Research Papers:

HDAC inhibition as a treatment concept to combat temsirolimus-resistant bladder cancer cells

Eva Juengel _, Ramin Najafi, Jochen Rutz, Sebastian Maxeiner, Jasmina Makarevic, Frederik Roos, Igor Tsaur, Axel Haferkamp and Roman A. Blaheta

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Oncotarget. 2017; 8:110016-110028. https://doi.org/10.18632/oncotarget.22454

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Eva Juengel1,2, Ramin Najafi1, Jochen Rutz1, Sebastian Maxeiner1, Jasmina Makarevic1, Frederik Roos1,2, Igor Tsaur1,2, Axel Haferkamp1,2 and Roman A. Blaheta1

1Department of Urology, Goethe-University, Frankfurt am Main, Germany

2Current address: Department of Urology and Pediatric Urology, Mainz University Medical Center, Mainz, Germany

Correspondence to:

Eva Juengel, email: [email protected]

Keywords: bladder cancer; temsirolimus-resistance; HDAC inhibition; valproic acid (VPA); tumor growth

Received: June 01, 2017     Accepted: October 12, 2017     Published: November 06, 2017


Introduction: Although the mechanistic target of rapamycin (mTOR) might be a promising molecular target to treat advanced bladder cancer, resistance develops under chronic exposure to an mTOR inhibitor (everolimus, temsirolimus). Based on earlier studies, we proposed that histone deacetylase (HDAC) blockade might circumvent resistance and investigated whether HDAC inhibition has an impact on growth of bladder cancer cells with acquired resistance towards temsirolimus.

Results: The HDAC inhibitor valproic acid (VPA) significantly inhibited growth, proliferation and caused G0/G1 phase arrest in RT112res and UMUC-3res. cdk1, cyclin B, cdk2, cyclin A and Skp1 p19 were down-regulated, p27 was elevated. Akt-mTOR signaling was deactivated, whereas acetylation of histone H3 and H4 in RT112res and UMUC-3res increased in the presence of VPA. Knocking down cdk2 or cyclin A resulted in a significant growth blockade of RT112res and UMUC-3res.

Materials And Methods: Parental (par) and resistant (res) RT112 and UMUC-3 cells were exposed to the HDAC inhibitor VPA. Tumor cell growth, proliferation, cell cycling and expression of cell cycle regulating proteins were then evaluated. siRNA blockade was used to investigate the functional impact of the proteins.

Conclusions: HDAC inhibition induced a strong response of temsirolimus-resistant bladder cancer cells. Therefore, the temsirolimus-VPA-combination might be an innovative strategy for bladder cancer treatment.

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