Review
Pharmacology & Pharmacy
Manasi S. Pote, Rajesh N. Gacche
Summary: This review provides updated information on the structure, function, and regulatory mechanisms of major multidrug resistance (MDR) related ATP binding cassette (ABC) transporters, which play a significant role in limiting the efficacy of anticancer drugs. The effects of modulators on the functions of ABC transporters such as P-glycoprotein, MRP1, and BCRP are discussed. Additionally, the potential use of these ABC transporter modulators in clinical practice to alleviate the emerging MDR crisis in cancer treatment is highlighted.
DRUG DISCOVERY TODAY
(2023)
Article
Medicine, Research & Experimental
Lara Garcia-Varela, Manuel Rodriguez-Perez, Antia Custodia, Rodrigo Moraga-Amaro, Nicola A. Colabufo, Pablo Aguiar, Tomas Sobrino, Rudi A. J. O. Dierckx, Aren van Waarde, Philip H. Elsinga, Gert Luurtsema
Summary: P-glycoprotein (P-gp) inducer MC111 increases P-gp functionality in the whole brain of rats, potentially offering a treatment option for neurodegenerative diseases.
MOLECULAR PHARMACEUTICS
(2021)
Article
Pharmacology & Pharmacy
Casey-Tyler Berezin, Nikolas Bergum, Glenda M. Torres Lopez, Jozsef Vigh
Summary: Opioids are effective analgesics, but their dangerous side effects need to be considered. Research on opioid pharmacokinetics provides crucial information on drug effects. This study found that morphine accumulates in the mouse retina at higher concentrations than in the brain and that reduced P-gp expression may be the cause. P-gp was identified as the main opioid transporter at the blood-retina barrier, and its expression correlated with morphine concentration in the retina.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Chao-Yun Cai, Qiu-Xu Teng, Megumi Murakami, Suresh V. Ambudkar, Zhe-Sheng Chen, Vijaya L. Korlipara
Summary: A series of 22 quinazolinamine derivatives with potent inhibitory activities on BCRP and P-gp were synthesized. Compound 22 was identified as a dual BCRP and P-gp inhibitor, while compound 33 showed BCRP inhibitory activity. These compounds changed the localization of BCRP and P-gp, inhibiting the efflux of anticancer drugs by the two ABC transporters. Compounds 22 and 33 also stimulated ATP hydrolysis, increasing the accumulation of mitoxantrone in BCRP-overexpressing cells.
Article
Biochemistry & Molecular Biology
Jae Pyun, Lachlan E. McInnes, Paul S. Donnelly, Celeste Mawal, Ashley Bush, Jennifer L. Short, Joseph A. Nicolazzo
Summary: The study found that copper II (ATSM) and copper II (GTSM) were able to modulate the expression and function of P-gp at the blood-brain barrier. Copper II (ATSM) significantly enhanced the expression and function of P-gp, while copper II (GTSM) reduced the expression and function of P-gp. This has important implications for brain drug delivery and clearance of Aβ.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Chemistry, Physical
Damian Krzyzanowski, Marcin Kruszewski, Agnieszka Grzelak
Summary: Silver nanoparticles (AgNPs) have unique properties that have attracted significant attention, showing antibacterial, antifungal, and anticancer properties. However, they can also exhibit cytotoxic effects and modulate the activity and expression of ABC transporters.
Article
Pharmacology & Pharmacy
Camila Juliana Dominguez, Guillermo Nicolas Tocchetti, Juan Pablo Rigalli, Aldo Domingo Mottino
Summary: The ABC transporters on the intestinal surface play a crucial role in regulating the absorption and efficacy of therapeutic agents, and the rapid modulation of their activity is of increasing interest to pharmacologists. Controlled regulation of these transporters could provide a basis for optimizing bioavailability of drugs and preventing potential drug interactions.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Kelli Monteiro da Costa, Leonardo Freire-de-Lima, Leonardo Marques da Fonseca, Jose Osvaldo Previato, Lucia Mendonca-Previato, Raphael do Carmo Valente
Summary: Multidrug resistance (MDR) and induction of metastasis are challenges in cancer chemotherapy. The ABC transporters play a role in MDR, while metastasis is associated with epithelial-mesenchymal transition (EMT). The study showed increased expression of ABCB1 and ABCC1 during EMT, with ABCC1 inhibitors partially inhibiting EMT-marker snail.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Diogo Henrique Kita, Gisele Alves de Andrade, Juliana Morais Missina, Kahoana Postal, Viktor Kalbermatter Boell, Francielli Sousa Santana, Ingrid Fatima Zattoni, Isadora da Silva Zanzarini, Vivian Rotuno Moure, Fabiane Gomes de Moraes Rego, Geraldo Picheth, Emanuel Maltempi de Souza, David A. Mitchell, Suresh Ambudkar, Giovana Gioppo Nunes, Glaucio Valdameri
Summary: The study found that polyoxovanadates can serve as inhibitors of ABC drug transporters, selectively inhibiting P-glycoprotein with V-10 and V-18 being the most promising compounds.
Article
Medicine, Research & Experimental
Lara Garcia-Varela, David Vallez Garcia, Takeharu Kakiuchi, Hiroyuki Ohba, Shingo Nishiyama, Tetsuro Tago, Philip H. Elsinga, Hideo Tsukada, Nicola A. Colabufo, Rudi A. J. O. Dierckx, Aren van Waarde, Jun Toyohara, Ronald Boellaard, Gert Luurtsema
Summary: This study aimed to evaluate the pharmacokinetics of (R)-[C-11]verapamil in nonhuman primates and establish it as a reference tracer for P-gp in comparison with other PET tracers. The results suggest that using the 1-tissue compartment model and shorter PET scan durations can be suitable for measuring P-gp function at the blood-brain barrier in nonhuman primates.
MOLECULAR PHARMACEUTICS
(2021)
Review
Multidisciplinary Sciences
Carlos Pilotto Heming, Wanjiru Muriithi, Lucy Wanjiku Macharia, Paulo Niemeyer Filho, Vivaldo Moura-Neto, Veronica Aran
Summary: Acquired resistance during cancer treatment is often caused by ABC transporters, such as P-gp, which export chemotherapeutic molecules and contribute to multidrug resistance. In addition to its role in drug resistance, P-gp may also have other functions and serve as a biomarker in cancer.
Review
Multidisciplinary Sciences
Iman Imtiyaz Ahmed Juvale, Azzmer Azzar Abdul Hamid, Khairul Bariyyah Abd Halim, Ahmad Tarmizi Che Has
Summary: The multidrug resistance phenomenon poses a significant threat to the pharmaceutical industry and is mediated by multidrug transporters like P-glycoprotein. P-glycoprotein, with its versatile binding sites, accommodates various compounds and plays crucial roles in both multidrug resistant diseases and physiological functions in the human body.
Article
Chemistry, Medicinal
Sarah Lazzaro, Mark A. West, Soraya Eatemadpour, Bo Feng, Manthena V. S. Varma, A. David Rodrigues, Csilla Temesszentandrasi-Ambrus, Peter Kovacs-Hajdu, Zsuzsanna Nerada, Zsuzsanna Gaborik, Chester Costales
Summary: This study evaluated the impact of potential IC50 discrepancies between two commonly utilized assay methods (cell-based and vesicle-based) on P-gp. Non-P-gp substrates showed good correlation between the two methods, while IC50s of P-gp substrates were lower in the vesicle assays. IC50s obtained from two independent laboratories using the same method showed good correlation.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Yuval Bin Kanner, Qiu-Xu Teng, Assaf Ganoth, Dan Peer, Jing-Quan Wang, Zhe-Sheng Chen, Yossi Tsfadia
Summary: This study aimed to investigate whether three antidepressant drugs from the SSRI family could be repurposed as inhibitors of MRP1 and MRP7 transporters and reverse multidrug resistance in cancer cells. The results show that these drugs exhibited inhibitory/reversal effects on both MRP1-overexpressed cells and MRP7-overexpressed cells in the presence of chemotherapies, suggesting their potential in targeting multidrug resistance in cancer cells.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sepehr Dehghani-Ghahnaviyeh, Karan Kapoor, Emad Tajkhorshid
Summary: This study used molecular dynamics simulations to investigate the ATP hydrolysis-induced conformational changes in Pgp nucleotide-binding domains (NBDs), revealing that ATP/ADP exchange induced conformational changes within the conserved signature motif of NBDs, resulting in relative orientational changes. Furthermore, putative hydrolysis-competent configurations were captured, with a conserved glutamate in the Walker-B motif acting as a catalytic base capturing a water molecule likely initiating ATP hydrolysis.