Epigarcinol and isogarcinol isolated from the root of Garcinia ovalifolia induce apoptosis of human promyelocytic leukemia (HL-60 cells)

Abstract

BackgroundPlants from garcinia genus have been used for centuries against several diseases.ObjectiveThis study aimed to investigate the mechanism of apoptosis induced by epigarcinol and isogarcinol isolated from the root of Garcinia ovalifolia (Clusiaceae) on human promyelocytic leukemia (HL-60 cells).MethodsEpigarcinol and isogarcinol were isolated from the root of G. ovalifolia by using column chromatography method. The antiproliferative property of these molecules and fractions were assessed with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The light fluorescence microscope was utilized to observe the morphological changes of HL-60 cells after 24 h treatment. Early apoptosis and cell cycle distribution were analyzed by using flow cytometry (FCM).ResultsThe results showed that epigarcinol and isogarcinol inhibited the proliferation of HL-60 and PC-3 cells in a concentration-dependent manner with IC50 varying between 4 and 76 µg/mL depending on the cell line and the molecule. The apoptosis rate and the number of apoptotic cells significantly increased with the augmentation of the concentration of the molecules. The results of flow cytometry (FCM) indicated that epigarcinol and isogarcinol induced significant G2/S arrest of HL-60 cells, the disruption of mitochondrial membrane potential and reactive oxygen species (ROS) generation.ConclusionThese results indicated that epigarcinol and isogarcinol demonstrated in vitro antiproliferative properties and induce apoptosis of HL-60 cells which is related to the G2/S arrest, and it exerts its apoptotic effect through the loosing of mitochondrial membrane potential.

Chemical and Biological Aspects of Garcinol and Isogarcinol: Recent Developments

“…In addition, garcinol and isogarcinol were recently found in the stem bark of the Garcinia species G. buchananii . Isogarcinol was also isolated from G. punctata and G. ovalifolia …”

“…Tumor cell growth inhibition [gallbladder carcinoma (garcinol), neuroblastoma (garcinol), melanoma (GAR‐NPs), hepatoma (GAR‐NPs), leukemia (isogarcinol)], synergism with STAT5‐SH2 domain inhibitor AC‐4‐130 (leukemia, garcinol), induction of apoptosis and G2/M arrest (leukemia, isogarcinol), induction of autophagy (osteosarcoma, garcinol)…”

“…The STAT5‐SH2 domain inhibitor AC‐4‐130 showed strongly synergistic effects against acute myeloid leukemia (AML) cells MV4‐11 and MOLM‐13 in combination with the HAT inhibitor garcinol probably because acetylation of STAT5 by the HATs p300 and PCAF is of importance for the regulation of STAT5 phosphorylation/dimerisation . Isogarcinol isolated from G. ovalifolia roots exhibited distinct activity against HL‐60 promyelocytic leukemia cells (IC 50 =4 μg/mL) and induced G 2 /M arrest as well as apoptosis via mitochondrial damage in these leukemia cells . While garcinol is only poorly soluble in water, PLGA nanoparticles modified with vitamin E as carriers of garcinol (GAR‐NPs) revealed significant growth inhibitory activities against B16‐F10 melanoma, HepG2 hepatocellular carcinoma, and KB cervical carcinoma cells.…”

“…[17] Isogarcinol was also isolated from G. punctata and G. ovalifolia. [18,19] Quantitative analyses of garcinol contents in biological material are usually carried out by LC/MS and HPLC methods. [20][21][22] Recently, the garcinol contents of Garcinia indica samples and of the commercially available formulations Tryodashang Guggul and Slimmerz capsules was determined by High Performance Thin Layer Chromatography (HPTLC).…”

“…Tumor cell growth inhibition [gallbladder carcinoma (garcinol), [50] neuroblastoma (garcinol), [51] melanoma (GAR-NPs), [53] hepatoma (GAR-NPs), [53] leukemia (isogarcinol)], [19] synergism with STAT5-SH2 domain inhibitor AC-4-130 (leukemia, garcinol), [52] induction of apoptosis and G2/M arrest (leukemia, isogarcinol), [19] induction of autophagy (osteosarcoma, garcinol) [56] Suppression MMP2 and MMP9 (gallbladder carcinoma) (garcinol), [50] synergism with STAT5 inhibition via HAT inhibition (leukemia, garcinol), [52] increased TRAIL-based apoptosis by induction of DR5 and suppression of c-FLIP (hepatoma, renal cancer, garcinol), [54] LC-3 shift (osteosarcoma, garcinol) [56] Moderate accumulation of garcinol nanoparticles in tumors of B16-F10 tumor bearing mice (GAR-NPs) [53] for this promising drug combination at low doses (1 mg/ kg garcinol orally three times per week + 5 mg/ kg taxol i. p. once per week) attributable to the downregulation of caspase-3/iPLA 2 and NF-κB/Twist1 signaling. [36] The chloroform extract of G. morella rich in bioactive garcinol exhibited distinct growth inhibitory effects against three breast cancer cell lines (MCF-7, MDA-MB-231, SKBR3).…”