Article
Endocrinology & Metabolism
Nicolas Tournier, Sebastien Goutal, Severin Mairinger, Irene Hernandez-Lozano, Thomas Filip, Michael Sauberer, Fabien Caille, Louise Breuil, Johann Stanek, Anna F. Freeman, Gaia Novarino, Charles Truillet, Thomas Wanek, Oliver Langer
Summary: This study investigated the feasibility of simultaneous inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar. The combination led to increased brain distribution of the model substrate in mice and macaques, potentially enhancing brain delivery of molecularly targeted anticancer drugs for the treatment of brain tumors. Additionally, tolerability and induction of apoptosis were assessed in human cerebral organoids, showing promising results for future applications.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2021)
Article
Chemistry, Medicinal
Hui Li, Sheng-Lie Zhang, Yan-Han Jia, Qian Li, Zi-Wen Feng, Shi-Duo Zhang, Wei Zheng, Ye-Ling Zhou, Lin-Lin Li, Xue-Chun Liu, Ya-Qiong Chen, Hui Peng, Qi-Dong You, Xiao-Li Xu
Summary: ABCB1 and ABCG2 are important ATP-binding cassette (ABC) transporters associated with multidrug resistance (MDR). In this study, we designed a series of imidazo[1,2-a]pyridine derivatives as dual-target inhibitors of ABCB1 and ABCG2 through scaffold hopping strategy. Compound Y22 demonstrated potential efflux function inhibition towards both ABCB1 and ABCG2 without cytotoxicity, and enhanced the potency of antiproliferative drugs in vitro. Mechanistic studies showed that Y22 slightly suppressed ATPase activity, but did not affect the protein expression of ABCB1 or ABCG2. Notably, Y22 exhibited negligible CYP3A4 inhibition and enhanced the antiproliferative activity of adriamycin in vivo by restoring the sensitivity of resistant cells. Thus, Y22 may be effective clinically in combination with common chemotherapy agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Jinyun Dong, Li Yuan, Can Hu, Xiangdong Cheng, Jiang -Jiang Qin
Summary: Multidrug resistance (MDR) is a major threat in chemotherapy, and the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp)/ABCB1, plays a role in MDR. Targeting P-gp with small molecule inhibitors is an effective approach, but no clinically useful inhibitors have been identified so far. Therefore, further research is needed to overcome MDR.
PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Multidisciplinary Sciences
Wang Yin, Dongxi Xiang, Tao Wang, Yumei Zhang, Cuong Pham, Shufeng Zhou, Guoqin Jiang, Yingchun Hou, Yimin Zhu, Yinglu Han, Liang Qiao, Phuong H-L Tran, Wei Duan
Summary: Inhibiting MDR1 or ABCG2 was found to increase the sensitivity of liver cancer stem cells to doxorubicin, leading to elevated intracellular concentration of the drug and increased apoptosis. This approach effectively reversed chemoresistance in liver cancer stem cells, demonstrating a promising strategy for enhancing the therapeutic efficacy of doxorubicin.
SCIENTIFIC REPORTS
(2021)
Article
Pharmacology & Pharmacy
Wenlong Li, Rolf W. Sparidans, Maria C. Lebre, Jos H. Beijnen, Alfred H. Schinkel
Summary: The study revealed that ABCB1 and ABCG2 restrict the brain accumulation and potential toxicity of repotrectinib, while also controlling its intestinal disposition. Oatp1a/1b mediates the liver uptake of repotrectinib, reducing its systemic exposure. Furthermore, CYP3A activity substantially limits the systemic exposure of repotrectinib.
Article
Pharmacology & Pharmacy
Chung-Pu Wu, Sung-Han Hsiao, Yu-Shan Wu
Summary: The overexpression of human ATP-binding cassette (ABC) transporters in cancer cells can lead to multidrug resistance (MDR), which poses a significant obstacle to chemotherapy. Currently, there are no approved drugs specifically designed to treat multidrug-resistant cancers. However, drug repurposing has emerged as a practical approach to discover effective modulators of drug transporters.
DRUG RESISTANCE UPDATES
(2023)
Article
Chemistry, Physical
Linna Liang, Wendi Huo, Bei Wang, Lingzhi Cao, Haoran Huo, Yixin Liu, Yi Jin, Xinjian Yang
Summary: Tumor multidrug resistance is a major cause of chemotherapy failure, and reversing tumor multidrug resistance is crucial for increasing the sensitivity of tumor cells to chemodrugs. The self-assembled DNAzyme nanoflowers can efficiently reverse multidrug resistance, enhance drug loading capacity, and suppress P-glycoprotein expression.
JOURNAL OF COLLOID AND INTERFACE SCIENCE
(2022)
Article
Pharmacology & Pharmacy
Zhanwei Zeng, Shiyi Liao, Huan Zhou, Hongyu Liu, Jiantao Lin, Yunsheng Huang, Chenhui Zhou, Daohua Xu
Summary: Multidrug resistance (MDR) is a major cause of chemotherapy failure in cancers, and ABCB1 and ABCG2 play crucial roles in cancer cell MDR. Sigma-2 receptor ligands have shown promising cytotoxic effects against cancer cells and regulate the activity of ABCB1, but their specific mechanisms are still unclear. In this study, a sigma(2) receptor ligand called A011 demonstrated significant cytotoxicity against breast cancer cells and reversed drug resistance. A011 achieved these effects by increasing drug accumulation and down-regulating ABC transport protein expression. Additionally, A011 inhibited tumor growth. These findings suggest that A011 has potential as a therapeutic agent for overcoming tumor resistance.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yasmeen Cheema, Yusra Sajid Kiani, Kenneth J. J. Linton, Ishrat Jabeen
Summary: Researchers developed a pharmacophore model based on the cryo-EM structure of ABCB1 to screen for new inhibitors, resulting in the identification of six potential inhibitors with distinct chemistries and favorable properties. The compounds exhibited low nanomolar range inhibitory concentrations and two of them were able to resensitize ABCB1-expressing cells to taxol. This study demonstrates the utility of cryo-electron microscopy in drug identification and design.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Iris L. K. Wong, Xuezhen Zhu, Kin-Fai Chan, Zhen Liu, Chin-Fung Chan, Tsun Sing Chow, Tsz Cheung Chong, Man Chun Law, Jiahua Cui, Larry M. C. Chow, Tak Hang Chan
Summary: The synthesized triazole-containing flavonoids exhibit potent and selective BCRP inhibitory activity in cells overexpressing BCRP, showing promise for combination therapy to overcome multidrug resistance in cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Nathalie Guragossian, Billel Belhani, Alexis Moreno, Magda Teixeira Nunes, Lucia Gonzalez-Lobato, Christelle Marminon, Laurent Berthier, Amanda Do Rocio Andrade Pires, Csilla Ozvegy-Laczka, Balazs Sarkadi, Raphael Terreux, Zouhair Bouaziz, Malika Berredjem, Joachim Jose, Attilio Di Pietro, Pierre Falson, Marc Le Borgne
Summary: New dimeric inhibitors targeting BCRP/ABCG2 were designed with high potency and therapeutic ratio, showing specificity in inhibiting drug efflux. The study suggests that the non-competitive mechanism by which substrate promotes inhibitor binding may be useful for targeting anticancer drug efflux.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Agriculture, Dairy & Animal Science
Michela Levi, Luisa Vera Muscatello, Barbara Brunetti, Cinzia Benazzi, Federico Parenti, Francesca Gobbo, Giancarlo Avallone, Barbara Bacci, Elisa Zambon, Paola Valenti, Giuseppe Sarli
Summary: Multidrug resistance in neoplastic cells is primarily mediated by P-glycoprotein and breast cancer resistance protein, with canine mammary carcinomas showing high intrinsic expression levels of both. However, no significant association was found between the expression of these proteins and immunophenotypes, Ki67 index, histological grade, or tumor-related death in this study.
Article
Multidisciplinary Sciences
Qin Yu, Dongchun Ni, Julia Kowal, Ioannis Manolaridis, Scott M. Jackson, Henning Stahlberg, Kaspar P. Locher
Summary: This study using cryo-EM structures of ABCG2 under turnover conditions reveals distinct conformational states, with two different turnover states observed. The relationship between ATP binding and closure of TMDs is highlighted as the likely bottleneck of the reaction cycle, where discrimination between substrates and inhibitors occurs.
NATURE COMMUNICATIONS
(2021)
Review
Pharmacology & Pharmacy
Julia A. Schulz, Anika M. S. Hartz, Bjorn Bauer
Summary: Drug efflux transporters at the blood-brain barrier limit drug delivery to the brain. Overcoming these transporters is a clinical challenge. Understanding the regulation mechanisms of these transporters is critical. This review summarizes the signaling pathways that regulate these transporters and discusses their clinical relevance.
PHARMACOLOGICAL REVIEWS
(2023)
Article
Oncology
Milica Nedeljkovic, Nasta Tanic, Mirjana Prvanovic, Zorka Milovanovic, Nikola Tanic
Summary: ABC transporters play a key role in chemoresistance of solid tumors, with higher expression in TNBC compared to ER+ breast cancer. Among the three transporters studied, ABCG2 and ABCC1 showed significantly higher levels of expression in TNBC compared to ABCB1, with ABCB1 associated with metastatic spread in TNBC patients. Surprisingly, high expression of ABCG2 was correlated with longer disease-free interval and overall survival in TNBC patients.
Article
Agriculture, Dairy & Animal Science
J. A. Otero, V. Miguel, L. Gonzalez-Lobato, R. Garcia-Villalba, J. C. Espin, J. G. Prieto, G. Merino, A. I. Alvarez
Article
Agriculture, Dairy & Animal Science
J. A. Otero, D. Gracia-Mateos, A. de la Fuente, J. G. Prieto, A. I. Alvarez, G. Merino
JOURNAL OF DAIRY SCIENCE
(2016)
Article
Food Science & Technology
Dafne Garcia-Mateos, Rocio Garcia-Villalba, Jose Angel Maranon, Juan Carlos Espin, Gracia Merino, Ana I. Alvarez
JOURNAL OF FUNCTIONAL FOODS
(2017)
Article
Veterinary Sciences
Jon Andoni Otero, Dafne Garcia-Mateos, Indira Alvarez-Fernandez, Rocio Garcia-Villalba, Juan Carlos Espin, Ana Isabel Alvarez, Gracia Merino
BMC VETERINARY RESEARCH
(2018)
Article
Biochemistry & Molecular Biology
Dafne Garcia-Mateos, Rocio Garcia-Villalba, Jon A. Otero, Jose A. Maranon, Juan C. Espin, Ana I. Alvarez, Gracia Merino
Article
Pharmacology & Pharmacy
Dafne Garcia-Mateos, Alba Maria Garcia-Lino, Indira Alvarez-Fernandez, Esther Blanco-Paniagua, Alvaro de la Fuente, Ana Isabel Alvarez, Gracia Merino
DRUG METABOLISM AND DISPOSITION
(2019)
Review
Nutrition & Dietetics
Alba M. Garcia-Lino, Indira Alvarez-Fernandez, Esther Blanco-Paniagua, Gracia Merino, Ana I. Alvarez
Article
Pharmacology & Pharmacy
Alba M. Garcia-Lino, Esther Blanco-Paniagua, Elsa N. Astorga-Simon, Laura Alvarez-Fernandez, Dafne Garcia-Mateos, Indira Alvarez-Fernandez, Ana Alvarez, Gracia Merino
BIOCHEMICAL PHARMACOLOGY
(2020)
Article
Chemistry, Applied
Alba M. Garcia-Lino, Alex Gomez-Gomez, Dafne Garcia-Mateos, Alvaro de la Fuente, Ana I. Alvarez, Oscar J. Pozo, Gracia Merino
Summary: ABCG2 is involved in the secretion of several compounds in milk, with higher levels of tryptophan-related compounds in wild-type mice compared to Abcg2(-/-) mice. The milk-to-plasma ratio of these compounds was also higher in dairy cows carrying the ABCG2 Y581S polymorphism compared to noncarrier animals. In vitro transport assays confirmed these findings and validated differences in the bovine protein variants.
Article
Veterinary Sciences
Alba M. Garcia-Lino, Dafne Garcia-Mateos, Indira Alvarez-Fernandez, Esther Blanco-Paniagua, Juan M. Medina, Gracia Merino, Ana Alvarez
Summary: The study demonstrated that eprinomectin is an effective ABCG2 inhibitor, reducing the transport of danofloxacin and meloxicam and increasing the systemic exposure of these drugs. The systemic concentration of meloxicam was significantly increased with coadministration of eprinomectin, showing an increase of over 40% in the AUC (0-72 h) value.
RESEARCH IN VETERINARY SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Esther Blanco-Paniagua, Alba M. Garcia-Lino, Dafne Garcia-Mateos, Ana Alvarez, Gracia Merino
Summary: The study showed tolfenamic acid is an in vitro substrate of Abcg2 and that Abcg2 affects its plasma levels and tissue distribution, potentially leading to pharmacological and toxicological consequences.
CHEMICO-BIOLOGICAL INTERACTIONS
(2021)
Article
Microbiology
Esther Blanco-Paniagua, Laura Alvarez-Fernandez, Alba M. Garcia-Lino, Ana Alvarez, Gracia Merino
Summary: ABZ metabolites ABZSO(2) and ABZSO(2)-NH2 are in vitro substrates of ABCG2 and actively secreted into milk by ABCG2.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Endocrinology & Metabolism
Laura Alvarez-Fernandez, Alex Gomez-Gomez, Noemi Haro, Alba M. Garcia-Lino, Ana Alvarez, Oscar J. Pozo, Gracia Merino
Summary: The ATP-binding cassette G2 (ABCG2) is an efflux transporter that impacts the bioavailability, tissue accumulation, and secretion of xenobiotics and endogenous compounds. This study characterized the role of ABCG2 in the distribution and secretion of melatonin and its metabolites. The researchers found that ABCG2 transported melatonin and its metabolites and that mice lacking Abcg2 exhibited higher plasma concentrations of melatonin metabolites, increased tissue accumulation, and lower milk concentrations compared to wild-type mice. These findings demonstrate the critical role of ABCG2 in the biodistribution and therapeutic activity of melatonin and its metabolites.
JOURNAL OF PINEAL RESEARCH
(2023)
Article
Microbiology
Esther Blanco-Paniagua, Laura Alvarez-Fernandez, Andrea Rodriguez-Alonso, Alicia Millan-Garcia, Ana I. Alvarez, Gracia Merino
Summary: Clorsulon is an effective drug for treating helminthic zoonoses and has high broad-spectrum antiparasitic efficacy when used in combination with ivermectin. The safety and efficacy of clorsulon should be studied by considering drug-drug interactions mediated by ABC transporters. This study demonstrates that clorsulon is actively secreted into milk by ABCG2 transporter and its secretion into milk is reduced by coadministration with ivermectin.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2023)