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

Abstract

The mechanism for improved therapeutic efficacy of the combination therapy with 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 and 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; (2)MSV through increasing accumulation of nAb-PTX in the tumor.

Differential Dependency of Human Pancreatic Cancer Cells on Targeting PTEN via PLK 1 Expression

“…The receptor tyrosine kinase HGFR is frequently overexpressed in pancreatic cancer and has been reported in drug resistance, metastasis, and angiogenesis in human pancreatic cancer [30,31]. Therefore, HGFR signaling is considered a prominent therapeutic target in pancreatic cancer [27]. Given that HGFR expression is regulated by silencing PTEN expression, our results are consistent with a previous study [32].…”

“…Of interest, a blockade of PTEN has shown a critical rationale beyond other anti-pancreatic cancer strategies. Treatment with chemotherapeutics such as gemcitabine, FOLFIRINOX, and nanoparticle albumin-bound paclitaxel (nAb-PTX) have been reported to induce severe side effects including anemia, depilation, diarrhea, and vomiting in almost all patients [22][23][24][25][26][27][28][29]. In our study, we demonstrated that targeting PTEN had no basal cytotoxicity on the human pancreatic duct epithelial cell line H6c7, which induced the viability and migration features of H6c7 cells.…”

“…These results indicate that the differential response of human pancreatic cancer cells to PTEN blockade is consistent with the intracellular mechanism underlying the altered HGFR expression. In addition, none of the effective inhibitors or antibodies against HGFR signaling have shown any benefit in clinical trials to date [27]. Based on altered HGFR signaling by targeting PTEN, the blockade of PTEN should be seriously considered as a strategy for the inhibition of HGFR signaling in a PTEN-blockade susceptible group.…”

“…Migration assays were performed using a 24-well Trans-well apparatus (Corning, Corning, NY, USA), as described previously [27]. The cells were transfected with scrambled si-RNA or si-PTEN for 72 h under normal culture conditions.…”

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

“…Nano albumin-bound (nab) paclitaxel delivers a high concentration of paclitaxel within pancreatic tumors, resulting in the inhibition of microtubule depolymerization and cancer cell division [134,135]. Benefiting from the synergistic effects [136,137], the clinical application of nab paclitaxel often occurs in combination with gemcitabine. In addition to gemcitabine, 5-fluorouracil (5-FU), an analogue of uracil, also exerts anticancer effects by damaging DNA and RNA and inhibiting thymidylate synthase (TS) [138].…”