Journal
CANCER LETTERS
Volume 403, Issue -, Pages 296-304Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.06.026
Keywords
Pancreatic cancer; Gemcitabine; Drug resistance; nAb-paclitaxel; Multistage nanovectors; Transport
Categories
Funding
- National Cancer Institute (NCI) [1-U54-CA143837]
- National Institutes of Health (NIH) [1-U54-CA151668-01]
- Ernest Cockrell Jr. Presidential Distinguished Chair
- MD Anderson Cancer Center
- Cancer Moonshots program
- Center for Advanced Biomedical Imaging
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The mechanism for improved therapeutic efficacy of the combination therapy with nanoparticle albumin-bound paclitaxel (nAb-PTX) and gemcitabine (gem) for pancreatic ductal adenocarcinoma (PDAC) has been ascribed to enhanced gem transport by nAb-PTX. Here, we used an orthotopic mouse model of gem-resistant human PDAC in which increasing gem transport would not improve the efficacy, thus revealing the importance of nAb-PTX transport. We aimed to evaluate therapeutic outcomes and transport of nAb-PTX to PDAC as a result of (1) encapsulating nAb-FIX in multistage nanovectors (MSV); (2) effect of gem on caveolin-1 expression. Treatment with MSV/nAb-PTX + gem was highly efficient in prolonging animal survival in comparison to other therapeutic regimens. MSV/nAb-PTX + gem also caused a substantial increase in tumor PTX accumulation, significantly reduced tumor growth and tumor cell proliferation, and increased apoptosis. Moreover, gem enhanced caveolin-1 expression in vitro and in vivo, thereby improving transport of nAb-PTX to PDAC. This data was confirmed by analysis of PDACs from patients who received gem-based neo-adjuvant chemotherapy. In conclusion, we found that nAb-PTX treatment of gem-resistant PDAC can be enhanced by (1) gem through up-regulation of caveolin-1 and (2) MSV through increasing accumulation of nAb-PTX in the tumor. (C) 2017 Elsevier B.V. All rights reserved.
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