Resistance to nanoparticle albumin-bound paclitaxel is mediated by ABCB1 in urothelial cancer cells

Vallo,Stefan; Köpp,Raoul; Michaelis,Martin; Rothweiler,Florian; Bartsch,Georg; Brandt,Maximilian  P.; Gust,Kilian  M.; Wezel,Felix; Blaheta,Roman  A.; Haferkamp,Axel; Cinatl ,Jindrich

doi:10.3892/ol.2017.5986

Resistance to nanoparticle albumin-bound paclitaxel is mediated by ABCB1 in urothelial cancer cells

Authors:
- Stefan Vallo
- Raoul Köpp
- Martin Michaelis
- Florian Rothweiler
- Georg Bartsch
- Maximilian P. Brandt
- Kilian M. Gust
- Felix Wezel
- Roman A. Blaheta
- Axel Haferkamp
- Jindrich Cinatl
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Affiliations: Institute of Medical Virology, University Hospital Frankfurt, D‑60596 Frankfurt am Main, Germany, Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK, Department of Urology, University Hospital Frankfurt, D‑60590 Frankfurt am Main, Germany, Department of Urology, University Hospital Ulm, D‑89075 Ulm, Germany
Published online on: April 5, 2017 https://doi.org/10.3892/ol.2017.5986
Pages: 4085-4092
Copyright: © Vallo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Nanoparticle albumin‑bound (nab)-paclitaxel appears to exhibit better response rates in patients with metastatic urothelial cancer of the bladder whom are pretreated with nab-paclitaxel compared with conventional paclitaxel. Paclitaxel may induce multidrug resistance in patients with cancer, while the mechanisms of resistance against paclitaxel are manifold. These include reduced function of pro‑apoptotic proteins, mutations of tubulin and overexpression of the drug transporter adenosine 5'‑triphosphate‑binding cassette transporter subfamily B, member 1 (ABCB1). To evaluate the role of ABCB1 in nab‑paclitaxel resistance in urothelial cancer cells, the bladder cancer cell lines T24 and TCC‑SUP, as well as sub‑lines with acquired resistance against gemcitabine (T24rGEMCI20 and TCC‑SUPrGEMCI20) and vinblastine (T24rVBL20 and TCC‑SUPrVBL20) were examined. For the functional inhibition of ABCB1, multi-tyrosine kinase inhibitors with ABCB1‑inhibiting properties, including cabozantinib and crizotinib, were used. Additional functional assessment was performed with cell lines stably transduced with a lentiviral vector encoding for ABCB1, and protein expression was determined by western blotting. It was indicated that cell lines overexpressing ABCB1 exhibited similar resistance profiles to nab‑paclitaxel and paclitaxel. Cabozantinib and crizotinib sensitized tumor cells to nab‑paclitaxel and paclitaxel in the same dose‑dependent manner in cell lines overexpressing ABCB1, without altering the downstream signaling of tyrosine kinases. These results suggest that the overexpression of ABCB1 confers resistance to nab‑paclitaxel in urothelial cancer cells. Additionally, small molecules may overcome resistance to anticancer drugs that are substrates of ABCB1.

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