Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines.
OBJECTIVE
Ovarian cancer accounts for the highest mortality among all gynecological cancers, mainly due to the fast developing chemoresistance. The death ligand TRAIL induces apoptosis and is able to sensitize tumor cells to cytostatic drugs without affecting physiological tissue. Combined treatment of TRAIL and the antidiabetic acting PPARγ ligands was shown to induce apoptosis synergistically in different ovarian cancer cell lines.


METHODS
To investigate feasible TRAIL-dependent inhibition of proliferation and induction of apoptosis in chemoresistant ovarian cancer cell lines, the drug- and TRAIL-sensitive HEY cell line was utilized to develop subclones with selective resistance against cisplatin, etoposide, docetaxel, paclitaxel, gemcitabine and pemetrexed, as well as against TRAIL as control cell line. Expression of the key factors of the TRAIL signaling pathway, TRAIL receptors 1-4, caspase-8, FLIP and XIAP, was analyzed before and after TRAIL treatment by immunoblotting.


RESULTS
Cell proliferation experiments showed TRAIL-dependent inhibition that was further increased by combination treatment with the PPARγ ligands. Simultaneous exposure of TRAIL and the PPARγ ligands also resulted in enhanced induction of apoptosis even in partial TRAIL-resistant HEY cell lines. In the parental HEY cell line, additional treatment with the PPARγ ligands led to an increased protein expression of DR5 and a further decline of XIAP expression.


CONCLUSIONS
Therefore, the combinational treatment with TRAIL and PPARγ ligands might be a promising experimental therapy because the PPARγ ligands, especially d15-PGJ(2), sensitize drug-resistant ovarian cancer cells to TRAIL-induced apoptosis.
Bräutigam
Karen
K
Department of Gynecology and Obstetrics, University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany. kbraeutigam@ukaachen.de
Biernath-Wüpping
Julia
J
Bauerschlag
Dirk O
DO
von Kaisenberg
Constantin S
CS
Jonat
Walter
W
Maass
Nicolai
N
Arnold
Norbert
N
Meinhold-Heerlein
Ivo
I
D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000502:physiology; D053181:Caspase 8 / Q000032:analysis; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047495:PPAR gamma / Q000502:physiology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
C477819:15-deoxyprostaglandin J2; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002839:Chromans; D047495:PPAR gamma; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D045162:Thiazolidinediones; D053181:Caspase 8; D000077288:Troglitazone; D015230:Prostaglandin D2; C039671:ciglitazone