A triterpenediol from Boswellia serrata induces apoptosis through both the intrinsic and extrinsic apoptotic pathways in human leukemia HL-60 cells.
A triterpenediol (TPD) comprising of isomeric mixture of 3alpha, 24-dihydroxyurs-12-ene and 3alpha, 24-dihydroxyolean-12-ene from Boswellia serrata induces apoptosis in cancer cells. An attempt was made in this study to investigate the mechanism of cell death by TPD in human leukemia HL-60 cells. It inhibited cell proliferation with IC50 approximately 12 microg/ml and produced apoptosis as measured by various biological end points e.g. increased sub-G0 DNA fraction, DNA ladder formation, enhanced AnnexinV-FITC binding of the cells. Further, initial events involved massive reactive oxygen species (ROS) and nitric oxide (NO) formation, which were significantly inhibited by their respective inhibitors. Persistent high levels of NO and ROS caused Bcl-2 cleavage and translocation of Bax to mitochondria, which lead to loss of mitochondrial membrane potential (Deltapsim) and release of cytochrome c, AIF, Smac/DIABLO to the cytosol. These events were associated with decreased expression of survivin and ICAD with attendant activation of caspases leading to PARP cleavage. Furthermore, TPD up regulated the expression of cell death receptors DR4 and TNF-R1 level, leading to caspase-8 activation. These studies thus demonstrate that TPD produces oxidative stress in cancer cells that triggers self-demise by ROS and NO regulated activation of both the intrinsic and extrinsic signaling cascades.
Bhushan
Shashi
S
Division of Pharmacology, Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
Kumar
Ajay
A
Malik
Fayaz
F
Andotra
Samar Singh
SS
Sethi
Vijay Kumar
VK
Kaur
Indu Pal
IP
Taneja
Subhash Chandra
SC
Qazi
Ghulam Nabi
GN
Singh
Jaswant
J
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D029743:Boswellia / Q000737:chemistry*; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins; D000077022:Survivin; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology
C527560:3alpha, 24-dihydroxyurs-12-ene; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C117749:Birc5 protein, mouse; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D010936:Plant Extracts; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D000077022:Survivin; D014315:Triterpenes; C109664:caspase-activated DNase inhibitor; D007550:Isothiuronium; D009569:Nitric Oxide; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; C027744:S-methylisothiopseudouronium; D000111:Acetylcysteine