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Updated: Apr 11, 2026
Models and Methods to Evaluate Transport of Drug Delivery Systems Across Cellular Barriers
Published on: October 17, 2013
EM-E-11-4 increases paclitaxel uptake by inhibiting P-glycoprotein-mediated transport in Caco-2 cells
Qian Liu1, Hua Sun, Xiao-Guang Chen
1a State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
Abstract:
P-glycoprotein (P-gp) overexpression is the main mechanism involved in chemotherapy drug resistance such as paclitaxel resistance and therapy failure. The most widely studied P-gp inhibitors still have limited ability to reverse resistance in the clinic. In this study, EM-E-11-4, a lathyrane-type diterpenoid isolated from Euphorbia micractina, was found to significantly increase paclitaxel uptake in Caco-2 cells, which functionally overexpressed P-gp. In vitro transport experiments, carried out in the Caco-2 monolayer model, indicated that EM-E-11-4 significantly reduced the efflux ratio of paclitaxel transport by inhibiting P-gp function without affecting P-gp expression. We also found that EM-E-11-4 enhanced the intracellular accumulation of paclitaxel in a dose-dependent manner by LC-MS/MS and EM-E-11-4 showed low cytotoxicity. Hence, EM-E-11-4 is an effective potential agent to reverse P-gp-mediated paclitaxel resistance by inhibiting P-gp transport function and increasing the intracellular concentration of paclitaxel.
Insights
A novel compound, EM-E-11-4, effectively reverses paclitaxel resistance by inhibiting P-glycoprotein (P-gp) function. This diterpenoid increases paclitaxel uptake and accumulation in cancer cells, offering a potential strategy against chemotherapy resistance.
Area of Science:
- Pharmacology
- Biochemistry
- Cancer Research
Background:
- P-glycoprotein (P-gp) overexpression is a primary cause of chemotherapy drug resistance, notably to paclitaxel, leading to treatment failure.
- Existing P-gp inhibitors show limited clinical efficacy in overcoming this resistance.
Purpose of the Study:
- To investigate the potential of EM-E-11-4, a diterpenoid from Euphorbia micractina, as an agent to reverse P-gp-mediated paclitaxel resistance.
- To evaluate the effect of EM-E-11-4 on paclitaxel uptake and intracellular accumulation in P-gp overexpressing cells.
Main Methods:
- In vitro transport experiments using a Caco-2 monolayer model to assess paclitaxel efflux.
- Liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify intracellular paclitaxel accumulation.
- Cytotoxicity assays to determine the safety profile of EM-E-11-4.
Main Results:
- EM-E-11-4 significantly increased paclitaxel uptake in Caco-2 cells overexpressing P-gp.
- EM-E-11-4 inhibited P-gp function, reducing paclitaxel efflux without altering P-gp expression levels.
- Intracellular paclitaxel accumulation was enhanced by EM-E-11-4 in a dose-dependent manner, with low observed cytotoxicity.
Conclusions:
- EM-E-11-4 demonstrates significant potential as an agent to overcome P-gp-mediated paclitaxel resistance.
- By inhibiting P-gp transport function, EM-E-11-4 enhances intracellular paclitaxel concentration, potentially improving chemotherapy efficacy.
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