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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Microparticles and their emerging role in cancer multidrug resistance
J Gong1, R Jaiswal, J-M Mathys
1Vascular Immunology Unit, Faculty of Medicine, The University of Sydney, Medical Foundation Building (K25), Room 208, 92-94 Parramatta Rd., Camperdown, NSW 2042, Australia. jgon7696@uni.sydney.edu.au
Abstract:
Drug resistance is a major obstacle to the successful treatment of cancer as tumor cells either fail to reduce in size following chemotherapy or the cancer recurs after an initial response. The phenomenon of multidrug resistance (MDR) is particularly problematic as it involves the simultaneous resistance to numerous chemotherapeutics of different classes. MDR is predominantly attributed to the overexpression of efflux transporters such as P-glycoprotein (P-gp) and the Multidrug Resistance-Associated Protein 1 (MRP1). P-gp and MRP1 are members of the ATP Binding Cassette (ABC) superfamily of transporters and are capable of effluxing many chemotherapeutics out of cancer cells, allowing them to survive the toxic insult. Numerous strategies have been developed over the years to circumvent MDR. Of these, the discovery and implementation of P-gp and MRP1 inhibitors have been most extensively studied. However, these inhibitors have not been able to be used clinically. While research continues in this area, it must also be acknowledged that other avenues must be explored. Recently, the novel 'non-genetic' acquisition of P-gp-mediated MDR by microparticles (MPs) has been reported. MPs are vesicles 0.1-1μm in diameter that are released via plasma membrane blebbing. They are important mediators of inflammation, coagulation and vascular homeostasis. In addition to surface P-gp protein, MPs also carry various nucleic acid species as cargo. This 'non-genetic' intercellular transfer provides an alternative pathway for the cellular acquisition and dissemination of traits and implicates MPs as important mediators in the spread of MDR and provides a novel pathway for the circumvention of MDR.
Insights
Multidrug resistance (MDR) in cancer is often caused by efflux transporters like P-glycoprotein (P-gp). Microparticles (MPs) can transfer P-gp, enabling non-genetic MDR acquisition and offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Drug resistance, particularly multidrug resistance (MDR), is a significant challenge in cancer treatment, leading to chemotherapy failure and recurrence.
- MDR is primarily mediated by ATP Binding Cassette (ABC) transporters, such as P-glycoprotein (P-gp) and Multidrug Resistance-Associated Protein 1 (MRP1), which efflux chemotherapeutics from cancer cells.
- Current strategies targeting P-gp and MRP1, like inhibitors, have faced clinical limitations, necessitating exploration of alternative approaches.
Purpose of the Study:
- To investigate the novel mechanism of 'non-genetic' acquisition of P-gp-mediated MDR through microparticles (MPs).
- To understand the role of MPs in the intercellular transfer of drug resistance traits.
- To identify new pathways for circumventing MDR in cancer therapy.
Main Methods:
- Characterization of microparticles (MPs) as vesicles involved in intercellular communication.
- Analysis of P-gp protein expression on MPs.
- Investigation of the cargo carried by MPs, including nucleic acid species.
- Assessment of the role of MPs in the transfer of MDR traits between cells.
Main Results:
- Microparticles (MPs) are identified as mediators of 'non-genetic' acquisition of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR).
- MPs, vesicles released from cells, carry surface P-gp protein and various nucleic acid species.
- This intercellular transfer mechanism facilitates the dissemination of MDR traits, offering an alternative pathway for MDR acquisition.
Conclusions:
- Microparticles (MPs) play a crucial role in the non-genetic spread of multidrug resistance (MDR) by transferring P-glycoprotein (P-gp).
- The discovery of MP-mediated MDR transfer provides a new understanding of cancer resistance mechanisms.
- This finding opens novel therapeutic avenues for circumventing MDR by targeting MP-mediated intercellular communication.
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