Gemcitabine enhances the transport of nanovector-albumin-bound paclitaxel in gemcitabine-resistant pancreatic ductal adenocarcinoma

Publication date: 10 September 2017
Source:Cancer Letters, Volume 403
Author(s): Carlotta Borsoi, Fransisca Leonard, Yeonju Lee, Mohamed Zaid, Dalia Elganainy, Jenolyn Francisca Alexander, Megumi Kai, Yan Ting Liu, Yaan Kang, Xuewu Liu, Eugene J. Koay, Mauro Ferrari, Biana Godin, Kenji Yokoi
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-PTX 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.



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