrome c Group; Enzyme Activation; HL-60 Cells; Humans; Intracellular Membranes; Membrane Potentials; Mitochondria; Oligopeptides; Terpenes; Garcinia indica
Type
journal article