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

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.

journal_name

Oncol Lett

journal_title

Oncology letters

authors

Vallo S,Köpp R,Michaelis M,Rothweiler F,Bartsch G,Brandt MP,Gust KM,Wezel F,Blaheta RA,Haferkamp A,Cinatl J Jr

doi

10.3892/ol.2017.5986

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

4085-4092

issue

6

eissn

1792-1074

issn

1792-1082

pii

OL-0-0-5986

journal_volume

13

pub_type

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