Coix Seed Extract Enhances the Anti-Pancreatic Cancer Efficacy of Gemcitabine through Regulating ABCB1- and ABCG2-Mediated Drug Efflux: A Bioluminescent Pharmacokinetic and Pharmacodynamic Study

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.

A phase I study of the anaplastic lymphoma kinase inhibitor ceritinib in combination with gemcitabine‐based chemotherapy in patients with advanced solid tumors

“…14,15 Additionally, ceritinib can increase the intracellular concentration of cytotoxic agents in ATPbinding cassette transporter ABCB1-and ABCG2-overexpressing tumor cells by preventing drug efflux, potentially through competition for their substrate-binding site. 16,17 Since ABCB1/ABCG2 inhibition can increase the intracellular concentration of gemcitabine, 18 ceritinib may improve gemcitabine-based treatment efficacy regardless of the presence of oncogenic ALK or ROS1 fusions. Gemcitabine, taxanes and platinum analogs are active agents in multiple malignancies and are therefore an appropriate "backbone" to develop ceritinib-containing chemotherapy combinations.…”

Natural Products for Pancreatic Cancer Treatment: From Traditional Medicine to Modern Drug Discovery

“…Although various therapies have been developed against cancer, including chemotherapy, radiation therapy, and so forth, pancreatic cancer is still deadly and represents 10% of the five-year survival rate [75]. Resistance is known to occur in gemcitabine treatment, which is the most common anti-cancer drug [76,77]. The drug resistance makes gemcitabine ineffective, and it consequently leads to difficulties in the successful treatment of cancer.…”

“…Gemcitabine-induced ABC transporters were previously reported to cause drug resistance [76]. Qian et al demonstrated that coix seed extract downregulated the expression of ABCB1 and ABCG2 and induced sensitivity to gemcitabine.…”

“…Terpinen-4-ol was the only one effective at resistance to anti-EGFR therapy [80]. Coix seed emulsion and coix seed extract were extracted from the same natural product [53,76]. Moreover, there was no statement about sources of ETAS [77].…”

Determination of Differentiating Markers in Coicis Semen From Multi-Sources Based on Structural Similarity Classification Coupled With UPCC-Xevo G2-XS QTOF

“…It is not only a commonly used TCM, but it is also a commonly consumed food. Coicis semen has been proven to have numerous functions, such as detoxification and dampness and arthralgia removal; it also reduces cancer risk ( Yu et al, 2011 ; Bai et al, 2018 ; Duan, 2018 ; Xu et al, 2018 ; Choi et al, 2019 ; Huang Q. et al, 2019 ; Huang Y. L. et al, 2019 ; Li et al, 2019 ; Liu H. Q. et al, 2019 ; Liu Y. N. et al, 2019 ; Manosroi et al, 2019 ; Qian et al, 2019 ; Zhang et al, 2019 ). Moreover, it has a wide range of anti-inflammatory, antioxidation, analgesic, and sedative effects, as well as pharmacological effects against gastric cancer, hepatocellular cancer, Lewis lung cancer, non-small cell lung cancer, pancreatic cancer, and pulmonary cancer (“Fuzheng” category represented by coicis semen oil) ( Manosroi et al, 2016a ; Manosroi et al, 2016b ; Qian et al, 2016 ; Xi et al, 2016 ; Wang et al, 2016 ; Han et al, 2017 ; Qu et al, 2017a ; Schwartzberg et al, 2017 ; Jang et al, 2018 ; Kim et al, 2018 ; Zhang et al, 2018 ).…”