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)
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
Biochemistry & Molecular Biology
Liadys Mora Lagares, Yunierkis Perez-Castillo, Nikola Minovski, Marjana Novic
Summary: P-gp is an important protein involved in drug efflux and multidrug resistance. Molecular dynamics simulations can provide valuable insights into the binding behavior and conformational changes of P-gp in the presence of different compounds.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Mingyue Liu, Chang Xu, Xiaochun Qin, Wenwu Liu, Deping Li, Hui Jia, Xudong Gao, Yuting Wu, Qiong Wu, Xiangbo Xu, Bo Xing, Xiaowen Jiang, Hongyuan Lu, Yingshi Zhang, Huaiwei Ding, Qingchun Zhao
Summary: This study investigated a novel P-gp inhibitor DHW-221 and its effects on non-small cell lung cancer (NSCLC) cells. DHW-221 exhibited antiproliferative activity, suppressed cell migration and invasion, and overcame resistance to paclitaxel by inhibiting P-gp. Furthermore, DHW-221 induced FOXO3a nuclear translocation via Akt inhibition, leading to mitochondrial apoptosis and G0/G1 cell cycle arrest.
FRONTIERS IN ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Simona Sucha, Ales Sorf, Martin Svoren, Dimitrios Vagiannis, Fahda Ahmed, Benjamin Visek, Martina Ceckova
Summary: This study evaluated the clinical relevance of ABCB1 in AML patients and found that overexpression of ABCB1 was associated with adverse prognosis. Midostaurin, as an ABCB1 inhibitor, increased the accumulation of anthracyclines in AML patients and promoted apoptosis in leukemic cells. Additionally, miR-9 was identified as a useful prognostic marker in AML.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Chemistry, Multidisciplinary
Jelena Vasiljeva, Marina Makrecka-Kuka, Ilona Domracheva, Karlis Vilks, Pavels Dimitrijevs, Pavel Arsenyan
Summary: This study reports the design and synthesis of novel selenophenoquinolinones and their ability to reverse doxorubicin resistance in uterus sarcoma cells. Compound 5e demonstrated the best cytotoxicity and attenuated cell resistance to doxorubicin by inhibiting ABCB1 transporter activity and suppressing ABCB1 gene expression.
NEW JOURNAL OF CHEMISTRY
(2022)
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
Biochemistry & Molecular Biology
Ewa Zeslawska, Waldemar Tejchman, Annamaria Kincses, Gabriella Spengler, Wojciech Nitek, Grzegorz Zuchowski, Ewa Szymanska
Summary: Multidrug resistance (MDR) is a major reason for the failure of anticancer and antiviral chemotherapies. In this study, a series of newly synthesized 5-arylidenerhodanines were investigated for their ability to inhibit the ABCB1 efflux pump in mouse T-lymphoma cancer cells. Compounds with a triphenylamine moiety and the carboxyl group showed strong inhibitory effects, with over 17-fold higher potency than verapamil. The cytotoxic and antiproliferative effects of these compounds on T-lymphoma cells were also examined.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Sabrina Lusvarghi, Stewart R. Durell, Suresh V. Ambudkar
Summary: This study demonstrates that the ATP hydrolysis-defective mutant does not follow the same steps as the wild-type P-gp. The conformational differences in the EQ mutant may provide insights into the catalytic cycle of P-gp, suggesting the need for additional structural studies with the wild-type protein.
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)
Article
Pharmacology & Pharmacy
Sofija Jovanovic Stojanov, Epole N. Ntungwe, Jelena Dinic, Ana Podolski-Renic, Milica Pajovic, Patricia Rijo, Milica Pesic
Summary: Coleon U, a natural compound not recognized as a substrate of P-glycoprotein, has equal efficacy against sensitive and multidrug-resistant cancer cells. It delays the decrease in P-glycoprotein activity by decreasing mitochondrial membrane potential and inhibiting P-glycoprotein expression.
Article
Oncology
Hadiar Rahman, Mark J. J. Ware, Andaleeb Sajid, Sabrina Lusvarghi, Stewart R. R. Durell, Suresh V. V. Ambudkar
Summary: This study investigates the conformational changes of P-glycoprotein (P-gp) during drug transport and reveals the critical role of TMHs 4 and 10 in substrate transport.
Article
Biochemistry & Molecular Biology
Keerthana Sasitharan, Hamzah Asad Iqbal, Foteini Bifsa, Aleksandra Olszewska, Kenneth J. Linton
Summary: The study investigates the role of hydrogen bonds and specific glutamines in drug recognition and transport by the ABCB1 efflux transporter. Results show that different glutamine mutations have varying effects on the transport of different drug classes, suggesting a complex mechanism of drug recognition. Surprisingly, some mutations improved drug transport, highlighting the intricate interactions within the drug binding pocket of ABCB1.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Retraction
Oncology
S. Mohana, M. Ganesan, N. Rajendra Prasad, D. Ananthakrishnan, D. Velmurugan
Summary: A correction to this paper has been published and is accessible through the original article.
Review
Biochemistry & Molecular Biology
Atsushi Kodan, Ryota Futamata, Yasuhisa Kimura, Noriyuki Kioka, Toru Nakatsu, Hiroaki Kato, Kazumitsu Ueda
Summary: ABCB1, also known as MDR1 or P-glycoprotein, plays a crucial role in exporting various hydrophobic compounds and serving as a protective physiological barrier in several organs. The mechanism involves an aromatic hydrophobic network triggering a conformational change in ABCB1, leading to a twist-and-squeeze motion that exports hydrophobic substrates directly to the extracellular space, distinct from other transporters.
