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Caspase-dependent apoptosis induction by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, in PC-3 human prostate cancer cells is mediated by Bax and Bak.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2005 Nov; Vol. 4 (11), pp. 1747-54. - Publication Year :
- 2005
-
Abstract
- The present study was undertaken to gain insights into the molecular mechanism of cell death (apoptosis) by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, using PC-3 human prostate cancer cells as a model. The viability of PC-3 cells, but not a normal prostate epithelial cell line (PrEC), was reduced significantly on treatment with guggulsterone in a concentration-dependent manner. Guggulsterone-mediated suppression of PC-3 cell proliferation was not due to perturbation in cell cycle progression but caused by apoptosis induction characterized by appearance of subdiploid cells and cytoplasmic histone-associated DNA fragmentation. Guggulsterone-induced apoptosis was associated with induction of multidomain proapoptotic Bcl-2 family members Bax and Bak. Interestingly, the expression of antiapoptotic proteins Bcl-2 and Bcl-xL was initially increased in guggulsterone-treated PC-3 cells but declined markedly following a 16- to 24-hour treatment with guggulsterone. Ectopic expression of Bcl-2 in PC-3 cells failed to confer significant protection against guggulsterone-induced cell death. On the other hand, SV40 immortalized mouse embryonic fibroblasts derived from Bax-Bak double knockout mice were significantly more resistant to guggulsterone-induced cell killing compared with wild-type cells. Guggulsterone treatment resulted in cleavage (activation) of caspase-9, caspase-8, and caspase-3, and guggulsterone-induced cell death was significantly attenuated in the presence of general caspase inhibitor as well as specific inhibitors of caspase-9 and caspase-8. In conclusion, the present study indicates that caspase-dependent apoptosis by guggulsterone is mediated in part by Bax and Bak.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Caspase 3
Caspase 8
Caspase 9
Cell Cycle
Cell Death
Cell Line, Tumor
Cells, Cultured
Commiphora metabolism
Cytoplasm metabolism
DNA Fragmentation
Enzyme Activation
Fibroblasts metabolism
Histones chemistry
Humans
Immunoblotting
Male
Mice
Mice, Knockout
Models, Chemical
Plants, Medicinal metabolism
Protein Binding
Protein Structure, Tertiary
Time Factors
bcl-2 Homologous Antagonist-Killer Protein metabolism
bcl-2-Associated X Protein metabolism
Apoptosis
Caspases metabolism
Pregnenediones pharmacology
Prostatic Neoplasms drug therapy
Prostatic Neoplasms pathology
bcl-2 Homologous Antagonist-Killer Protein physiology
bcl-2-Associated X Protein physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1535-7163
- Volume :
- 4
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 16275996
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-05-0223