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

• Published in: Oncology letters 2017-06, Vol.13 (6), p.4085-4092
• Main Authors: Vallo, Stefan, Köpp, Raoul, Michaelis, Martin, Rothweiler, Florian, Bartsch, Georg, Brandt, Maximilian P, Gust, Kilian M, Wezel, Felix, Blaheta, Roman A, Haferkamp, Axel, Cinatl, Jr, Jindrich
• Format: Article
• Language: English
• Subjects: Bladder cancer; Cancer therapies; Chemotherapy; Dosage and administration; Drug resistance; Drug therapy; FDA approval; Gene expression; Genetic aspects; Inhibitor drugs; Kinases; Metastasis; Nanoparticles; Oncology; Paclitaxel; Proteins; Response rates; Standard deviation; Targeted cancer therapy; Urinary tract cancer
• ISSN: 1792-1074; 1792-1082
• DOI: 10.3892/ol.2017.5986

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 (T24 GEMCI and TCC-SUP GEMCI ) and vinblastine (T24 VBL and TCC-SUP VBL ) 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.