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Vesicle-Transported Multidrug Resistance as a Possible Therapeutic Target of Natural Compounds
Salvatrice Rigogliuso1, Alessandra Cusimano1, Lucia Condorelli1
1Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy.
Pharmaceuticals (Basel, Switzerland)
|October 26, 2024
Summary
Multidrug-resistant cancer cells release extracellular vesicles (EVs) carrying P-glycoprotein (P-gp), promoting drug resistance. Natural compounds can block this EV transfer, potentially reversing resistance in cancer cells.
Area of Science:
- Cancer Biology
- Cell Biology
- Biochemistry
Background:
- Extracellular vesicles (EVs) mediate intercellular communication in various conditions.
- EVs from multidrug-resistant (MDR) cancer cells can transfer P-glycoprotein (P-gp), conferring resistance to recipient cells.
- This horizontal transfer of P-gp via EVs contributes to the propagation of the MDR phenotype.
Purpose of the Study:
- To isolate and characterize EVs from MDR cancer models (MCF-7R and HL-60R).
- To investigate the role of P-gp in EVs in mediating drug resistance.
- To identify natural compounds that can inhibit EV release and P-gp transfer.
Main Methods:
- EVs were isolated and characterized using nanoparticle tracking analysis (NTA) and Western blotting for markers like CD63, Hsp70, and Syntenin.
- P-glycoprotein (P-gp) presence and transfer via EVs were confirmed by Western blotting and functional assays.
- Drug sensitivity was assessed using the MTS assay after EV treatment and exposure to doxorubicin.
Main Results:
- MDR cell lines (MCF-7R, HL-60R) released P-gp-loaded EVs, unlike sensitive cells.
- Recipient sensitive cells acquired doxorubicin resistance upon incorporating P-gp from EVs.
- Natural compounds (curcumin, lupeol, heptacosane) inhibited EV transfer and restored drug sensitivity.
Conclusions:
- EVs play a significant role in the horizontal transfer of P-gp, driving multidrug resistance in cancer.
- Natural compounds demonstrate potential as therapeutic agents to block EV-mediated drug resistance.
- Targeting EV release and P-gp transfer offers a novel strategy against resistant cancer phenotypes.
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