Related Experiment Video
Updated: Aug 23, 2026
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Milk derived exosomes sensitize Gefitinib-resistant lung cancer cells to Pemetrexed via CAV1-mediated endocytosis
Tao Liu1,2, Yong Zhang3, Tao Ren2
1Department of Medical Oncology, Cancer Center & Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Abstract:
Lung cancer patients resistant to EGFR-TKIs often demonstrate a decreased response to Pemetrexed. Therefore, it is urgent to explore the mechanisms of drug resistance and develop new strategies. We investigated the potential of milk-derived exosomes as drug carriers, focusing specifically on pemetrexed encapsulated in these exosomes. We isolated exosomes from milk and loaded them with pemetrexed through electroporation to form a drug delivery carrier named as mExoPEM. Then, we examined how mExoPEM exerts anti-tumor effects in Gefitinib-resistant lung cancer cells, as well as the molecular mechanisms involved. Gefitinib-resistant cells were insensitive to the cytotoxicity of pemetrexed, due to the drug reflux caused by the elevated P-glycoprotein. When co-cultured with mExoPEM, resistant cells demonstrated enhanced anti-tumor responses in vitro and in vivo. Moreover, mExoPEM facilitated cellular uptake via Caveolin-1 (CAV1)-mediated endocytosis, which was regulated by the PPARγ/CAV1 pathway. Notably, pioglitazone, a PPARγ agonist, augmented mExoPEM uptake and synergized with mExoPEM to inhibit the proliferation of resistant cells. In conclusion, our study presents a promising strategy to address pemetrexed resistance in GR lung cancer cells through the use of milk exosome as drug carriers. Moreover, we elucidate the molecular mechanism underlying pemetrexed resistance and its enhanced delivery via milk exosome-mediated endocytosis.
Insights
Milk-derived exosomes loaded with pemetrexed (mExoPEM) overcome drug resistance in Gefitinib-resistant lung cancer cells. This novel drug delivery system enhances anti-tumor effects by utilizing Caveolin-1 mediated endocytosis.
Area of Science:
- Oncology
- Nanotechnology
- Drug Delivery
Background:
- Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) resistance is a significant challenge in lung cancer treatment.
- Pemetrexed efficacy is often reduced in patients with EGFR-TKI resistance, necessitating alternative therapeutic strategies.
Purpose of the Study:
- To investigate milk-derived exosomes as a novel drug delivery system for pemetrexed in Gefitinib-resistant lung cancer.
- To elucidate the molecular mechanisms underlying enhanced anti-tumor activity and cellular uptake of pemetrexed-loaded exosomes.
Main Methods:
- Isolation of exosomes from milk and loading with pemetrexed via electroporation to create mExoPEM.
- Evaluation of mExoPEM's anti-tumor effects in Gefitinib-resistant lung cancer cells in vitro and in vivo.
- Investigation of the Caveolin-1 (CAV1)-mediated endocytosis pathway and its regulation by the PPARγ/CAV1 pathway.
Main Results:
- mExoPEM demonstrated enhanced anti-tumor efficacy in Gefitinib-resistant lung cancer cells, overcoming pemetrexed resistance linked to P-glycoprotein.
- Cellular uptake of mExoPEM was facilitated by CAV1-mediated endocytosis, regulated by the PPARγ/CAV1 pathway.
- Pioglitazone, a PPARγ agonist, enhanced mExoPEM uptake and synergized with mExoPEM to inhibit resistant cell proliferation.
Conclusions:
- Milk-derived exosomes represent a promising drug carrier for overcoming pemetrexed resistance in Gefitinib-resistant lung cancer.
- The study elucidates the molecular mechanisms of drug resistance and enhanced delivery via exosome-mediated endocytosis.
