Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein
Multidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR)...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/14/12/1292 |
| _version_ | 1797501608914845696 |
|---|---|
| author | Anunay J. Pulukuri Anthony J. Burt Larissa K. Opp Colin M. McDowell Maryam Davaritouchaee Amy E. Nielsen Rock J. Mancini |
| author_facet | Anunay J. Pulukuri Anthony J. Burt Larissa K. Opp Colin M. McDowell Maryam Davaritouchaee Amy E. Nielsen Rock J. Mancini |
| author_sort | Anunay J. Pulukuri |
| collection | DOAJ |
| description | Multidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating immune cells in local proximity to cancer cells and could, therefore, benefit from the enhanced drug efflux in MDR cancers. However, the effect of acquired drug resistance on TLR agonist efflux is largely unknown. We begin to address this by investigating P-gp mediated efflux of TLR 7/8 agonists. First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod, Resiquimod, and Gardiquimod are substrates for P-gp. Interestingly, the least potent imidazoquinoline (Imiquimod) was the best P-gp substrate. Next, we compared imidazoquinoline efflux in MDR cancer cell lines with enhanced P-gp expression relative to parent cancer cell lines. Using P-gp competitive substrates and inhibitors, we observed that imidazoquinoline efflux occurs through P-gp and, for Imiquimod, is enhanced as a consequence of acquired drug resistance. This suggests that enhancing efflux susceptibility could be an important consideration in the rational design of next generation immunotherapies that modulate activity of tumor-infiltrating immune cells. |
| first_indexed | 2024-03-10T03:20:59Z |
| format | Article |
| id | doaj.art-e88ae5d7dce54698afd6230e636e2d85 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:20:59Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-e88ae5d7dce54698afd6230e636e2d852023-11-23T10:03:40ZengMDPI AGPharmaceuticals1424-82472021-12-011412129210.3390/ph14121292Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-GlycoproteinAnunay J. Pulukuri0Anthony J. Burt1Larissa K. Opp2Colin M. McDowell3Maryam Davaritouchaee4Amy E. Nielsen5Rock J. Mancini6Department of Chemistry, Washington State University, Pullman, WA 99164, USADepartment of Chemistry, Washington State University, Pullman, WA 99164, USADepartment of Chemistry, Washington State University, Pullman, WA 99164, USASchool of Molecular Biosciences, Washington State University, Pullman, WA 99164, USADepartment of Chemistry, Washington State University, Pullman, WA 99164, USADepartment of Chemistry, Washington State University, Pullman, WA 99164, USADepartment of Chemistry, Washington State University, Pullman, WA 99164, USAMultidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating immune cells in local proximity to cancer cells and could, therefore, benefit from the enhanced drug efflux in MDR cancers. However, the effect of acquired drug resistance on TLR agonist efflux is largely unknown. We begin to address this by investigating P-gp mediated efflux of TLR 7/8 agonists. First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod, Resiquimod, and Gardiquimod are substrates for P-gp. Interestingly, the least potent imidazoquinoline (Imiquimod) was the best P-gp substrate. Next, we compared imidazoquinoline efflux in MDR cancer cell lines with enhanced P-gp expression relative to parent cancer cell lines. Using P-gp competitive substrates and inhibitors, we observed that imidazoquinoline efflux occurs through P-gp and, for Imiquimod, is enhanced as a consequence of acquired drug resistance. This suggests that enhancing efflux susceptibility could be an important consideration in the rational design of next generation immunotherapies that modulate activity of tumor-infiltrating immune cells.https://www.mdpi.com/1424-8247/14/12/1292Imiquimoddrug effluxmultidrug resistanceimmunotherapyToll-Like Receptor |
| spellingShingle | Anunay J. Pulukuri Anthony J. Burt Larissa K. Opp Colin M. McDowell Maryam Davaritouchaee Amy E. Nielsen Rock J. Mancini Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein Pharmaceuticals Imiquimod drug efflux multidrug resistance immunotherapy Toll-Like Receptor |
| title | Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein |
| title_full | Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein |
| title_fullStr | Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein |
| title_full_unstemmed | Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein |
| title_short | Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein |
| title_sort | acquired drug resistance enhances imidazoquinoline efflux by p glycoprotein |
| topic | Imiquimod drug efflux multidrug resistance immunotherapy Toll-Like Receptor |
| url | https://www.mdpi.com/1424-8247/14/12/1292 |
| work_keys_str_mv | AT anunayjpulukuri acquireddrugresistanceenhancesimidazoquinolineeffluxbypglycoprotein AT anthonyjburt acquireddrugresistanceenhancesimidazoquinolineeffluxbypglycoprotein AT larissakopp acquireddrugresistanceenhancesimidazoquinolineeffluxbypglycoprotein AT colinmmcdowell acquireddrugresistanceenhancesimidazoquinolineeffluxbypglycoprotein AT maryamdavaritouchaee acquireddrugresistanceenhancesimidazoquinolineeffluxbypglycoprotein AT amyenielsen acquireddrugresistanceenhancesimidazoquinolineeffluxbypglycoprotein AT rockjmancini acquireddrugresistanceenhancesimidazoquinolineeffluxbypglycoprotein |