Curcumin enhances Apo2L/TRAIL-induced apoptosis in chemoresistant ovarian cancer cells.
OBJECTIVE
Curcumin, the active component of turmeric (Curcuma longa), exhibits growth inhibitory activity against prostate, colon, and breast cancer; however, the effect of curcumin on ovarian cancer cells is not known. We hypothesized that curcumin could induce cell death in ovarian cancer cells, and enhance apoptosis induced by tumor necrosis factor-related apoptosis inducing Apo2 ligand/TRAIL.


METHODS
Chemoresistant ovarian cancer cell lines SKOV3 and ES-2 were used. The cytotoxic effect of curcumin, Apo2L/TRAIL, and curcumin+Apo2L/TRAIL in combination was determined by sulforhodamine assay. Apoptotic fraction was determined by staining cells with propidium iodide followed by analysis of the sub-G0 DNA content of cells by flow cytometry. Caspase activation was determined by immunoblotting.


RESULTS
Curcumin alone had a cytotoxic effect in cisplatin-resistant cells at 25 microM. Curcumin at low doses (5-15 microM) or Apo2L/TRAIL alone was not significantly cytotoxic to the cell lines tested. Preincubating cells with curcumin at low doses prior to treating with Apo2L/TRAIL resulted in markedly enhanced cell death. The combined treatment of curcumin and Apo2L/TRAIL resulted in activation of both the extrinsic, receptor-mediated apoptotic pathway (cleavage of caspase-8) and the intrinsic, mitochondria-mediated apoptotic pathway (cleavage of caspase-9).


CONCLUSIONS
Combined curcumin and Apo2L/TRAIL treatment results in enhanced induction of apoptotic cell death. Because curcumin and Apo2L/TRAIL together can activate both the extrinsic and intrinsic pathways of apoptosis, they may circumvent chemoresistance to conventional chemotherapeutic agents.
Wahl
Heather
H
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, 4219 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48128, USA.
Tan
Lijun
L
Griffith
Kent
K
Choi
Miheon
M
Liu
J Rebecca
JR
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*
D053221:TNF-Related Apoptosis-Inducing Ligand; D003474:Curcumin