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Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines

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Abstract

Purpose

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.

Conclusion

Therefore, the combinational treatment with TRAIL and PPARγ ligands might be a promising experimental therapy because the PPARγ ligands, especially d15-PGJ2, sensitize drug-resistant ovarian cancer cells to TRAIL-induced apoptosis.

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Acknowledgments

The authors thank Ursula Grünn for developing the HEY subclones resistant to cisplatin, etoposide, docetaxel, paclitaxel and TRAIL.

Conflict of interest

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany

    Karen Bräutigam, Dirk O. Bauerschlag, Nicolai Maass & Ivo Meinhold-Heerlein

  2. Department of Gynecology and Obstetrics, University Hospital Schleswig–Holstein, Arnold-Heller-Str. 3, 24105, Kiel, Germany

    Julia Biernath-Wüpping, Walter Jonat & Norbert Arnold

  3. Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Constantin S. von Kaisenberg

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  1. Karen Bräutigam
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  2. Julia Biernath-Wüpping
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  3. Dirk O. Bauerschlag
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  4. Constantin S. von Kaisenberg
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Correspondence to Karen Bräutigam.

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Bräutigam, K., Biernath-Wüpping, J., Bauerschlag, D.O. et al. Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines. J Cancer Res Clin Oncol 137, 875–886 (2011). https://doi.org/10.1007/s00432-010-0952-2

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