Abstract
A deep insight into the function and kinetics of ATP-binding cassette (ABC) transporters may aid in the development of pharmaceutics that can minimize the particular facet of chemo-resistance. We utilized bioluminescence imaging to monitor the ABC transporter mediated intracellular drug efflux function. We also investigated the potential association between the intracellular bioluminescent pharmacokinetic profiles and the anti-tumor efficacy of the coix seed extract and gemcitabine against pancreatic cancer cells in vitro and in vivo. The bioluminescent pharmacokinetic parameters and pharmacodynamic index (IC50 and TGI) were determined. The expression levels ABCB1 and ABCG2 were assessed. Results showed that coix seed extract could synergistically enhance the anti-cancer efficacy of gemcitabine (p < 0.05). Meanwhile coix seed extract alone or in combination with gemcitabine could significantly increase the AUCluc while decreasing the Kluc (p < 0.01). Western blot and immunohistochemistry assay demonstrated that coix seed extract could significantly mitigate gemcitabine-induced upregulation of ABCB1 and ABCG2 protein. The Pearson correlation analysis demonstrated that the bioluminescent pharmacokinetic parameters and pharmacodynamic index have strong association in vitro and in vivo. In conclusion coix seed extract could augment the efficacy of gemcitabine therapy in pancreatic cancer cells may at least partly due to the alteration of ABC transporter-mediated drug efflux function.
Highlights
Pancreatic cancer (PC) is an infamous diagnosis known for its poor prognosis, with a less than 6% overall five-year survival rate [1]
To avoid a super-saturation effect of bioluminescence signals in pancreatic cancer cells, the D-luciferin concentration was set at a range from 0 to 8 μg/mL, which was covered within a linear correlation to the photon number of the bioluminescence signal (y = 239376x + 267912, R2 = 0.95), as illustrated in Supplementary Figure S1A
Our findings indicated that the co-treatment with coix seed extract may reverse gemcitabine-induced upregulation of ABCB1 and ABCG2 expression
Summary
Pancreatic cancer (PC) is an infamous diagnosis known for its poor prognosis, with a less than 6% overall five-year survival rate [1]. There are various mechanisms of drug resistance, including drug efflux, changes in genes or signaling pathways and the influence of tumor microenvironment [4,5] Amongst these mechanisms, ATP-binding cassette (ABC) transports mediated drug efflux is considered as one of the most critical mechanisms associated with gemcitabine resistance in pancreatic cancer [6,7,8]. ABCB1 and ABCG2 were found to be an important indicator of drug-resistance in pancreatic cancer [12]. It remains largely unclear whether the coix seed extract overcome gemcitabine resistance in pancreatic cancer cells through modulating the ABC transporter activity
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