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Updated: Aug 20, 2025
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Study of Drug Resistance in Chemotherapy Induced by Extracellular Vesicles on a Microchip
Tianyuan Fang1, Wei Lu2, Jingfeng Zhang1
1Department of Chemistry, Zhejiang University, Hangzhou 310030, China.
Abstract:
Drug resistance in chemotherapy has been greatly challenging for cancer treatment. Research has revealed that extracellular vesicles (EVs) secreted by drug-resistant cells could induce chemoresistance in susceptible cells. However, there are few ways to give direct evidence of it. Herein, we have proposed a microchip-based system to study the drug resistance of a wild-type human lung adenocarcinoma cell line (A549/WT) induced by EVs derived from A549/DDP cells that are resistant to cisplatin (DDP) inherently. EVs derived from A549/DDP were proved to be the crucial factor that enhanced the resistance of A549/WT to DDP through live and dead cell staining, cell viability testing, and immunofluorescence of P-glycoprotein in the off-chip assay. Then, it was further validated that drug resistance of A549/WT cells to DDP significantly increased after being cocultured with A549/DDP cells within 96 h in the on-chip assay. These findings proved that the change of A549/WT drug resistance was caused by intercellular interaction, which was mainly mediated by EVs. In addition, we successfully reversed the EV-induced drug resistance of A549/WT cells by combining DDP and metformin, a hypoglycemic drug with low cytotoxicity when used alone. This microchip system provides a novel tool that has great potential for the investigation of cell interaction, drug resistance, and the tumor microenvironment in fundamental and clinical medicine.
Insights
Extracellular vesicles (EVs) from drug-resistant lung cancer cells can induce chemoresistance in susceptible cells. A novel microchip system demonstrated this effect and showed that combining cisplatin and metformin can reverse this resistance.
Area of Science:
- Oncology
- Biotechnology
- Cell Biology
Background:
- Drug resistance poses a significant challenge in cancer chemotherapy.
- Extracellular vesicles (EVs) secreted by drug-resistant cancer cells are implicated in transferring chemoresistance to susceptible cells.
- Direct evidence and efficient methods for studying EV-mediated chemoresistance are limited.
Purpose of the Study:
- To develop and utilize a microchip-based system to investigate chemoresistance induction in lung adenocarcinoma cells by EVs.
- To demonstrate the role of EVs from cisplatin-resistant cells (A549/DDP) in conferring resistance to cisplatin (DDP) in sensitive cells (A549/WT).
- To explore potential therapeutic strategies for reversing EV-induced drug resistance.
Main Methods:
- Development of a microchip system for studying intercellular interactions and drug resistance.
- Off-chip assays including live/dead cell staining, cell viability testing, and P-glycoprotein immunofluorescence.
- On-chip co-culture experiments to validate EV-mediated drug resistance.
- Combination therapy using cisplatin (DDP) and metformin to reverse chemoresistance.
Main Results:
- EVs derived from cisplatin-resistant A549/DDP cells significantly enhanced the resistance of A549/WT cells to DDP.
- The microchip system validated increased drug resistance in A549/WT cells upon co-culture with A549/DDP cells within 96 hours.
- Intercellular interaction, primarily mediated by EVs, was identified as the cause of altered A549/WT drug resistance.
- Combined treatment with DDP and metformin effectively reversed the EV-induced chemoresistance in A549/WT cells.
Conclusions:
- The study successfully demonstrated EV-mediated chemoresistance transfer using a novel microchip platform.
- The findings highlight the critical role of EVs in mediating intercellular communication and drug resistance in the tumor microenvironment.
- The developed microchip system offers a valuable tool for fundamental and clinical research on cell interactions and therapeutic resistance.
- Metformin in combination with DDP shows promise in overcoming EV-induced chemoresistance.
