1
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Briante R, Zhai Q, Mohanty S, Zhang P, O’Connor A, Misker H, Wang W, Tan C, Abuhay M, Morgan J, Theolis R, Ponath P, Arathoon R. Successful targeting of multidrug-resistant tumors with bispecific antibodies. MAbs 2025; 17:2492238. [PMID: 40248904 PMCID: PMC12013451 DOI: 10.1080/19420862.2025.2492238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/19/2025] Open
Abstract
Multidrug resistance (MDR) hinders efficacious cancer chemotherapy. Overexpression of the P-glycoprotein (P-gp) efflux pump (EP) on cancer cells is a primary cause of MDR since it expels numerous anticancer drugs. Small molecule intracellular P-gp antagonists have been investigated clinically to redress MDR but have failed primarily due to adverse effects on P-gp in normal tissue. We used a new approach to counteract P-gp with bispecific antibodies (BsAbs) that simultaneously bound P-gp and CD47 in cis on MDR cells but not normal tissue. Affinities of the individual arms of the BsAbs were low enough to minimize normal tissue binding, but, when the two targets were co-located on MDR cancer cells, both arms of the BsAb engaged with effective avidity. Proof-of-concept was shown in three different MDR xenograft tumor models with a non-humanized chimeric BsAb (targeting P-gp and CD47) that potently restored tumor sensitivity to paclitaxel. Fully humanized variants were successfully developed and characterized. Significant anti-tumor efficacy was observed with the BsAbs both when combined with paclitaxel and as single agents in the absence of paclitaxel. Treatment of MDR cancers with BsAbs using this novel approach has several distinct advantages over prior efforts with small molecule antagonists, including 1) invoking a direct immune attack on the tumors, 2) multimodal mechanisms of action, 3) tumor-specific targeting (with reduced toxicity to normal tissue), and 4) broad applicability as single agents and compatibility with other therapeutics.
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MESH Headings
- Humans
- Antibodies, Bispecific/pharmacology
- Antibodies, Bispecific/immunology
- Antibodies, Bispecific/therapeutic use
- Animals
- Drug Resistance, Neoplasm/drug effects
- Mice
- Xenograft Model Antitumor Assays
- Cell Line, Tumor
- Drug Resistance, Multiple/drug effects
- CD47 Antigen/immunology
- Paclitaxel/pharmacology
- Neoplasms/drug therapy
- Neoplasms/immunology
- ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors
- ATP Binding Cassette Transporter, Subfamily B, Member 1/immunology
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Female
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Affiliation(s)
- Raffaella Briante
- Antibody Engineering, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Qianting Zhai
- Antibody Discovery, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | | | - Pingping Zhang
- Antibody Discovery, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Alissa O’Connor
- Antibody Engineering, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Hiwot Misker
- Antibody Engineering, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Willie Wang
- Antibody Engineering, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Cindy Tan
- Antibody Engineering, Kenjockety Biotechnology Inc, Tiburon, CA, USA
- Antibody Discovery, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Mastewal Abuhay
- Antibody Development, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Jessica Morgan
- Antibody Engineering, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Richard Theolis
- Antibody Discovery, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Paul Ponath
- Antibody Development, Kenjockety Biotechnology Inc, Tiburon, CA, USA
| | - Robert Arathoon
- Antibody Engineering, Kenjockety Biotechnology Inc, Tiburon, CA, USA
- Antibody Discovery, Kenjockety Biotechnology Inc, Tiburon, CA, USA
- Antibody Development, Kenjockety Biotechnology Inc, Tiburon, CA, USA
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Romano B, Molaro MC, Somma F, Battisegola C, Failla M, Lazzarato L, Chegaev K, Rolando B, Kopecka J, Ianaro A, Rimoli MG, Della Corte CM, Riganti C, Sodano F, Ercolano G. FS536, a novel nitric oxide-releasing doxorubicin hybrid, reverts multidrug resistance in lung cancer cells. J Control Release 2025; 382:113732. [PMID: 40228667 DOI: 10.1016/j.jconrel.2025.113732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 04/10/2025] [Accepted: 04/11/2025] [Indexed: 04/16/2025]
Abstract
The design of molecular hybrids that chemically conjugate nitric oxide (NO)-donors with anticancer drugs, offering site-specific and time-controlled properties, is a promising strategy in cancer therapy. In this work, we designed, synthesized, and characterized a novel doxorubicin (DOXO)-NO-donor hybrid, named FS536, by chemically conjugating DOXO with a diazeniumdiolate moiety. Upon incubation in human serum, FS536 simultaneously released both DOXO and NO through enzymatic hydrolysis. FS536 significantly inhibited the proliferation of the DOXO-resistant A549 lung cancer cell line (A549-DR), overcoming the resistance typically observed with DOXO alone. This enhanced efficacy is attributed to the release of NO, which induces the nitration of the MRP1 efflux pump, reducing its activity, increasing intracellular drug concentrations, and thus sensitizing resistant cells to DOXO. Our findings suggest that FS536 is a promising therapeutic strategy for combating multidrug-resistant cancers by leveraging the synergistic effects of DOXO and NO.
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Affiliation(s)
- Benedetta Romano
- Department of Pharmacy, "Federico II" University of Napoli, 80131 Napoli, Italy
| | | | - Fabio Somma
- Department of Pharmacy, "Federico II" University of Napoli, 80131 Napoli, Italy
| | - Chiara Battisegola
- Department of Pharmacy, "Federico II" University of Napoli, 80131 Napoli, Italy
| | - Mariacristina Failla
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy
| | - Loretta Lazzarato
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy
| | - Konstantin Chegaev
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy
| | - Barbara Rolando
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy
| | - Joanna Kopecka
- Department of Oncology, Molecular Biotechnology Center "G. Tarone", University of Torino, 10126 Torino, Italy
| | - Angela Ianaro
- Department of Pharmacy, "Federico II" University of Napoli, 80131 Napoli, Italy
| | - Maria Grazia Rimoli
- Department of Pharmacy, "Federico II" University of Napoli, 80131 Napoli, Italy
| | | | - Chiara Riganti
- Department of Oncology, Molecular Biotechnology Center "G. Tarone", University of Torino, 10126 Torino, Italy
| | - Federica Sodano
- Department of Pharmacy, "Federico II" University of Napoli, 80131 Napoli, Italy.
| | - Giuseppe Ercolano
- Department of Pharmacy, "Federico II" University of Napoli, 80131 Napoli, Italy.
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3
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Sawada R, Furugen A, Ueda A, Nishimura A, Umazume T, Narumi K, Kobayashi M. Analysis of drug transporter expression in syncytiotrophoblast derived from human placental stem cells: Expression and function of efflux transporters. Placenta 2025; 165:23-32. [PMID: 40184769 DOI: 10.1016/j.placenta.2025.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 02/17/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
OBJECTIVE The placenta is a vital organ for exchanging nutrients, endogenous substances, and xenobiotics between mother and fetus. The syncytiotrophoblast (ST) is crucial in maintaining the placental barrier. Human trophoblast stem cells (hTSCs) have been recently established; however, their utility in studying placental transport functions has not been fully elucidated. This study investigated the expression and function of transporters in hTSC-derived ST cells. METHODS TSCT cells, as hTSCs, were differentiated into ST-like cells (ST-TSCT), and the gene expression of 84 transporters in ST-TSCT cells was evaluated using a PCR array. BeWo cells, a widely used trophoblast model, were used for comparison. BeWo cells were differentiated into ST-like cells using forskolin [BeWo (FK)]. The protein levels of efflux transporters were examined by western blotting, and functional assays were performed using typical fluorescent substrates. RESULTS Transporter gene expression levels were higher in ST-TSCT than in BeWo (FK) cells, with 27 genes showing more than a 3-fold increase. Ten of these genes were exclusively expressed in ST-TSCT. Western blotting revealed the presence of efflux transporters, including P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 2 (MRP2/ABCC2). Furthermore, the accumulation of typical substrates (Rhodamine123 for P-gp, Hoechst33342 and BODIPY™ FL Prazosin for BCRP, and 5(6)-carboxy-2',7'-dichlorofluorescein diacetate for MRP) significantly increased when transporter inhibitors (elacridar, Ko143, and MK571) were applied. CONCLUSION This study showed higher transporter expression in ST-TSCT than that in a traditional trophoblast model. Furthermore, the functional expression of efflux transporters was observed. ST-TSCT is valuable for investigating placental transport functions.
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Affiliation(s)
- Riko Sawada
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
| | - Ayako Furugen
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan; Division of Healthcare Innovation in Pharmacy, Faculty of Pharmacy, Keio University, Japan.
| | - Ayami Ueda
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
| | | | - Takeshi Umazume
- Department of Obstetrics, Hokkaido University Hospital, Japan
| | - Katsuya Narumi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
| | - Masaki Kobayashi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan.
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4
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Pienta KJ, Goodin PL, Amend SR. Defeating lethal cancer: Interrupting the ecologic and evolutionary basis of death from malignancy. CA Cancer J Clin 2025; 75:183-202. [PMID: 40057846 PMCID: PMC12061633 DOI: 10.3322/caac.70000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 12/11/2024] [Accepted: 01/07/2025] [Indexed: 05/11/2025] Open
Abstract
Despite the advances in cancer prevention, early detection, and treatments, all of which have led to improved cancer survival, globally, there is an increased incidence in cancer-related deaths. Although each patient and each tumor is wholly unique, the tipping point to incurable disease is common across all patients: the dual capacity for cancers to metastasize and resist systemic treatment. The discovery of genetic mutations and epigenetic variation that emerges during cancer progression highlights that evolutionary and ecology principles can be used to understand how cancer evolves to a lethal phenotype. By applying such an eco-evolutionary framework, the authors reinterpret our understanding of the metastatic process as one of an ecologic invasion and define the eco-evolutionary paths of evolving therapy resistance. With this understanding, the authors draw from successful strategies optimized in evolutionary ecology to define strategic interventions with the goal of altering the evolutionary trajectory of lethal cancer. Ultimately, studying, understanding, and treating cancer using evolutionary ecology principles provides an opportunity to improve the lives of patients with cancer.
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Affiliation(s)
- Kenneth J. Pienta
- Urology, Oncology, Pharmacology and Molecular Sciences, and Chemical and Biomolecular EngineeringCancer Ecology Center at the Brady Urological InstituteJohns Hopkins UniversityBaltimoreMarylandUSA
| | | | - Sarah R. Amend
- Urology and OncologyCancer Ecology Center at the Brady Urological InstituteJohns Hopkins School of MedicineBaltimoreMarylandUSA
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5
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Helal MH, Alsehli MH, Al-Dies AAM, Moussa Z, Elgammal WE, Halawa AH, Elhenawy AA, El-Agrody AM. Unraveling the interaction of pyranocoumarins with P-glycoprotein: Implications for overcoming multidrug resistance in cancer therapy. Bioorg Chem 2025; 158:108314. [PMID: 40058220 DOI: 10.1016/j.bioorg.2025.108314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/08/2025] [Accepted: 02/22/2025] [Indexed: 03/19/2025]
Abstract
This study aimed to investigate the antiproliferative activity and P-glycoprotein (P-gp) inhibitory potential of a series of novel pyranocoumarin derivatives. Compounds 4a-c and 4f-i showed the most potent activity against MCF-7 (breast cancer), MCF-7/ADR (human breast cancer cell) resistant to Adriamycin (ADR), and Caco-2 (colon carcinoma) cell lines compared to Sorafenib and Doxorubicin, while all the compounds 4a-i demonstrated week growth inhibitory impact toward two normal cell lines, HFL-1 and WI-38 with IC50 values between 56.5 and 81.8 μM. Compounds 4b, 4g, and 4h, featuring trifluoromethyl, ethoxy, and benzyloxy substituents, demonstrated significant efficacy against P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cells, with IC50 values between 15.88 and 21.96 μM, outperforming Doxorubicin (IC50 = 50.9 μM). Flow cytometric efflux assays confirmed increased intracellular accumulation of Rho123 in MCF-7/ADR cells treated with pyranocoumarin derivatives (4g, 4h). Mechanistic studies, including molecular docking and molecular dynamic (MD), leading to inhibition of P-glycoprotein (P-gp) function. Compound 4h exhibited the strongest binding affinity, and molecular dynamics simulations of the 4h-4ASD complex indicated a stable association with the binding site. These findings enhance our understanding of the binding mechanisms and potential functional implications of compound 4h's inhibition of P-glycoprotein.
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Affiliation(s)
- Mohamed H Helal
- Center for Scientific Research and Entrepreneurship, Northern, Border University, Arar 73213, Saudi Arabia
| | - Mosa H Alsehli
- Chemistry Department, College of Science, Taibah University, Medina 30002, Saudi Arabia
| | - Al-Anood M Al-Dies
- Chemistry Department, Umm Al-Qura University, Al-Qunfudah University College, Al-Qunfudah 21912, Saudi Arabia
| | - Ziad Moussa
- Department of Chemistry, College of Science, United Arab Emirates University, P. O. Box 15551, Al Ain, United Arab Emirates
| | - Walid E Elgammal
- Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt
| | - Ahmed H Halawa
- Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt
| | - Ahmed A Elhenawy
- Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt.; Al-Baha University, Faculty of Sciences, Department of Chemistry, Saudi Arabia..
| | - Ahmed M El-Agrody
- Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt..
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6
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Gao Y, Gao C, Nie H. Effects of water-accommodated fractions of crude oil on detoxification and antioxidant mechanisms in Ruditapes philippinarum. ENVIRONMENTAL RESEARCH 2025; 278:121687. [PMID: 40287042 DOI: 10.1016/j.envres.2025.121687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/08/2025] [Accepted: 04/23/2025] [Indexed: 04/29/2025]
Abstract
To assess the impact of crude oil pollution on Manila clams (Ruditapes philippinarum), we analyzed the effects of exposure to water-accommodated fraction (WAF) at different concentrations (nominal TPH concentrations of 0.5, 1.0 and 3.0 mg/L), including survival rate, histopathology observation and antioxidant enzyme detection. Results demonstrated that the activities of antioxidant enzymes-Catalase (CAT), Superoxide dismutase (SOD), Glutathione peroxidase (GSH-PX) and Malondialdehyde (MDA) in Manila clams was significantly elevated in 3.0 mg/L WAF group compared with the control group (P < 0.05). In addition, RNA-seq was performed to analyze clam hepatopancreas tissue in 0 d (control group, CG), 7 d (exposure group, O7d), 15 d (exposure group, O15d) after the exposure to WAF (3 mg/L) and recovery in clean water for 7 d after 15 d WAF exposure (recovery group, R7d). The results showed that a total of 129 differentially expressed genes (DEGs) were detected in the O7d vs CG group, 123 DEGs were detected in the O15d vs CG group, and 2113 DEGs were detected in the R7d vs CG group. Of these genes, the expression of cytochrome P450 2J2 (6.30-fold), bile salt sulfotransferase (8.06-fold), multidrug resistance-associated protein 1 (8.17-fold) was significantly induced at 15 d under the WAF exposure. DEGs were significantly enriched in pathways such as cysteine and methionine metabolism, as well as glycine, serine and threonine metabolism. Furthermore, eight DEGs, including metabolism-related genes (ABCC1, ABCG2, SULT2A1, CYP2J2), ion transport genes (SLC39a14, RFT2), an immune-related gene (Gvin1), and a cellular structure and signal regulatory gene (Ank3) were selected for qRT-PCR analysis. The results confirmed that DEG expression levels were consistent with RNA-seq findings. This study provides crucial molecular insights into the adaptive responses and recovery processes of marine bivalves in response to oil pollution, thereby contributing a scientific foundation for evaluating and monitoring marine environmental pollution.
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Affiliation(s)
- Yang Gao
- College of Fisheries and Life Science, Dalian Ocean University, 116023, Dalian, China; Engineering Research Center of Shellfish Culture and Breeding in Liaoning Province, Dalian Ocean University, 116023, Dalian, China
| | - Changsheng Gao
- College of Fisheries and Life Science, Dalian Ocean University, 116023, Dalian, China; Engineering Research Center of Shellfish Culture and Breeding in Liaoning Province, Dalian Ocean University, 116023, Dalian, China
| | - Hongtao Nie
- College of Fisheries and Life Science, Dalian Ocean University, 116023, Dalian, China; Engineering Research Center of Shellfish Culture and Breeding in Liaoning Province, Dalian Ocean University, 116023, Dalian, China.
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7
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Wang J, Li Y, Dong J, Liu S, Tao L, Yin J, Zhu Q, Garí M, Liao C, Jiang G. Analogue-Specific Transplacental Transfer of Organophosphate Flame Retardants in ICR Mouse Mediated by Active Transport. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:7320-7337. [PMID: 40177966 DOI: 10.1021/acs.est.4c14153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Prenatal exposure to organophosphate flame retardants (OPFRs) may pose potential health risks to offspring. While prior studies have demonstrated that OPFRs can be transferred from mothers to fetuses, the mechanism underlying transplacental transfer remains unclear. The pregnant ICR mouse and JAR cell (a monolayer model), in combination with molecular docking, were used to explore the underlying mechanism. OPFRs were rapidly metabolized into diester metabolites following oral gavage in the ICR mouse, with considerable concentrations detected in maternal serum, amniotic fluid, and placenta, as well as fetus within 3 h. After 6 h, the accumulation ratios of OPFRs between the mother and fetus exhibited a parabolic relationship with log KOW. Oral exposure resulted in a decrease in interstitial cells in the decidua and an expansion of vascular systems in the labyrinthine area. RT-qPCR analysis revealed upregulated expression levels of transporter mRNA in the placenta, suggesting a protective mechanism characterized by greater efflux than influx transport efficiency. Metabolic inhibitors applied during in vitro transepithelial transport experiments using the JAR cells significantly reduced the transport efficiency, indicating that active transport facilitated the transplacental transport of aryl-OPFRs, with reductions exceeding 50%. Molecular docking analysis indicated that aryl-OPFRs exhibited greater binding affinities to placental transporters compared to other types of OPFRs, with more bonding interactions. These findings offer new insights into the potential health impacts of OPFR exposure and highlight the importance of elucidating their transplacental transport mechanisms.
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Affiliation(s)
- Jiaying Wang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yongting Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jingcun Dong
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuang Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang 310024, China
| | - Le Tao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jia Yin
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang 310024, China
| | - Qingqing Zhu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mercè Garí
- Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona, 18, 08034 Barcelona, Catalonia, Spain
| | - Chunyang Liao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang 310024, China
- Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, School of Environment and Health, Jianghan University, Wuhan 430056, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guibin Jiang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
- School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang 310024, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
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Abdelfattah EK, Hosny SM, Kassem AB, Moustafa HAM, Tawfeik AM, Abdelhafez MN, El-Sheshtawy W, Alsfouk BA, Saleh A, Salem HA. Pharmacogenetics as a Future Tool to Risk-Stratify Breast Cancer Patients According to Chemotoxicity Potential from the Doxorubicin Hydrochloride and Cyclophosphamide (AC) Regimen. Pharmaceuticals (Basel) 2025; 18:539. [PMID: 40283974 PMCID: PMC12029990 DOI: 10.3390/ph18040539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 03/31/2025] [Accepted: 04/01/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Studying single-nucleotide polymorphisms (SNPs) in xenobiotic-transporting and metabolizing enzyme genes before administering the doxorubicin hydrochloride and cyclophosphamide (AC) regimen may help optimize breast cancer (BC) treatment for individual patients. Objective: Genotyping specific SNPs on genes encoding for the transport and metabolism of the AC regimen and study their association with its chemotherapeutic toxicity. Method: This prospective cohort study was conducted in two hospitals in Egypt. Before receiving AC therapy, venous blood was collected from female patients with BC for DNA extraction and the genotyping of four SNPs: rs2228100 in ALDH3A1 gene, rs12248560 in CYP2C19 gene, rs1045642 in ABCB1 gene, and rs6907567 in SLC22A16 gene. Patients were then prospectively monitored for hematological, gastrointestinal, and miscellaneous toxicities throughout the treatment cycles. Results: The ALDH3A1 gene polymorphism demonstrated a significant increase in nausea, stomachache, and peripheral neuropathy among patients carrying the GC+CC genotype, compared to those with the GG genotype (p = 0.023, 0.036, and 0.008, respectively). Conversely, patients with the GG genotype exhibited significantly higher fever grades after cycles 1, 2, and 3 of the AC regimen compared to those with the GC+CC genotype (p = 0.009, 0.017, and 0.018, respectively). Additionally, fatigue severity was significantly increased among patients with the GG genotype compared to those with the GC+CC genotype following AC administration (p = 0.008). Conclusions: The SNP variation of ALDH3A1 (rs2228100) gene significantly influenced AC regimen toxicity in female BC patients. Meanwhile, SNPs in CYP2C19 (rs12248560), ABCB1 (rs1045642), and SLC22A16 (rs6907567) genes showed a significant influence on the recurrence rate of certain toxicities.
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Affiliation(s)
- Esraa K. Abdelfattah
- Department of Clinical Pharmacy, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt; (E.K.A.); (S.M.H.)
| | - Sanaa M. Hosny
- Department of Clinical Pharmacy, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt; (E.K.A.); (S.M.H.)
| | - Amira B. Kassem
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Damanhour University, Damanhour 22514, Egypt
| | | | - Amany M. Tawfeik
- Medical Microbiology and Immunology Department, Faculty of Medicine, Badr University in Cairo, Cairo 11829, Egypt;
- Medical Microbiology and Immunology Department, Faculty of Medicine, Al Azhar University (Girls) Cairo, Cairo 11754, Egypt
| | - Marwa N. Abdelhafez
- Department of Medical Oncology, National Cancer Institute, Cairo University, Al Giza 12613, Egypt;
| | - Wael El-Sheshtawy
- Department of Medical Oncology, Faculty of Medicine, Al Azhar University, Cairo 11651, Egypt;
| | - Bshra A. Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (B.A.A.); (A.S.)
| | - Asmaa Saleh
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (B.A.A.); (A.S.)
| | - Hoda A. Salem
- Department of Pharmacy Practice, University of Tabuk, Tabuk 47512, Saudi Arabia;
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9
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Yin R, Gao J, Liu Y, Guo C. Functional analysis of the effects of propofol on tamoxifen‑resistant breast cancer cells: Insights into transcriptional regulation. Oncol Lett 2025; 29:194. [PMID: 40041408 PMCID: PMC11878209 DOI: 10.3892/ol.2025.14940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/06/2025] [Indexed: 03/06/2025] Open
Abstract
Although 70% of patients with estrogen receptor-positive breast cancer benefit from tamoxifen (TAM) therapy, the development of resistance to TAM leads to high rates of metastasis and a poor prognosis. Propofol, a commonly used anesthetic, can inhibit the occurrence and progression of breast cancer. In the present study, the effects of propofol on TAM-resistant (TR) breast cancer cells were evaluated. MCF7-TR cells were treated with or without propofol. Subsequently, cell cycle progression and the induction of apoptosis were detected by flow cytometry, whereas cell proliferation was assessed using Cell Counting Kit-8 and colony formation assays. Furthermore, the potential transcriptional regulatory effects of propofol on MCF7-TR cells were investigated using RNA sequencing. The results indicated that propofol significantly promoted cell cycle arrest, induced apoptosis, and inhibited proliferation and colony formation in MCF7-TR cells. Furthermore, transcriptome sequencing analysis revealed 1,065 differentially expressed genes between propofol-treated MCF7-TR and untreated MCF7-TR cells. Gene Ontology annotation enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and Gene Set Enrichment Analysis indicated that propofol affected the expression levels of genes located on the 'plasma membrane' and 'cell periphery', while mainly regulating signals involved in cancer biology, immune response and metabolic pathways. These results identified the potential effects of propofol on TR breast cancer cells and provided a theoretical basis for clinical treatment, particularly for individuals with TAM resistance.
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Affiliation(s)
- Runyang Yin
- Department of Anesthesiology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010050, P.R. China
| | - Jing Gao
- First Clinical Medical College, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010050, P.R. China
| | - Yang Liu
- Department of Clinical Laboratory, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010050, P.R. China
| | - Chunyan Guo
- Department of Anesthesiology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010050, P.R. China
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10
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Boima V, Agyekum AB, Ganatra K, Agyekum F, Kwakyi E, Inusah J, Ametefe EN, Adu D. Advances in kidney disease: pathogenesis and therapeutic targets. Front Med (Lausanne) 2025; 12:1526090. [PMID: 40027896 PMCID: PMC11868101 DOI: 10.3389/fmed.2025.1526090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
Chronic kidney disease (CKD) is a global public health issue characterized by progressive loss of kidney function, of which end-stage kidney disease (ESKD) is the last stage. The global increase in the prevalence of CKD is linked to the increasing prevalence of traditional risk factors, including obesity, hypertension, and diabetes mellitus, as well as metabolic factors, particularly insulin resistance, dyslipidemia, and hyperuricemia. Mortality and comorbidities, such as cardiovascular complications, rise steadily as kidney function deteriorates. Patients who progress to ESKD require long-term kidney replacement therapy, such as transplantation or hemodialysis/peritoneal dialysis. It is currently understood that a crucial aspect of CKD involves persistent, low-grade inflammation. In addition, increased oxidative and metabolic stress, endothelial dysfunction, vascular calcification from poor calcium and phosphate metabolism, and difficulties with coagulation are some of the complex molecular pathways underlying CKD-related and ESKD-related issues. Novel mechanisms, such as microbiome dysbiosis and apolipoprotein L1 gene mutation, have improved our understanding of kidney disease mechanisms. High kidney disease risk of Africa has been linked to APOL1 high-risk alleles. The 3-fold increased risk of ESKD in African Americans compared to European Americans is currently mainly attributed to variants in the APOL1 gene in the chromosome 22q12 locus. Additionally, the role of new therapies such as SGLT2 inhibitors, mineralocorticoid receptor antagonists, and APOL1 channel function inhibitors offers new therapeutic targets in slowing down the progression of chronic kidney disease. This review describes recent molecular mechanisms underlying CKD and emerging therapeutic targets.
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Affiliation(s)
- Vincent Boima
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Alex Baafi Agyekum
- National Cardio-Thoracic Center, KorleBu Teaching Hospital, Accra, Ghana
| | - Khushali Ganatra
- Department of Medicine and Therapeutics, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Francis Agyekum
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Edward Kwakyi
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Jalil Inusah
- Department of Medicine and Therapeutics, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Elmer Nayra Ametefe
- Department of Biochemistry, Cell and Molecular Biology, School of Biological Sciences, College of Basic and Applied Science, University of Ghana, Accra, Ghana
| | - Dwomoa Adu
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
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11
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Kurre D, Dang PX, Le LTM, Gadkari VV, Alam A. Structural insights into binding-site access and ligand recognition by human ABCB1. EMBO J 2025; 44:991-1006. [PMID: 39806099 PMCID: PMC11833089 DOI: 10.1038/s44318-025-00361-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 01/16/2025] Open
Abstract
ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates remains poorly understood. Here we present cryo-EM structures of lipid-embedded human ABCB1 in conformationally distinct apo-, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4-3.9 Å resolution, in the absence of stabilizing antibodies or mutations. The substrate-binding site is located within one half of the molecule and, in the apo state, is obstructed by the transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major TM rearrangements and their ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Furthermore, our data identify secondary structure-breaking residues that impart localized TM flexibility and asymmetry between the two transmembrane domains. The resulting structural changes and lipid interactions that are induced by substrate and inhibitor binding can predict substrate-binding profiles and may direct ABCB1 inhibitor design.
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Affiliation(s)
- Devanshu Kurre
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
| | - Phuoc X Dang
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
- Department of Pharmacy-Inpatient, Mayo Clinic, Rochester, MN, 55901, USA
| | - Le T M Le
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55901, USA
| | - Varun V Gadkari
- Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Amer Alam
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
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12
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El-Ghiaty MA, Alqahtani MA, El-Mahrouk SR, Isse FA, Alammari AH, El-Kadi AOS. Alteration of Hepatic Cytochrome P450 Expression and Arachidonic Acid Metabolism by Arsenic Trioxide (ATO) in C57BL/6 Mice. Biol Trace Elem Res 2025; 203:1000-1015. [PMID: 38758479 DOI: 10.1007/s12011-024-04225-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 05/05/2024] [Indexed: 05/18/2024]
Abstract
The success of arsenic trioxide (ATO) in acute promyelocytic leukemia has driven a plethora studies to investigate its efficacy in other malignancies. However, the inherent toxicity of ATO limits the expansion of its clinical applications. Such toxicity may be linked to ATO-induced metabolic derangements of endogenous substrates. Therefore, the primary objective of this study was to investigate the effect of ATO on the hepatic formation of arachidonic acid (AA) metabolites, hydroxyeicosatetraenoic acids (HETEs), as well as their most notable producing machinery, cytochrome P450 (CYP) enzymes. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO for 6 and 24 h. Total RNA was extracted from harvested liver tissues for qPCR analysis of target genes. Hepatic microsomal proteins underwent incubation with AA, followed by identification/quantification of the produced HETEs. ATO downregulated Cyp2e1, while induced Cyp2j9 and most of Cyp4a and Cyp4f, and this has resulted in a significant increase in 17(S)-HETE and 18(R)-HETE, while significantly decreased 18(S)-HETE. Additionally, ATO induced Cyp4a10, Cyp4a14, Cyp4f13, Cyp4f16, and Cyp4f18, resulting in a significant elevation in 20-HETE formation. In conclusion, ATO altered hepatic AA metabolites formation through modulating the underlying network of CYP enzymes. Modifying the homeostatic production of bioactive AA metabolites, such as HETEs, may entail toxic events that can, at least partly, explain ATO-induced hepatotoxicity. Such modification can also compromise the overall body tolerability to ATO treatment in cancer patients.
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Affiliation(s)
- Mahmoud A El-Ghiaty
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Mohammed A Alqahtani
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Sara R El-Mahrouk
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Fadumo A Isse
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Ahmad H Alammari
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada
| | - Ayman O S El-Kadi
- Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, Canada.
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13
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Wada Y, Inoko M, Ishihara K, Fukumoto K, Tsurudome Y, Horiguchi M, Fujimura A, Ushijima K. Aging Reduces ATP-Binding Cassette Transporter Expression in Brain Microvessels of Mice. Pharmaceuticals (Basel) 2025; 18:191. [PMID: 40006002 PMCID: PMC11859312 DOI: 10.3390/ph18020191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
Background: ATP-binding cassette (ABC) transporters are expressed in the vascular walls of brain capillaries and remove toxic chemicals from the brain. The expression of ABC transporters in peripheral organs is transcriptionally regulated by clock genes and exhibits 24 h periodic fluctuations. In addition, clock gene outputs diminish with aging. In this study, we evaluated whether the expression of ABC transporters in the blood-brain barrier (BBB) of young mice had a 24 h cycle, and whether the expression of ABC transporters in the BBB decreased with age. Methods: Brain microvascular (BMV) fractions from the cerebral cortex of male C57BL/6J mice were prepared using dextran. BMV fractions from young mice (12 weeks old) were prepared every four hours to evaluate 24 h rhythmicity. BMV fractions from both young and aged mice (85 weeks old) were prepared when protein expression peaked (Zeitgeber Time 5). Protein and mRNA expression of ABC transporters in BMV fractions were measured. Results: In young mice, protein expression of P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein 4 showed time-dependent variations with a peak in the light phase (Zeitgeber Time 5); mRNA expression showed no time-dependent variation. The protein expression of these transporters was lower in the BBB of aged mice than in that of young mice, although mRNA expression did not differ between young and aged mice. Conclusions: ABC transporter protein expression levels in BMV endothelial cells decreased with aging; however, mRNA levels did not change, which suggests changes in protein expression did not result from diminished clock gene output. Further studies are needed to elucidate the mechanisms by which ABC transporter expression in the BBB decreases with aging.
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Affiliation(s)
- Yukiyo Wada
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan (Y.T.); (M.H.)
| | - Masaki Inoko
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan (Y.T.); (M.H.)
| | - Kanako Ishihara
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan (Y.T.); (M.H.)
| | - Karin Fukumoto
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan (Y.T.); (M.H.)
| | - Yuya Tsurudome
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan (Y.T.); (M.H.)
| | - Michiko Horiguchi
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan (Y.T.); (M.H.)
- Department of Pharmaceutical Engineering, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan
| | - Akio Fujimura
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan (Y.T.); (M.H.)
- Division of Clinical Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan
| | - Kentaro Ushijima
- Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan (Y.T.); (M.H.)
- Division of Clinical Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan
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14
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Macêdo AKS, da Silva JRP, Brighenti LS, de Azambuja Ribeiro RI, Dos Santos HB, Thomé RG. Variations in liver histology and P-gp expression among fish species in Doce River Basin, Brazil: implications for pollution sensitivity. J Mol Histol 2024; 56:47. [PMID: 39695022 DOI: 10.1007/s10735-024-10334-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 12/08/2024] [Indexed: 12/20/2024]
Abstract
Fish may have different sensitivity to pollutants present in the water. We analyzed the liver histology, and P-gp expression in six species of fish from the Doce River basin. Fish were caught at six different points in the Doce River, and liver samples were taken for histological analysis. P-gp expression was analyzed using an immunohistochemical technique. In Astyanax lacustris, Hoplias intermedius, Hypostomus affinis, Trachelyopterus striatulus and Oligosarcus acutirostris, a double arrangement of hepatocyte plates was generally observed (tubular-form), while in Deutorodon taeniatus, a single arrangement of hepatocyte plates was frequently observed (cord-like). Histological changes, such as cytoplasmic vacuolation and nuclear alteration, were observed in the livers of all species analyzed, however, the species A. lacustris (34.1%) and H. affinis (33.3%) were those with the fewest individuals with histological changes. The H. intermedius, T. striatulus, and O. acutirostris were the species that presented more than 80% of their individuals with histological changes. The A. lacustris and H. affinis were the species that showed the highest P-pg immunolabeling in the liver, while the T. striatulus and O. acutirostris had the lowest levels. These results support the hypothesis that levels of P-gp expression could respond to the resistance or sensitivity of each species to environmental pollutants.
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Affiliation(s)
- Anderson Kelvin Saraiva Macêdo
- Laboratório de Processamento de Tecidos - LAPROTEC, Universidade Federal de São João Del-Rei, Campus Centro Oeste, Rua Sebastião Gonçalves Coelho, 400, Divinópolis, Minas Gerais, 35501-296, Brazil
| | - Jicaury Roberta Pereira da Silva
- Laboratório de Processamento de Tecidos - LAPROTEC, Universidade Federal de São João Del-Rei, Campus Centro Oeste, Rua Sebastião Gonçalves Coelho, 400, Divinópolis, Minas Gerais, 35501-296, Brazil
| | - Ludmila Silva Brighenti
- Universidade do Estado de Minas Gerais, Campus Divinópolis, Avenida Paraná, 3001, Divinópolis, Minas Gerais, 35501- 170, Brazil
| | - Rosy Iara de Azambuja Ribeiro
- Laboratório de Patologia Experimental - LAPATEX, Universidade Federal de São João Del-Rei, Campus Centro Oeste, Rua Sebastião Gonçalves Coelho, 400, Divinópolis, Minas Gerais, 35501-296, Brazil
| | - Hélio Batista Dos Santos
- Laboratório de Processamento de Tecidos - LAPROTEC, Universidade Federal de São João Del-Rei, Campus Centro Oeste, Rua Sebastião Gonçalves Coelho, 400, Divinópolis, Minas Gerais, 35501-296, Brazil
| | - Ralph Gruppi Thomé
- Laboratório de Processamento de Tecidos - LAPROTEC, Universidade Federal de São João Del-Rei, Campus Centro Oeste, Rua Sebastião Gonçalves Coelho, 400, Divinópolis, Minas Gerais, 35501-296, Brazil.
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15
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Zhang Z, Zhong C, Guo M, Yin Y, Ye H, Lu X, Liu Z, Yu G. Cryo-EM structures of ABCC1 revealing new conformational dynamics in the resting state. Biochem Biophys Res Commun 2024; 738:150953. [PMID: 39515093 DOI: 10.1016/j.bbrc.2024.150953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 11/03/2024] [Indexed: 11/16/2024]
Abstract
ABCC1/MRP1 in the C branch of Adenosine triphosphate binding cassette (ABC) transporters superfamily, is directly linked to multiple drug resistance in chemotherapy. Here, to further understand the conformational dynamics of ABCC1, we performed single-particle cryo-electron microscopy analysis of purified bovine ABCC1. Two conformational states were found coexisted with nearly equal population. While one state has a wider substrate transporting pathway, akin to the previously reported apo structure, the other is narrower, despite the empty substrate pocket. In addition, multiple lipid-binding interfaces were identified based on the presence of rod-shaped, unmodeled, non-protein densities in the resolved density maps, potentially contributing to the stabilization of TMD0 domain and activity regulation of ABCC1. Further, we found that three asparagine residues in bovine ABCC1 are glycosylated. Together, our study provides fresh insights into the structural features and conformational dynamics of bovine ABCC1, offering a new framework for understanding the function and regulatory mechanisms of ABCC1.
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Affiliation(s)
- Zhengtian Zhang
- College of Life Sciences, Nanyang Normal University, Nanyang, China
| | - Chunhui Zhong
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Menghui Guo
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yongyou Yin
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Heng Ye
- Shenzhen Focalon Applied Academy, Shenzhen Practical Scientific Research Co., Ltd., Shenzhen, China
| | - Xiting Lu
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Zheng Liu
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
| | - Guimei Yu
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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16
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Murcia HW, Diaz G, Acosta RD. In silico approximation to aflatoxin B 1 metabolism and sensitivity in commercial poultry species based on empirical mathematical equations. Toxicol Rep 2024; 13:101752. [PMID: 39421230 PMCID: PMC11483326 DOI: 10.1016/j.toxrep.2024.101752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Enzyme kinetic parameters for aflatoxin B1 metabolism have been reported for chicken, quail, turkey and duck, but an integrated in silico model has not been proposed. Both enzyme-catalyzed reactions and spontaneous reactions were modeled in the CellDesigner software and results were adjusted to Hill, Rational and Hoerl models. Results revealed that the higher amount of aflatoxin B1 epoxide produced in a short lapse of time and a low production of epoxide conjugated to glutathione explains the severe genotoxic effect of aflatoxin B1 in duck. Also, the higher amount of aflatoxicol produced is time-associated to aflatoxin B1 resistance in chicken. Finally, the cytotoxic effects in quail and duck are caused by a large aflatoxin B1 dialdehyde production in a short period of time.
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Affiliation(s)
- Hansen W. Murcia
- Departamento de Biología, Facultad de Ciencias, Universidad Antonio Nariño, Carrera 3 este 47A – 15, Bogotá D.C., Colombia
| | - Gonzalo Diaz
- Laboratorio de Toxicología y Nutrición Aviar. Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional de Colombia, Bogotá D.C., Colombia
| | - Rubén Darío Acosta
- Departamento de Sistemas Computacionales e Ingeniería Industrial, Facultad de Ingeniería, Universidad Nacional de Colombia, Bogotá D.C., Colombia
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17
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Johnston CU, Kennedy CJ. Potency and mechanism of p-glycoprotein chemosensitizers in rainbow trout (Oncorhynchus mykiss) hepatocytes. FISH PHYSIOLOGY AND BIOCHEMISTRY 2024; 50:2149-2164. [PMID: 39026113 DOI: 10.1007/s10695-024-01376-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 07/02/2024] [Indexed: 07/20/2024]
Abstract
The membrane efflux transporter P-glycoprotein (P-gp, [ABCB1, MDR1]) exports a wide range of xenobiotic compounds, resulting in a continuous first line of defense against toxicant accumulation at basal expression levels, and contributing to the multixenobiotic resistance (MXR) phenotype at elevated expression levels. Relatively little information exists on P-gp inhibition in fish by chemosensitizers, compounds which lower toxicity thresholds for harmful P-gp substrates in complex mixtures. The effects of four known mammalian chemosensitizers (cyclosporin A [CsA], quinidine, valspodar [PSC833], and verapamil) on the P-gp-mediated transport of rhodamine 123 (R123) and cortisol in primary cultures of rainbow trout (Oncorhynchus mykiss) hepatocytes were examined. Competitive accumulation assays using 25 µM R123 or cortisol and varying concentrations of chemosensitizers (0-500 µM) were used. CsA, quinidine, and verapamil inhibited R123 export (IC50 values ± SE: 132 ± 60, 83.3 ± 27.2, and 43.2 ± 13.6 µM, respectively). CsA and valspodar inhibited cortisol export (IC50 values: 294 ± 106 and 92.2 ± 34.9 µM, respectively). In an ATP depletion assay, hepatocytes incubated with all four chemosensitizers resulted in lower free ATP concentrations, suggesting that they act via competitive inhibition. Chemosensitizers that inhibit MXR transporters are an important class of environmental pollutant, and these results show that rainbow trout transporters are inhibited by similar chemosensitizers (and mostly at similar concentrations) as seen in mammals and other fish species.
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Affiliation(s)
- Christina U Johnston
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive Burnaby, British Columbia, Canada
| | - Christopher J Kennedy
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive Burnaby, British Columbia, Canada.
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18
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Chen J, Wang D, Liu W, Zhou Y, Yang Q. Potential pesticide substrates of an insect ABCC transporter. INSECT SCIENCE 2024. [PMID: 39614641 DOI: 10.1111/1744-7917.13476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/30/2024] [Accepted: 10/10/2024] [Indexed: 12/01/2024]
Abstract
The use of synthetic pesticides carries a significant risk of pests developing resistance, leading to decreased pesticide effectiveness. ATP-binding cassette (ABC) transporters, especially the ABCC subfamily members, have been suggested to act as efflux pumps for various pesticides, thereby contributing to pesticide resistance. So far, the identification of potential pesticide substrates of insect ABC transporters is most often based on the quantification of transcript in arthropods. Here, we screened and identified the potential pesticide substrates of ABCC-9C from Tribolium castaneum based on an in vitro ATPase activity assay. Together with affinity evaluation-, cytotoxicity analysis-, and RNA interference-based bioactivity tests, we revealed that the insecticides, carbofuran, and buprofezin, are potential substrates of TcABCC-9C. Additionally, we identified an amphipathic translocation channel in the transmembrane domain of TcABCC-9C formed by 8 transmembrane helices. Molecular docking suggested that both carbofuran and buprofezin bind at the same site within the translocation channel via hydrophobic interactions. These findings indicate that TcABCC-9C might play a critical role in multi-pesticide resistance, providing a potential target for managing pesticide resistance and laying the groundwork for future pest control strategies. Given the conservations among ABCC subfamily members, the experimental model we developed in this study can be also applied to identify the potential substrates of other ABCC transporters, as well as to predict insecticide resistance mediated by ABCC transporters.
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Affiliation(s)
- Jinli Chen
- School of Bioengineering, Dalian University of Technology, Dalian, China
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Dong Wang
- School of Bioengineering, Dalian University of Technology, Dalian, China
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Wei Liu
- School of Bioengineering, Dalian University of Technology, Dalian, China
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yuanyuan Zhou
- School of Bioengineering, Dalian University of Technology, Dalian, China
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Qing Yang
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
- State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China
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19
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Pashaei-Asl R, Motaali S, Ebrahimie E, Mohammadi-Dehcheshmeh M, Ebrahimi M, Pashaiasl M. Delivery of doxorubicin by Fe 3O 4 nanoparticles, reduces multidrug resistance gene expression in ovarian cancer cells. Pathol Res Pract 2024; 263:155667. [PMID: 39471527 DOI: 10.1016/j.prp.2024.155667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/14/2024] [Accepted: 10/17/2024] [Indexed: 11/01/2024]
Abstract
BACKGROUND Ovarian cancer is one of the most common malignancy in women with significant mortality rate due to the resistance to chemotherapy drugs. Doxorubicin (DOX) is a chemotropic agent in ovarian cancer treatment. Overexpression of multidrug resistance (MDR) genes, such as ABCB1, in cancer cells after chemotherapy is one of main problems in clinical applications. Here we have compared the efficiency of doxorubicin-loaded (NIPAAM-DMAEMA) Fe3O4 nanocomposite (DOX-NANO) against DOX on ABCB1(MDR1) gene expression in the ovarian cancer cell line. MATERIALS AND METHODS The cell viability of SKOV-3 cells were evaluated by MTT assay. Real Time PCR was used to measure the expression level of MDR1. MTT data were normalized in 10 different attribute weighting models, also to reveal the interaction between DOX, ABCB1, and ovarian cancer genes, Pathway Studio Database (Elsevier) was used. RESULTS Cell viability of SKOV-3cells was significantly decreased after 24, 48 and 72 hours (P < 0.0001) of either DOX with IC50 22.38, 0.61 and 0.072 µg/ml or DOX-NANO treatment with IC50 11.54, 1.01, 0.0126 µg/ ml respectively. TREATMENT Notable decrease in the expression of MDR gene, ABCB1, was observed 48 hours after treatment with DOX-NANO (P < 0.0001) with 26 % in the assessed with control group. Meta-analysis showed the concentration of 10 μg/ml variables was the second most significant feature, whereas the concentration of 0.01 μg/ml recognized the lowest weights. Also, LGALS3 is an extra cellular receptor with upregulation in ovarian cancer that interacts with ABCB1. CONCLUSION Our findings highlight the beneficial effects of DOX delivery in ovarian cancer cells by nanocomposite as efficient drug delivery method. DOX-NANO is a promising therapeutic reagent to overcome chemotherapy resistance in ovarian cancer.
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Affiliation(s)
- Roghiyeh Pashaei-Asl
- Interdisciplinary Research Development Center, Iran University of Medical Sciences, Tehran, Iran; Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Soheila Motaali
- Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Medical University of Tabriz, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Esmaeil Ebrahimie
- Genomics Research Platform, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC, Australia; School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Manijeh Mohammadi-Dehcheshmeh
- Genomics Research Platform, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC, Australia; School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Mansour Ebrahimi
- School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, SA, Australia; School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC, Australia
| | - Maryam Pashaiasl
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Anatomical Sciences, School of Medicine, Tabriz University of Medical Sciences, Iran.
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20
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Collier GE, Lavado R. An in-depth examination of Per- and Polyfluoroalkyl (PFAS) effects on transporters, with emphasis on the ABC superfamily: A critical review. Toxicology 2024; 508:153901. [PMID: 39094918 DOI: 10.1016/j.tox.2024.153901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/27/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
Per- and polyfluoroalkyl (PFAS) substances are a type of chemical compound unique for their multiple carbon-fluorine bonds, imbuing them with strength and environmental permanence. While legacy substances have been phased out due to human health risks, short-chain and alternative PFAS remain omnipresent. However, a detailed explanation for the pathways through which PFAS interact on a cellular and molecular level is still largely unknown, and the human health effects remain mechanistically unexplained. Of particular interest when focusing on this topic are the interactions between these exogenous chemicals and plasma and membrane proteins. Such proteins include serum albumin which can transport PFAS throughout the body, solute carrier proteins (SLC) and ATP binding cassette (ABC) transporters which are able to move PFAS into and out of cells, and proteins and nuclear receptors which interact with PFAS intracellularly. ABC transporters as a family have little available human data despite being responsible for the export of endogenous substances and drugs throughout the body. The multifactorial regulation of these crucial transporters is affected directly and indirectly by PFAS. Changes, which can include alterations to membrane transport activity and differences in protein expression, vary greatly depending on the specific PFAS and protein of interest. Together, the myriad of changes caused by understudied PFAS exposure to a class of understudied proteins crucial to cellular function and drug treatments has not been fully explored regarding human health and presents room for further exploration. This critical work aims to provide a novel framework of existing human data on PFAS and ABC transporters, allowing for future advancement and investigation into human transporter activity, mechanisms of regulation, and interactions with emerging contaminants.
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Affiliation(s)
- Gracen E Collier
- Department of Environmental Science, Baylor University, Waco, TX 76798, United States
| | - Ramon Lavado
- Department of Environmental Science, Baylor University, Waco, TX 76798, United States.
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21
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Chen A, Tian M, Luo Z, Cao X, Gu Y. Analysis of the evolution of placental oxidative stress research from a bibliometric perspective. Front Pharmacol 2024; 15:1475244. [PMID: 39484166 PMCID: PMC11524950 DOI: 10.3389/fphar.2024.1475244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 10/07/2024] [Indexed: 11/03/2024] Open
Abstract
Background Research on placental oxidative stress is pivotal for comprehending pregnancy-related physiological changes and disease mechanisms. Despite recent advancements, a comprehensive review of current status, hotspots, and trends remains challenging. This bibliometric study systematically analyzes the evolution of placental oxidative stress research, offering a reference for future studies. Objective To conduct a comprehensive bibliometric analysis of the literature on placental oxidative stress to identify research hotspots, trends, and key contributors, thereby providing guidance for future research. Methods Relevant data were retrieved from the Web of Science Core Collection database and analyzed using VOSviewer, CiteSpace, and the bibliometrix package. An in-depth analysis of 4,796 publications was conducted, focusing on publication year, country/region, institution, author, journal, references, and keywords. Data collection concluded on 29 April 2024. Results A total of 4,796 papers were retrieved from 1,173 journals, authored by 18,835 researchers from 4,257 institutions across 103 countries/regions. From 1991 to 2023, annual publications on placental oxidative stress increased from 7 to 359. The United States (1,222 publications, 64,158 citations), the University of Cambridge (125 publications, 13,562 citations), and Graham J. Burton (73 publications, 11,182 citations) were the most productive country, institution, and author, respectively. The journal Placenta had the highest number of publications (329) and citations (17,152), followed by the International Journal of Molecular Sciences (122 publications). The most frequent keywords were "oxidative stress," "expression," "pregnancy," "preeclampsia," and "lipid peroxidation." Emerging high-frequency keywords included "gestational diabetes mellitus," "health," "autophagy," "pathophysiology," "infection," "preterm birth," "stem cell," and "inflammation." Conclusion Over the past 3 decades, research has concentrated on oxidative stress processes, antioxidant mechanisms, pregnancy-related diseases, and gene expression regulation. Current research frontiers involve exploring pathophysiology and mechanisms, assessing emerging risk factors and environmental impacts, advancing cell biology and stem cell research, and understanding the complex interactions of inflammation and immune regulation. These studies elucidate the mechanisms of placental oxidative stress, offering essential scientific evidence for future intervention strategies, therapeutic approaches, and public health policies.
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Affiliation(s)
| | | | | | - Xiaohui Cao
- Department of Obstetrics and Gynecology, Women’s Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, China
| | - Yanfang Gu
- Department of Obstetrics and Gynecology, Women’s Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, China
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22
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Marin JJG, Cives-Losada C, Macias RIR, Romero MR, Marijuan RP, Hortelano-Hernandez N, Delgado-Calvo K, Villar C, Gonzalez-Santiago JM, Monte MJ, Asensio M. Impact of liver diseases and pharmacological interactions on the transportome involved in hepatic drug disposition. Biochem Pharmacol 2024; 228:116166. [PMID: 38527556 DOI: 10.1016/j.bcp.2024.116166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/14/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024]
Abstract
The liver plays a pivotal role in drug disposition owing to the expression of transporters accounting for the uptake at the sinusoidal membrane and the efflux across the basolateral and canalicular membranes of hepatocytes of many different compounds. Moreover, intracellular mechanisms of phases I and II biotransformation generate, in general, inactive compounds that are more polar and easier to eliminate into bile or refluxed back toward the blood for their elimination by the kidneys, which becomes crucial when the biliary route is hampered. The set of transporters expressed at a given time, i.e., the so-called transportome, is encoded by genes belonging to two gene superfamilies named Solute Carriers (SLC) and ATP-Binding Cassette (ABC), which account mainly, but not exclusively, for the uptake and efflux of endogenous substances and xenobiotics, which include many different drugs. Besides the existence of genetic variants, which determines a marked interindividual heterogeneity regarding liver drug disposition among patients, prevalent diseases, such as cirrhosis, non-alcoholic steatohepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, viral hepatitis, hepatocellular carcinoma, cholangiocarcinoma, and several cholestatic liver diseases, can alter the transportome and hence affect the pharmacokinetics of drugs used to treat these patients. Moreover, hepatic drug transporters are involved in many drug-drug interactions (DDI) that challenge the safety of using a combination of agents handled by these proteins. Updated information on these questions has been organized in this article by superfamilies and families of members of the transportome involved in hepatic drug disposition.
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Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
| | - Candela Cives-Losada
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Rebeca P Marijuan
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | | | - Kevin Delgado-Calvo
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Carmen Villar
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Department of Gastroenterology and Hepatology, University Hospital of Salamanca, Salamanca, Spain
| | - Jesus M Gonzalez-Santiago
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Department of Gastroenterology and Hepatology, University Hospital of Salamanca, Salamanca, Spain
| | - Maria J Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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23
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Johnston CU, Azevedo VC, Kennedy CJ. Ivermectin toxicokinetics in rainbow trout (Oncorhynchus mykiss) following P-glycoprotein inhibition. Vet Res Commun 2024; 48:3139-3155. [PMID: 39106005 DOI: 10.1007/s11259-024-10480-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 07/22/2024] [Indexed: 08/07/2024]
Abstract
Changes to ivermectin (IVM [22,23-dihydro avermectin B1a + 22,23-dihydro avermectin B1b]) toxicokinetics (TK) with and without P-glycoprotein (P-gp) inhibition by cyclosporin A (CsA) were examined in rainbow trout (Oncorhynchus mykiss). Rainbow trout were injected with 175 μg/kg 3H-IVM (8.6 μCi/mg IVM) with or without co-administration of 480 μg/kg CsA into the caudal vasculature. Fish were sacrificed at various time points (0.25, 0.5, 1, 3, 24, 48, 96, and 168 h) for organ and tissue sampling (blood, liver, kidney, gill, intestines, brain [5 regions], eye, gonad, and fat) which were analyzed for IVM-derived radioactivity. The IVM concentration decreased over time in blood, liver, kidney, and gill, while concentrations in other tissues remained constant. The highest maximum IVM concentration (Cmax) was found in kidney, followed by liver; the lowest Cmax was found in eye, followed by brain and adipose tissue. The highest % of the administered dose was found in the blood 15 min post-IVM administration, followed by the intestine at 60 min post-IVM administration. P-gp inhibition by CsA did not significantly affect calculated TK parameters (AUC [7.33 ± 0.73 - 11.5 ± 2.5 mg•h/kg], mean residence time [84.7 ± 21 - 125 ± 55 h], T1/2 [58.7 ± 15 - 86.8 ± 38 h], clearance rate [0.0152 ± 0.0033 - 0.0239 ± 0.0024 L/kg•h], or volume of distribution [1.91 ± 0.47 - 2.02 ± 0.33 L/kg]), but resulted in small but significant changes in the % administered dose found in blood and medulla. These results suggest that P-gp plays a limited role in overall IVM TK, and that its role in xenobiotic protection may be much less robust in fish than it is in mammals.
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Affiliation(s)
- Christina U Johnston
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada
| | - Vinicius Cavicchioli Azevedo
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada
| | - Christopher J Kennedy
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada.
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24
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Parida KK, Lahiri M, Ghosh M, Dalal A, Kalia NP. P-glycoprotein inhibitors as an adjunct therapy for TB. Drug Discov Today 2024; 29:104108. [PMID: 39032811 DOI: 10.1016/j.drudis.2024.104108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/08/2024] [Accepted: 07/15/2024] [Indexed: 07/23/2024]
Abstract
The primary challenge in TB treatment is the emergence of multidrug-resistant TB (MDR-TB). One of the major factors responsible for MDR is the upregulation of efflux pumps. Permeation-glycoprotein (P-gp), an efflux pump, hinders the bioavailability of the administered drugs inside the infected cells. Simultaneously, angiogenesis, the formation of new blood vessels, contributes to drug delivery complexities. TB infection triggers a cascade of events that upregulates the expression of angiogenic factors and P-gp. The combined action of P-gp and angiogenesis foster the emergence of MDR-TB. Understanding these mechanisms is pivotal for developing targeted interventions to overcome MDR in TB. P-gp inhibitors, such as verapamil, and anti-angiogenic drugs, including bevacizumab, have shown improvement in TB drug delivery to granuloma. In this review, we discuss the potential of P-gp inhibitors as an adjunct therapy to shorten TB treatment.
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Affiliation(s)
- Kishan Kumar Parida
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Monali Lahiri
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Mainak Ghosh
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Aman Dalal
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Nitin Pal Kalia
- Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India.
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25
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Güleç Taşkıran AE, Hüsnügil HH, Soltani ZE, Oral G, Menemenli NS, Hampel C, Huebner K, Erlenbach-Wuensch K, Sheraj I, Schneider-Stock R, Akyol A, Liv N, Banerjee S. Post-Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient-Limited Cancer Cells. Traffic 2024; 25:e12956. [PMID: 39313937 DOI: 10.1111/tra.12956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 07/17/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024]
Abstract
Limited nutrient availability in the tumor microenvironment can cause the rewiring of signaling and metabolic networks to confer cancer cells with survival advantages. We show here that the limitation of glucose, glutamine and serum from the culture medium resulted in the survival of a population of cancer cells with high viability and capacity to form tumors in vivo. These cells also displayed a remarkable increase in the abundance and size of lysosomes. Moreover, lysosomes were located mainly in the perinuclear region in nutrient-limited cells; this translocation was mediated by a rapid post-transcriptional increase in the key endolysosomal trafficking protein Rab7a. The acidic lysosomes in nutrient-limited cells could trap weakly basic drugs such as doxorubicin, mediating resistance of the cells to the drug, which could be partially reversed with the lysosomal inhibitor bafilomycin A1. An in vivo chorioallantoic membrane (CAM) assay indicated a remarkable decrease in microtumor volume when nutrient-limited cells were treated with 5-Fluorouracil (5-FU) and bafilomycin A1 compared to cells treated with either agent alone. Overall, our data indicate the activation of complementary pathways with nutrient limitation that can enable cancer cells to survive, proliferate and acquire drug resistance.
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Affiliation(s)
- Aliye Ezgi Güleç Taşkıran
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkiye
- Department of Molecular Biology and Genetics, Başkent University, Ankara, Turkiye
| | - Hepşen H Hüsnügil
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkiye
| | - Zahra E Soltani
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Göksu Oral
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkiye
| | - Nazlı S Menemenli
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkiye
| | - Chuanpit Hampel
- Experimental Tumor Pathology, Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Kerstin Huebner
- Experimental Tumor Pathology, Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Katharina Erlenbach-Wuensch
- Experimental Tumor Pathology, Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Ilir Sheraj
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkiye
| | - Regine Schneider-Stock
- Experimental Tumor Pathology, Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Aytekin Akyol
- Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Nalan Liv
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Sreeparna Banerjee
- Department of Biological Sciences, Orta Dogu Teknik Universitesi, Ankara, Turkiye
- Cancer Systems Biology Laboratory (CanSyL), Orta Dogu Teknik Universitesi, Ankara, Turkiye
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26
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Zhang L, Chu Y, You Y, Dong M, Pang X, Chen L, Zhu L, Yang S, Zhou L, Shang K, Deng G, Xiao J, Wang W, Qin C, Tian D. Systematic Druggable Genome-Wide Mendelian Randomization Identifies Therapeutic Targets for Functional Outcome After Ischemic Stroke. J Am Heart Assoc 2024; 13:e034749. [PMID: 39119979 PMCID: PMC11963950 DOI: 10.1161/jaha.124.034749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 07/15/2024] [Indexed: 08/10/2024]
Abstract
BACKGROUND Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke . METHODS AND RESULTS Cis-expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3-6 versus 0-2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome-wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes (ABCC2, ATRAID, BLK, CD93, CHST13, NR1H3, NRBP1, PI3, RIPK4, SEMG1, SLC22A4, SLC22A5, SLCO3A1, TEK, TLR4, and WNT10B) demonstrated the causal associations with ordinal modified Rankin Scale (P<1.892×10-5) or poor functional outcome (modified Rankin Scale 3-6 versus 0-2, P<1.893×10-5). Steiger filtering analysis suggested potential directional stability (P<0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of ABCC2, NRBP1, PI3, and SEMG1 with functional outcome after ischemic stroke. Furthermore, phenome-wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting ABCC2, NRBP1, PI3, and SEMG1, but the robustness of these results was limited by low power. CONCLUSIONS The present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation.
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Affiliation(s)
- Lu‐Yang Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yun‐Hui Chu
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yun‐Fan You
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Ming‐Hao Dong
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiao‐Wei Pang
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Lian Chen
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Li‐Fang Zhu
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Sheng Yang
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Luo‐Qi Zhou
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Ke Shang
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Gang Deng
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jun Xiao
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Wei Wang
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Chuan Qin
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Dai‐Shi Tian
- Department of Neurology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Hubei Key Laboratory of Neural Injury and Functional ReconstructionHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Kurre D, Dang PX, Le LT, Gadkari VV, Alam A. Structural insight into binding site access and ligand recognition by human ABCB1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.12.607598. [PMID: 39185192 PMCID: PMC11343101 DOI: 10.1101/2024.08.12.607598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, its mechanisms of poly-specific substrate recognition and transport remain poorly resolved. Here we present cryo-EM structures of lipid embedded human ABCB1 in its apo, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4-3.9 Å resolution without using stabilizing antibodies or mutations and each revealing a distinct conformation. The substrate binding site is located within one half of the molecule and, in the apo state, is obstructed by transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major differences in TM arrangement and ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Our data offer fundamental new insights into the role structural asymmetry, secondary structure breaks, and lipid interactions play in ABCB1 function and have far-reaching implications for ABCB1 inhibitor design and predicting its substrate binding profiles.
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Affiliation(s)
- Devanshu Kurre
- The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States
| | - Phuoc X. Dang
- The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States
- Current Address: Department of Pharmacy - Inpatient, Mayo Clinic, Rochester, Minnesota 55901, United States
| | - Le T.M. Le
- The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States
- Current Address: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55901, United States
| | - Varun V. Gadkari
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Amer Alam
- The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States
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de Souza TL, da Luz JZ, Roque ADA, Opuskevitch I, Ferreira FCADS, Ribeiro CADO, Neto FF. Exploring the endocrine disrupting potential of a complex mixture of PAHs in the estrogen pathway in Oreochromis niloticus hepatocytes. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2024; 273:107002. [PMID: 38936242 DOI: 10.1016/j.aquatox.2024.107002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/09/2024] [Accepted: 06/12/2024] [Indexed: 06/29/2024]
Abstract
This study aimed to investigate the toxicity and endocrine disrupting potential of a complex mixture of polycyclic aromatic hydrocarbons (PAHs) in the estrogen pathway using hepatocytes of Nile tilapia Oreochromis niloticus, the hepatocytes were exposed to various concentrations of the PAH mixture, and multiple endpoints were evaluated to assess their effects on cell viability, gene expression, oxidative stress markers, and efflux activity. The results revealed that the PAH mixture had limited effects on hepatocyte metabolism and cell adhesion, as indicated by the non-significant changes observed in MTT metabolism, neutral red retention, and crystal violet staining. However, significant alterations were observed in the expression of genes related to the estrogen pathway. Specifically, vitellogenin (vtg) exhibited a substantial increase of approximately 120% compared to the control group. Similarly, estrogen receptor 2 (esr2) showed a significant upregulation of approximately 90%. In contrast, no significant differences were observed in the expression of estrogen receptor 1 (esr1) and the G protein-coupled estrogen receptor 1 (gper1). Furthermore, the PAH mixture elicited complex responses in oxidative stress markers. While reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels remained unchanged, the activity of catalase (Cat) was significantly reduced, whereas superoxide dismutase (Sod) activity, glutathione S-transferase (Gst) activity, and non-protein thiols levels were significantly elevated. In addition, the PAH mixture significantly influenced efflux activity, as evidenced by the increased efflux of rhodamine and calcein, indicating alterations in multixenobiotic resistance (MXR)-associated proteins. Overall, these findings, associated with bioinformatic analysis, highlight the potential of the PAH mixture to modulate the estrogen pathway and induce oxidative stress in O. niloticus hepatocytes. Understanding the mechanisms underlying these effects is crucial for assessing the ecological risks of PAH exposure and developing appropriate strategies to mitigate their adverse impacts on aquatic organisms.
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Affiliation(s)
- Tugstênio Lima de Souza
- Laboratório de Toxicologia Celular, Departamento de Biologia Celular, Universidade Federal do Paraná, CEP 81.531-980, Curitiba, PR, Brazil.
| | - Jessica Zablocki da Luz
- Laboratório de Toxicologia Celular, Departamento de Biologia Celular, Universidade Federal do Paraná, CEP 81.531-980, Curitiba, PR, Brazil
| | - Aliciane de Almeida Roque
- Laboratório de Toxicologia Celular, Departamento de Biologia Celular, Universidade Federal do Paraná, CEP 81.531-980, Curitiba, PR, Brazil
| | - Iracema Opuskevitch
- Copel GeT-SOS/DNGT - Rua José Izidoro Biazetto, no. 18, Bloco A, CEP 81200-240, Curitiba, PR, Brazil
| | | | - Ciro Alberto de Oliveira Ribeiro
- Laboratório de Toxicologia Celular, Departamento de Biologia Celular, Universidade Federal do Paraná, CEP 81.531-980, Curitiba, PR, Brazil
| | - Francisco Filipak Neto
- Laboratório de Toxicologia Celular, Departamento de Biologia Celular, Universidade Federal do Paraná, CEP 81.531-980, Curitiba, PR, Brazil.
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Julson JR, Quinn CH, Nazam N, Bownes LV, Stewart JE, Beierle EA. PIM Kinase Inhibition Sensitizes Neuroblastoma to Doxorubicin. J Pediatr Surg 2024; 59:1334-1341. [PMID: 38570263 PMCID: PMC11164644 DOI: 10.1016/j.jpedsurg.2024.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 03/01/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND Chemoresistance contributes to relapse in high-risk neuroblastoma. Cancer cells acquire resistance through multiple mechanisms, including drug efflux pumps. In neuroblastoma, multidrug resistance-associated protein-1 (MRP1/ABCC1) efflux pump expression correlates with worse outcomes. These pumps are regulated by PIM kinases, a family of serine-threonine kinases, overexpressed in neuroblastoma. We hypothesized PIM kinase inhibition would sensitize neuroblastoma cells by modulating MRP1. METHODS Kocak database query evaluated ABCC1, PIM1, PIM2, and PIM3 expression in neuroblastoma patients. SK-N-AS and SK-N-BE(2) cells were treated with doxorubicin or the pan-PIM kinase inhibitor, AZD1208. Flow cytometry assessed intracellular doxorubicin accumulation. AlamarBlue assay measured viability. The lethal dose 50% (LD50) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. RESULTS Kocak database query demonstrated positive correlation between PIM genes and ABCC1. PIM kinase inhibition increased intracellular doxorubicin accumulation in both cell lines, suggesting PIM kinase regulation of MRP1. Isobolograms showed synergy between AZD1208 and doxorubicin. CONCLUSIONS The correlation between PIM and ABCC1 gene expression suggests PIM kinases may contribute to neuroblastoma chemotherapeutic resistance. PIM kinase inhibition increased intracellular doxorubicin accumulation. Combination treatment with AZD1208 and doxorubicin decreased neuroblastoma cell viability in a synergistic fashion. These findings support further investigations of PIM kinase inhibition in neuroblastoma. TYPE OF STUDY Basic Science Research. LEVEL OF EVIDENCE NA.
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Affiliation(s)
- Janet R Julson
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Colin H Quinn
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Nazia Nazam
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Laura V Bownes
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Jerry E Stewart
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Elizabeth A Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
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Thévenod F, Lee WK. Cadmium transport by mammalian ATP-binding cassette transporters. Biometals 2024; 37:697-719. [PMID: 38319451 PMCID: PMC11101381 DOI: 10.1007/s10534-024-00582-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024]
Abstract
Cellular responses to toxic metals depend on metal accessibility to intracellular targets, reaching interaction sites, and the intracellular metal concentration, which is mainly determined by uptake pathways, binding/sequestration and efflux pathways. ATP-binding cassette (ABC) transporters are ubiquitous in the human body-usually in epithelia-and are responsible for the transfer of indispensable physiological substrates (e.g. lipids and heme), protection against potentially toxic substances, maintenance of fluid composition, and excretion of metabolic waste products. Derailed regulation and gene variants of ABC transporters culminate in a wide array of pathophysiological disease states, such as oncogenic multidrug resistance or cystic fibrosis. Cadmium (Cd) has no known physiological role in mammalians and poses a health risk due to its release into the environment as a result of industrial activities, and eventually passes into the food chain. Epithelial cells, especially within the liver, lungs, gastrointestinal tract and kidneys, are particularly susceptible to the multifaceted effects of Cd because of the plethora of uptake pathways available. Pertinent to their broad substrate spectra, ABC transporters represent a major cellular efflux pathway for Cd and Cd complexes. In this review, we summarize current knowledge concerning transport of Cd and its complexes (mainly Cd bound to glutathione) by the ABC transporters ABCB1 (P-glycoprotein, MDR1), ABCB6, ABCC1 (multidrug resistance related protein 1, MRP1), ABCC7 (cystic fibrosis transmembrane regulator, CFTR), and ABCG2 (breast cancer related protein, BCRP). Potential detoxification strategies underlying ABC transporter-mediated efflux of Cd and Cd complexes are discussed.
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Affiliation(s)
- Frank Thévenod
- Institute for Physiology, Pathophysiology and Toxicology & ZBAF, Witten/Herdecke University, 58453, Witten, Germany
- Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, Morgenbreede 1, 33615, Bielefeld, Germany
| | - Wing-Kee Lee
- Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, Morgenbreede 1, 33615, Bielefeld, Germany.
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31
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Loeffler DA. Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches. Front Aging Neurosci 2024; 16:1368200. [PMID: 38872626 PMCID: PMC11170721 DOI: 10.3389/fnagi.2024.1368200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/01/2024] [Indexed: 06/15/2024] Open
Abstract
Clearance of amyloid-beta (Aβ) from the brain is impaired in both early-onset and late-onset Alzheimer's disease (AD). Mechanisms for clearing cerebral Aβ include proteolytic degradation, antibody-mediated clearance, blood brain barrier and blood cerebrospinal fluid barrier efflux, glymphatic drainage, and perivascular drainage. ATP-binding cassette (ABC) transporters are membrane efflux pumps driven by ATP hydrolysis. Their functions include maintenance of brain homeostasis by removing toxic peptides and compounds, and transport of bioactive molecules including cholesterol. Some ABC transporters contribute to lowering of cerebral Aβ. Mechanisms suggested for ABC transporter-mediated lowering of brain Aβ, in addition to exporting of Aβ across the blood brain and blood cerebrospinal fluid barriers, include apolipoprotein E lipidation, microglial activation, decreased amyloidogenic processing of amyloid precursor protein, and restricting the entrance of Aβ into the brain. The ABC transporter superfamily in humans includes 49 proteins, eight of which have been suggested to reduce cerebral Aβ levels. This review discusses experimental approaches for increasing the expression of these ABC transporters, clinical applications of these approaches, changes in the expression and/or activity of these transporters in AD and transgenic mouse models of AD, and findings in the few clinical trials which have examined the effects of these approaches in patients with AD or mild cognitive impairment. The possibility that therapeutic upregulation of ABC transporters which promote clearance of cerebral Aβ may slow the clinical progression of AD merits further consideration.
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Affiliation(s)
- David A. Loeffler
- Department of Neurology, Beaumont Research Institute, Corewell Health, Royal Oak, MI, United States
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32
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Rasmussen AJ, Pedersen M, Griffin BT, Holm R, Nielsen CU. Digestion of surfactants does not affect their ability to inhibit P-gp-mediated transport in vitro. Int J Pharm 2024; 656:124120. [PMID: 38621613 DOI: 10.1016/j.ijpharm.2024.124120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/11/2024] [Accepted: 04/12/2024] [Indexed: 04/17/2024]
Abstract
While various non-ionic surfactants at low concentrations have been shown to increase the transport of P-gp substrates in vitro, in vivo studies in rats have shown that a higher surfactant concentration is needed to increase the oral absorption of e.g. the P-gp substrates digoxin and etoposide. The aim of the present study was to investigate if intestinal digestion of surfactants could be the reason for this deviation between in vitro and in vivo data. Therefore, Kolliphor EL, Brij-L23, Labrasol and polysorbate 20 were investigated for their ability to inhibit P-gp and increase digoxin absorption in vitro. Transport studies were performed in Caco-2 cells, while P-gp inhibition and cell viability assays were performed in MDCKII-MDR1 cells. Polysorbate 20, Kolliphor EL and Brij-L23 increased absorptive transport and decreased secretory digoxin transport in Caco-2 cells, whereas only polysorbate 20 and Brij-L23 showed P-gp inhibiting properties in the MDCKII-MDR1 cells. Polysorbate 20 and Brij-L23 were chosen for in vitro digestion prior to transport- or P-gp inhibiting assays. Brij-L23 was not digestible, whereas polysorbate 20 reached a degree of digestion around 40%. Neither of the two surfactants showed any significant difference in their ability to affect absorptive or secretory transport of digoxin after pre-digestion. Furthermore, the P-gp inhibiting effects of polysorbate 20 were not decreased significantly. In conclusion, the mechanism behind the non-ionic surfactant mediated in vitro P-gp inhibition seemed independent of the intestinal digestion and the results presented here did not suggest it to be the cause of the observed discrepancy between in vitro and in vivo.
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Affiliation(s)
- Asbjørn Jaensch Rasmussen
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55 DK-5230, Odense M, Denmark
| | - Maria Pedersen
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55 DK-5230, Odense M, Denmark
| | - Brendan T Griffin
- School of Pharmacy, University College Cork, College Road, Cork T12 YN60, Ireland
| | - René Holm
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55 DK-5230, Odense M, Denmark
| | - Carsten Uhd Nielsen
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55 DK-5230, Odense M, Denmark.
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Morau MV, Seguin CS, Visacri MB, Pincinato EDC, Moriel P. Genetic Variants in the ABCB1 and ABCG2 Gene Drug Transporters Involved in Gefitinib-Associated Adverse Reaction: A Systematic Review and Meta-Analysis. Genes (Basel) 2024; 15:591. [PMID: 38790220 PMCID: PMC11120674 DOI: 10.3390/genes15050591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
This systematic review and meta-analysis aimed to verify the association between the genetic variants of adenosine triphosphate (ATP)-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) genes and the presence and severity of gefitinib-associated adverse reactions. We systematically searched PubMed, Virtual Health Library/Bireme, Scopus, Embase, and Web of Science databases for relevant studies published up to February 2024. In total, five studies were included in the review. Additionally, eight genetic variants related to ABCB1 (rs1045642, rs1128503, rs2032582, and rs1025836) and ABCG2 (rs2231142, rs2231137, rs2622604, and 15622C>T) genes were analyzed. Meta-analysis showed a significant association between the ABCB1 gene rs1045642 TT genotype and presence of diarrhea (OR = 5.41, 95% CI: 1.38-21.14, I2 = 0%), the ABCB1 gene rs1128503 TT genotype and CT + TT group and the presence of skin rash (OR = 4.37, 95% CI: 1.51-12.61, I2 = 0% and OR = 6.99, 95%CI: 1.61-30.30, I2= 0%, respectively), and the ABCG2 gene rs2231142 CC genotype and presence of diarrhea (OR = 3.87, 95% CI: 1.53-9.84, I2 = 39%). No ABCB1 or ABCG2 genes were positively associated with the severity of adverse reactions associated with gefitinib. In conclusion, this study showed that ABCB1 and ABCG2 variants are likely to exhibit clinical implications in predicting the presence of adverse reactions to gefitinib.
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Affiliation(s)
- Mariana Vieira Morau
- Department of Pharmacology, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas 13083-888, SP, Brazil; (M.V.M.); (C.S.S.)
| | - Cecília Souto Seguin
- Department of Pharmacology, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas 13083-888, SP, Brazil; (M.V.M.); (C.S.S.)
| | - Marília Berlofa Visacri
- Department of Pharmacy, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo 05508-000, SP, Brazil;
| | - Eder de Carvalho Pincinato
- Department of Clinical Pathology, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas 13083-888, SP, Brazil;
| | - Patricia Moriel
- Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas, Campinas 13083-859, SP, Brazil
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Svane N, Pedersen ABV, Rodenberg A, Ozgür B, Saaby L, Bundgaard C, Kristensen M, Tfelt-Hansen P, Brodin B. The putative proton-coupled organic cation antiporter is involved in uptake of triptans into human brain capillary endothelial cells. Fluids Barriers CNS 2024; 21:39. [PMID: 38711118 DOI: 10.1186/s12987-024-00544-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 04/25/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Triptans are anti-migraine drugs with a potential central site of action. However, it is not known to what extent triptans cross the blood-brain barrier (BBB). The aim of this study was therefore to determine if triptans pass the brain capillary endothelium and investigate the possible underlying mechanisms with focus on the involvement of the putative proton-coupled organic cation (H+/OC) antiporter. Additionally, we evaluated whether triptans interacted with the efflux transporter, P-glycoprotein (P-gp). METHODS We investigated the cellular uptake characteristics of the prototypical H+/OC antiporter substrates, pyrilamine and oxycodone, and seven different triptans in the human brain microvascular endothelial cell line, hCMEC/D3. Triptan interactions with P-gp were studied using the IPEC-J2 MDR1 cell line. Lastly, in vivo neuropharmacokinetic assessment of the unbound brain-to-plasma disposition of eletriptan was conducted in wild type and mdr1a/1b knockout mice. RESULTS We demonstrated that most triptans were able to inhibit uptake of the H+/OC antiporter substrate, pyrilamine, with eletriptan emerging as the strongest inhibitor. Eletriptan, almotriptan, and sumatriptan exhibited a pH-dependent uptake into hCMEC/D3 cells. Eletriptan demonstrated saturable uptake kinetics with an apparent Km of 89 ± 38 µM and a Jmax of 2.2 ± 0.7 nmol·min-1·mg protein-1 (n = 3). Bidirectional transport experiments across IPEC-J2 MDR1 monolayers showed that eletriptan is transported by P-gp, thus indicating that eletriptan is both a substrate of the H+/OC antiporter and P-gp. This was further confirmed in vivo, where the unbound brain-to-unbound plasma concentration ratio (Kp,uu) was 0.04 in wild type mice while the ratio rose to 1.32 in mdr1a/1b knockout mice. CONCLUSIONS We have demonstrated that the triptan family of compounds possesses affinity for the H+/OC antiporter proposing that the putative H+/OC antiporter plays a role in the BBB transport of triptans, particularly eletriptan. Our in vivo studies indicate that eletriptan is subjected to simultaneous brain uptake and efflux, possibly facilitated by the putative H+/OC antiporter and P-gp, respectively. Our findings offer novel insights into the potential central site of action involved in migraine treatment with triptans and highlight the significance of potential transporter related drug-drug interactions.
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Affiliation(s)
- Nana Svane
- Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark
| | | | - Anne Rodenberg
- Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark
| | - Burak Ozgür
- Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark
- Biotherapeutic Discovery, H. Lundbeck A/S, Valby, Denmark
| | - Lasse Saaby
- Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark
- Bioneer: FARMA, Bioneer A/S, Copenhagen, Denmark
| | | | - Mie Kristensen
- Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark
| | - Peer Tfelt-Hansen
- Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Glostrup, Denmark
| | - Birger Brodin
- Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
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Lin IL, Lin YT, Chang YC, Kondapuram SK, Lin KH, Chen PC, Kuo CY, Coumar MS, Cheung CHA. The SMAC mimetic GDC-0152 is a direct ABCB1-ATPase activity modulator and BIRC5 expression suppressor in cancer cells. Toxicol Appl Pharmacol 2024; 485:116888. [PMID: 38452945 DOI: 10.1016/j.taap.2024.116888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 02/20/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024]
Abstract
Upregulation of the multidrug efflux pump ABCB1/MDR1 (P-gp) and the anti-apoptotic protein BIRC5/Survivin promotes multidrug resistance in various human cancers. GDC-0152 is a DIABLO/SMAC mimetic currently being tested in patients with solid tumors. However, it is still unclear whether GDC-0152 is therapeutically applicable for patients with ABCB1-overexpressing multidrug-resistant tumors, and the molecular mechanism of action of GDC-0152 in cancer cells is still incompletely understood. In this study, we found that the potency of GDC-0152 is unaffected by the expression of ABCB1 in cancer cells. Interestingly, through in silico and in vitro analysis, we discovered that GDC-0152 directly modulates the ABCB1-ATPase activity and inhibits ABCB1 multidrug efflux activity at sub-cytotoxic concentrations (i.e., 0.25×IC50 or less). Further investigation revealed that GDC-0152 also decreases BIRC5 expression, induces mitophagy, and lowers intracellular ATP levels in cancer cells at low cytotoxic concentrations (i.e., 0.5×IC50). Co-treatment with GDC-0152 restored the sensitivity to the known ABCB1 substrates, including paclitaxel, vincristine, and YM155 in ABCB1-expressing multidrug-resistant cancer cells, and it also restored the sensitivity to tamoxifen in BIRC5-overexpressing tamoxifen-resistant breast cancer cells in vitro. Moreover, co-treatment with GDC-0152 restored and potentiated the anticancer effects of paclitaxel in ABCB1 and BIRC5 co-expressing xenograft tumors in vivo. In conclusion, GDC-0152 has the potential for use in the management of cancer patients with ABCB1 and BIRC5-related drug resistance. The findings of our study provide essential information to physicians for designing a more patient-specific GDC-0152 clinical trial program in the future.
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Affiliation(s)
- I-Li Lin
- Department of Radiology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
| | - Yu-Ting Lin
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Yung-Chieh Chang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University 701, Tainan, Taiwan
| | - Sree Karani Kondapuram
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India
| | - Kai-Hsuan Lin
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University 701, Tainan, Taiwan
| | - Pin-Chen Chen
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Chung-Ying Kuo
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Mohane Selvaraj Coumar
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India
| | - Chun Hei Antonio Cheung
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University 701, Tainan, Taiwan.
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Mitchell-White JI, Briggs DA, Mistry SJ, Mbiwan HA, Kellam B, Holliday ND, Briddon SJ, Kerr ID. A time-resolved Förster resonance energy transfer assay to investigate drug and inhibitor binding to ABCG2. Arch Biochem Biophys 2024; 753:109915. [PMID: 38307314 DOI: 10.1016/j.abb.2024.109915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/21/2023] [Accepted: 01/17/2024] [Indexed: 02/04/2024]
Abstract
The human ATP-binding cassette (ABC) transporter, ABCG2, is responsible for multidrug resistance in some tumours. Detailed knowledge of its activity is crucial for understanding drug transport and resistance in cancer, and has implications for wider pharmacokinetics. The binding of substrates and inhibitors is a key stage in the transport cycle of ABCG2. Here, we describe a novel binding assay using a high affinity fluorescent inhibitor based on Ko143 and time-resolved Förster resonance energy transfer (TR-FRET) to measure saturation binding to ABCG2. This binding is displaced by Ko143 and other known ABCG2 ligands, and is sensitive to the addition of AMP-PNP, a non-hydrolysable ATP analogue. This assay complements the arsenal of methods for determining drug:ABCG2 interactions and has the possibility of being adaptable for other multidrug pumps.
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Affiliation(s)
- James I Mitchell-White
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, UK.
| | - Deborah A Briggs
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Sarah J Mistry
- School of Pharmacy, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Hannah A Mbiwan
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK; School of Pharmacy, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Barrie Kellam
- School of Pharmacy, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Nicholas D Holliday
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Stephen J Briddon
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, UK
| | - Ian D Kerr
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
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To KKW, Huang Z, Zhang H, Ashby CR, Fu L. Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy. Drug Resist Updat 2024; 73:101058. [PMID: 38277757 DOI: 10.1016/j.drup.2024.101058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/27/2023] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Multidrug resistance (MDR) is one of the primary factors that produces treatment failure in patients receiving cancer chemotherapy. MDR is a complex multifactorial phenomenon, characterized by a decrease or abrogation of the efficacy of a wide spectrum of anticancer drugs that are structurally and mechanistically distinct. The overexpression of the ATP-binding cassette (ABC) transporters, notably ABCG2 and ABCB1, are one of the primary mediators of MDR in cancer cells, which promotes the efflux of certain chemotherapeutic drugs from cancer cells, thereby decreasing or abolishing their therapeutic efficacy. A number of studies have suggested that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a pivotal role in mediating the upregulation of ABC transporters in certain MDR cancer cells. This review will provide updated information about the induction of ABC transporters due to the aberrant regulation of ncRNAs in cancer cells. We will also discuss the measurement and biological profile of circulating ncRNAs in various body fluids as potential biomarkers for predicting the response of cancer patients to chemotherapy. Sequence variations, such as alternative polyadenylation of mRNA and single nucleotide polymorphism (SNPs) at miRNA target sites, which may indicate the interaction of miRNA-mediated gene regulation with genetic variations to modulate the MDR phenotype, will be reviewed. Finally, we will highlight novel strategies that could be used to modulate ncRNAs and circumvent ABC transporter-mediated MDR.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
| | - Zoufang Huang
- Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Hang Zhang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, United States
| | - Liwu Fu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
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Fan W, Shao K, Luo M. Structural View of Cryo-Electron Microscopy-Determined ATP-Binding Cassette Transporters in Human Multidrug Resistance. Biomolecules 2024; 14:231. [PMID: 38397468 PMCID: PMC10886794 DOI: 10.3390/biom14020231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
ATP-binding cassette (ABC) transporters, acting as cellular "pumps," facilitate solute translocation through membranes via ATP hydrolysis. Their overexpression is closely tied to multidrug resistance (MDR), a major obstacle in chemotherapy and neurological disorder treatment, hampering drug accumulation and delivery. Extensive research has delved into the intricate interplay between ABC transporter structure, function, and potential inhibition for MDR reversal. Cryo-electron microscopy has been instrumental in unveiling structural details of various MDR-causing ABC transporters, encompassing ABCB1, ABCC1, and ABCG2, as well as the recently revealed ABCC3 and ABCC4 structures. The newly obtained structural insight has deepened our understanding of substrate and drug binding, translocation mechanisms, and inhibitor interactions. Given the growing body of structural information available for human MDR transporters and their associated mechanisms, we believe it is timely to compile a comprehensive review of these transporters and compare their functional mechanisms in the context of multidrug resistance. Therefore, this review primarily focuses on the structural aspects of clinically significant human ABC transporters linked to MDR, with the aim of providing valuable insights to enhance the effectiveness of MDR reversal strategies in clinical therapies.
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Affiliation(s)
| | | | - Min Luo
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore; (W.F.); (K.S.)
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Okamura T, Kikuchi T, Ogawa M, Zhang MR. Improved synthesis of 6-bromo-7-[ 11C]methylpurine for clinical use. EJNMMI Radiopharm Chem 2024; 9:10. [PMID: 38334858 PMCID: PMC10857989 DOI: 10.1186/s41181-024-00240-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 01/25/2024] [Indexed: 02/10/2024] Open
Abstract
BACKGROUND Multidrug resistance-associated protein 1 (MRP1), an energy-dependent efflux pump, is expressed widely in various tissues and contributes to many physiological and pathophysiological processes. 6-Bromo-7-[11C]methylpurine ([11C]7m6BP) is expected to be useful for the assessment of MRP1 activity in the human brain and lungs. However, the radiochemical yield (RCY) in the synthesis of [11C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [11C]CH3I provided primarily the undesired isomer, 6-bromo-9-[11C]methylpurine ([11C]9m6BP). To increase the RCY of [11C]7m6BP, we investigated conditions for improving the [11C]7m6BP/[11C]9m6BP selectivity of the methylation reaction. RESULTS [11C]7m6BP was manually synthesized via the methylation of 6-bromopurine with [11C]CH3I in various solvents and at different temperatures in the presence of potassium carbonate for 5 min. Several less polar solvents, including tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate (AcOEt) improved the [11C]7m6BP/[11C]9m6BP selectivity from 1:1 to 2:1, compared with the conventionally used solvents for the alkylation of 6-halopurines, acetone, acetonitrile, and N,N-dimethylformamide. However, a higher temperature (140 °C or 180 °C) was needed to progress the 11C-methylation in the less polar solvents, and the manual conditions could not be directly translated to an automated synthesis. [11C]Methyl triflate ([11C]CH3OTf) was thus used as a methylating agent to increase the conversion at a lower temperature. The 11C-methylation using [11C]CH3OTf at 100 °C proceeded efficiently in THF, 2-MeTHF, and AcOEt with maintenance of the improved selectivity. Starting from 28 to 34 GBq [11C]CO2, [11C]7m6BP was produced with 2.3-2.6 GBq for THF, 2.7-3.3 GBq for AcOEt, and 2.8-3.9 GBq for 2-MeTHF at approximately 30 min after the end of bombardment (n = 3 per solvent). The isolated RCYs (decay corrected) for THF, 2-MeTHF, and AcOEt were 24-28%, 29-35%, and 22-31% (n = 3), respectively. CONCLUSIONS The use of THF, 2-MeTHF, and AcOEt improved the [11C]7m6BP/[11C]9m6BP selectivity in the methylation reaction, and the improved method provided [11C]7m6BP with sufficient radioactivity for clinical use.
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Affiliation(s)
- Toshimitsu Okamura
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.
| | - Tatsuya Kikuchi
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
| | - Masanao Ogawa
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
- SHI Accelerator Service, Ltd., 7-1-1 Nishigotanda, Shinagawa-ku, Tokyo, 141-0031, Japan
| | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan
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Mora Lagares L, Pérez-Castillo Y, Novič M. Exploring the dynamics of the ABCB1 membrane transporter P-glycoprotein in the presence of ATP and active/non-active compounds through molecular dynamics simulations. Toxicology 2024; 502:153732. [PMID: 38272384 DOI: 10.1016/j.tox.2024.153732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024]
Abstract
P-glycoprotein (Pgp) is a member of the ATP-binding cassette family of transporters that confers multidrug resistance to cancer cells and is actively involved in the pharmacokinetics and toxicokinetics of a big variety of drugs. Extensive studies have provided insights into the binding of many compounds, but the precise mechanism of translocation across the membrane remains unknown; in this context, the major challenge has been to understand the basis for its polyspecificity. In this study, molecular dynamics (MD) simulations of human P-gp (hP-gp) in an explicit membrane-and-water environment were performed to investigate the dynamic behavior of the transporter in the presence of different compounds (active and inactive) in the binding pocket and ATP molecules within the nucleotide binding domains (NBDs). The complexes studied involve four compounds: cyclosporin A (CSA), amiodarone (AMI), pamidronate (APD), and valproic acid (VPA). While CSA and AMI are known to interact with P-gp, APD and VPA do not. The results highlighted how the presence of ATP notably contributed to increased flexibility of key residues in NBD1 of active systems, indicating potential conformational changes activating the translocation mechanism. MD simulations reveal how these domains adapt and respond to the presence of different substrates, as well as the influence of ATP binding on their flexibility. Furthermore, distinctive behavior was observed in the presence of active and inactive compounds, particularly in the arrangement of ATP between NBDs, supporting the proposed nucleotide sandwich dimer mechanism for ATP binding. This study provides comprehensive insights into P-gp behavior with various ligands and ATP, offering implications for drug development, toxicity assessment and demonstrating the validity of the results derived from the MD simulations.
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Affiliation(s)
- Liadys Mora Lagares
- Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, 1000 Ljubljana, Slovenia.
| | - Yunierkis Pérez-Castillo
- Bio-Cheminformatics Research Group and Escuela de Ciencias Físicas y Matemáticas, Universidad de Las, Américas, Quito 170513, Ecuador
| | - Marjana Novič
- Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, 1000 Ljubljana, Slovenia.
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Lopes BCH, Amado EM, Oliveira-Neto MA, Zampaulo RDA, Zeppelini D. Multixenobiotic response of Collembola to soil contamination, the phisiological basis for bioindicative environmental monitoring. CHEMOSPHERE 2024; 349:140851. [PMID: 38072203 DOI: 10.1016/j.chemosphere.2023.140851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/14/2023] [Accepted: 11/28/2023] [Indexed: 12/25/2023]
Abstract
Collembola are well-established models in ecotoxicological research, extensively employed to investigate the effects of various contaminants, including heavy metals. The Multixenobiotic Resistance Mechanism (MXR) is a physiological response based on transmembrane efflux proteins that play a pivotal role in pumping xenobiotics and conferring resistance. This mechanism is firmly established as a biomarker of aquatic contamination and has recently shown promise as a soil biomonitoring tool. In this study, we aimed to assess the feasibility of utilizing the MXR mechanism as a biomonitoring tool, specifically by investigating the response of two Collembola species exposed to soil contaminated in a real-life situation. Soil samples were obtained from the site of Brazil's largest mine disaster, a dam rupture in Brumadinho-MG. We explored MXR activity in the model species Folsomia candida and a tropical native species, Cyphoderus sp. Our findings reveal efflux activity in both species, confirmed by model MXR protein inhibitors. Moreover, we observed distinct MXR activity levels corresponding to the degree of heavy metal contamination in the soil samples. Consequently, our results underscore the potential of combining an established soil bioindicator, such as Collembola, with the physiological response of a molecular biomarker like MXR. This approach may represent a valuable strategy for biomonitoring terrestrial ecosystems.
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Affiliation(s)
- Bruna Carolline Honório Lopes
- Programa de Pós-Graduação em Ciências Biológicas (Zoologia). Centro de Ciências Exatas e da Natureza. Universidade Federal da Paraíba, Campus I, João Pessoa, Paraíba, Brazil; Laboratório de Sistemática de Collembola e Conservação. Instituto de Biologia de Solo. Universidade Estadual da Paraíba, Campus V, João Pessoa, Paraíba, Brazil; Laboratório de Ecofisiologia Animal, Departamento de Biologia, Centro de Ciências Biológicas e Sociais Aplicadas. Universidade Estadual da Paraíba, Campus V, João Pessoa, Paraíba, Brazil.
| | - Enelise Marcelle Amado
- Laboratório de Ecofisiologia Animal, Departamento de Biologia, Centro de Ciências Biológicas e Sociais Aplicadas. Universidade Estadual da Paraíba, Campus V, João Pessoa, Paraíba, Brazil
| | - Misael Augusto Oliveira-Neto
- Programa de Pós-Graduação em Ciências Biológicas (Zoologia). Centro de Ciências Exatas e da Natureza. Universidade Federal da Paraíba, Campus I, João Pessoa, Paraíba, Brazil; Laboratório de Sistemática de Collembola e Conservação. Instituto de Biologia de Solo. Universidade Estadual da Paraíba, Campus V, João Pessoa, Paraíba, Brazil
| | | | - Douglas Zeppelini
- Programa de Pós-Graduação em Ciências Biológicas (Zoologia). Centro de Ciências Exatas e da Natureza. Universidade Federal da Paraíba, Campus I, João Pessoa, Paraíba, Brazil; Laboratório de Sistemática de Collembola e Conservação. Instituto de Biologia de Solo. Universidade Estadual da Paraíba, Campus V, João Pessoa, Paraíba, Brazil
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Yao C, Liu C, Hong S, Zhou J, Gao Z, Li Y, Lv W, Zhou W. Potential nervous threat of nanoplastics to Monopterus albus: Implications from a metabolomics study. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 910:168482. [PMID: 37981139 DOI: 10.1016/j.scitotenv.2023.168482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/21/2023] [Accepted: 11/09/2023] [Indexed: 11/21/2023]
Abstract
Nanoplastics, as a new class of environmental pollutants, have been frequently detected in environmental media and organisms. Monopterus albus (M. albus) is an important economic aquatic product with a high dietary consumption. However, the potential biological effects of nanoplastics on M. albus remain unknown. In this study, the effects of polystyrene nanoplastics (PS-NPs) at different concentrations (0, 0.5, 1, 5 and 10 mg/L) on M. albus were investigated using an untargeted metabolomics approach. The results showed that 59, 44, 24, and 31 individual differential metabolites and 16, 9, 6, and 2 significant differential metabolic pathways were significantly changed in 0.5, 1, 5, and 10 mg/L respectively, indicating the greater effect of PS-NPs at the relatively low concentrations. After further analysis, there are four same significant differential metabolic pathways for the 0.5 and 1 mg/L groups, i.e., ABC transporters, cAMP signaling pathway, Neuroactive ligand-receptor interaction, and Synaptic vesicle cycle. In addition, there was one mutual differential metabolic pathway (Neuroactive ligand-receptor interaction) among the four groups, indicative of the probably universal nervous influence of nanoplastics on M. albus. In a word, the current work suggests that PS-NPs might affect the nervous systems of M. albus through disturbing their liver metabolism, and nanoplastics at relatively low concentrations may possess a greater effect, which provides significant information for assessing the toxic effect and exposure risk of nanoplastics to organisms in aquatic environment.
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Affiliation(s)
- Chunxia Yao
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China; Key Laboratory of Food Quality Safety and Nutrition (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shanghai 201403, China
| | - Chengbin Liu
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China; Key Laboratory of Food Quality Safety and Nutrition (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shanghai 201403, China
| | - Shuang Hong
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China; College of Fisheries and Life Science, Shanghai Ocean university, Shanghai 201306, China
| | - Jiaxin Zhou
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China; Key Laboratory of Food Quality Safety and Nutrition (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Shanghai 201403, China
| | - Zhaoliang Gao
- Institute of Fruit and Forest, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China
| | - Yiming Li
- Fishery Machinery and Instrument Research Institute, Chinese Academy of Fisheries Sciences, Shanghai 200092, China
| | - Weiwei Lv
- Eco-environmental Protection Research Institute, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China.
| | - Wenzong Zhou
- Eco-environmental Protection Research Institute, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China.
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Zhang F, Lei X, Yang X. Emerging roles of ncRNAs regulating ABCC1 on chemotherapy resistance of cancer - a review. J Chemother 2024; 36:1-10. [PMID: 38263773 DOI: 10.1080/1120009x.2023.2247202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 07/20/2023] [Indexed: 01/25/2024]
Abstract
In the process of chemotherapy, drug resistance of cancer cells is a common and difficult problem of chemotherapy failure, and it is also the main cause of cancer recurrence and metastasis. Non-coding RNAs (ncRNAs) refer to the RNA that does not encode proteins, including microRNA (miRNA), long non-coding RNA (lncRNA) and circularRNA (circRNA), etc. NcRNAs are involved in a series of important life processes and further regulate the expression of ABCC1 by directly or indirectly up-regulating or down-regulating the expression of targeted mRNAs, making cancer cells more susceptible to drug resistance. A growing number of studies have shown that ncRNAs have effects on cancer cell proliferation, invasion, metastasis, and drug sensitivity, by regulating the expression of ABCC1. In this review, we will discuss the emerging roles of ncRNAs regulating ABCC1 in chemotherapy resistance and mechanisms to reverse drug resistance as well as provide potential targets for future cancer treatment.
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Affiliation(s)
- Feng Zhang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, People's Republic of China
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, People's Republic of China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, People's Republic of China
| | - Xiaoyan Yang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, People's Republic of China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, People's Republic of China
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Wagner JB, Abdel-Rahman S, Raghuveer G, Gaedigk A, Boone EC, Gaedigk R, Staggs VS, Reed GA, Zhang N, Leeder JS. SLCO1B1 Genetic Variation Influence on Atorvastatin Systemic Exposure in Pediatric Hypercholesterolemia. Genes (Basel) 2024; 15:99. [PMID: 38254988 PMCID: PMC10815823 DOI: 10.3390/genes15010099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/04/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
This clinical study examined the influence of SLCO1B1 c.521T>C (rs4149056) on plasma atorvastatin concentrations in pediatric hypercholesterolemia. The participants (8-21 years), including heterozygous (c.521T/C, n = 13), homozygous (c.521C/C, n = 2) and controls (c.521T/T, n = 13), completed a single-oral-dose pharmacokinetic study. Similar to in adults, the atorvastatin (AVA) area-under-concentration-time curve from 0 to 24 h (AUC0-24) was 1.7-fold and 2.8-fold higher in participants with c.521T/C and c.521C/C compared to the c.521T/T participants, respectively. The inter-individual variability in AVA exposure within these genotype groups ranged from 2.3 to 4.8-fold, indicating that additional factors contribute to the inter-individual variability in the AVA dose-exposure relationship. A multivariate model reinforced the SLCO1B1 c.521T>C variant as the central factor contributing to AVA systemic exposure in this pediatric cohort, accounting for ~65% of the variability in AVA AUC0-24. Furthermore, lower AVA lactone concentrations in participants with increased body mass index contributed to higher exposure within the c.521T/T and c.521T/C genotype groups. Collectively, these factors contributing to higher systemic exposure could increase the risk of toxicity and should be accounted for when individualizing the dosing of atorvastatin in eligible pediatric patients.
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Affiliation(s)
- Jonathan B. Wagner
- Ward Family Heart Center, Children’s Mercy, Kansas City, MO 64108, USA
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Susan Abdel-Rahman
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Geetha Raghuveer
- Ward Family Heart Center, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Andrea Gaedigk
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Erin C. Boone
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
| | - Roger Gaedigk
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Vincent S. Staggs
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
- Health Services & Outcomes Research, Children’s Mercy, Kansas City, MO 64108, USA
| | - Gregory A. Reed
- Clinical Pharmacology Shared Resource, University of Kansas Cancer Center, Fairway, KS 66205, USA
| | - Na Zhang
- Clinical Pharmacology Shared Resource, University of Kansas Cancer Center, Fairway, KS 66205, USA
| | - J. Steven Leeder
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
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45
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Chen J, Sun Y, Li J, Lyu M, Yuan L, Sun J, Chen S, Hu C, Wei Q, Xu Z, Guo T, Cheng X. In-depth metaproteomics analysis of tongue coating for gastric cancer: a multicenter diagnostic research study. MICROBIOME 2024; 12:6. [PMID: 38191439 PMCID: PMC10773145 DOI: 10.1186/s40168-023-01730-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 11/21/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND Our previous study revealed marked differences in tongue images between individuals with gastric cancer and those without gastric cancer. However, the biological mechanism of tongue images as a disease indicator remains unclear. Tongue coating, a major factor in tongue appearance, is the visible layer on the tongue dorsum that provides a vital environment for oral microorganisms. While oral microorganisms are associated with gastric and intestinal diseases, the comprehensive function profiles of oral microbiota remain incompletely understood. Metaproteomics has unique strength in revealing functional profiles of microbiota that aid in comprehending the mechanism behind specific tongue coating formation and its role as an indicator of gastric cancer. METHODS We employed pressure cycling technology and data-independent acquisition (PCT-DIA) mass spectrometry to extract and identify tongue-coating proteins from 180 gastric cancer patients and 185 non-gastric cancer patients across 5 independent research centers in China. Additionally, we investigated the temporal stability of tongue-coating proteins based on a time-series cohort. Finally, we constructed a machine learning model using the stochastic gradient boosting algorithm to identify individuals at high risk of gastric cancer based on tongue-coating microbial proteins. RESULTS We measured 1432 human-derived proteins and 13,780 microbial proteins from 345 tongue-coating samples. The abundance of tongue-coating proteins exhibited high temporal stability within an individual. Notably, we observed the downregulation of human keratins KRT2 and KRT9 on the tongue surface, as well as the downregulation of ABC transporter COG1136 in microbiota, in gastric cancer patients. This suggests a decline in the defense capacity of the lingual mucosa. Finally, we established a machine learning model that employs 50 microbial proteins of tongue coating to identify individuals at a high risk of gastric cancer, achieving an area under the curve (AUC) of 0.91 in the independent validation cohort. CONCLUSIONS We characterized the alterations in tongue-coating proteins among gastric cancer patients and constructed a gastric cancer screening model based on microbial-derived tongue-coating proteins. Tongue-coating proteins are shown as a promising indicator for identifying high-risk groups for gastric cancer. Video Abstract.
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Affiliation(s)
- Jiahui Chen
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
| | - Yingying Sun
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, School of Life Sciences, Westlake University, Hangzhou, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, China
| | - Jie Li
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
- MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing, China
| | - Mengge Lyu
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
- School of Medicine, School of Life Sciences, Westlake University, Hangzhou, China
- Research Center for Industries of the Future, Westlake University, Hangzhou, China
| | - Li Yuan
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
| | - Jiancheng Sun
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shangqi Chen
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Can Hu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
| | - Qing Wei
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
| | - Zhiyuan Xu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China.
| | - Tiannan Guo
- Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
- School of Medicine, School of Life Sciences, Westlake University, Hangzhou, China.
- Research Center for Industries of the Future, Westlake University, Hangzhou, China.
| | - Xiangdong Cheng
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China.
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46
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Cavicchioli Azevedo V, Johnston CU, Kennedy CJ. Ivermectin Toxicokinetics in Rainbow Trout (Oncorhynchus mykiss) following P-glycoprotein Induction. ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2024; 86:58-72. [PMID: 38103085 DOI: 10.1007/s00244-023-01045-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/14/2023] [Indexed: 12/17/2023]
Abstract
Alterations in ivermectin (IVM, 22,23-dihydro avermectin B1a+22,23-dihydro avermectin B1b) toxicokinetics following P-glycoprotein (P-gp) induction by clotrimazole (CTZ) were examined in rainbow trout (Oncorhynchus mykiss) to assess the potential importance of P-gp activity levels in xenobiotic distribution and kinetics in fish. Control and fish pretreated with CTZ (30 µmol/kg) were administered 175 µg/kg 3H-IVM into the caudal vasculature. At various time points (0.25, 0.5, 1, 3, 24, 48, 96, and 168 h) following injection, tissues (blood, liver, kidney, gill, intestines, brain [5 regions], eye, gonad and fat) were removed analyzed for IVM-derived radioactivity. IVM concentration declined in blood, liver, kidney and gill, and concentrations in other tissues remained constant over the sampling period. The highest measured concentrations were found in kidney, followed by liver, with the lowest values found in brain, eye and gonad. The highest % of the administered dose was found in the liver and kidney in the immediate hours post-administration, and in the intestines and fat at 24 h post-administration. P-gp induction by CTZ did not alter IVM distribution or any calculated toxicokinetic parameter (AUC, mean residence time, T1/2, clearance rate, volume of distribution), suggesting that P-gp induction may be limited or that P-gp plays a lesser role in xenobiotic kinetics in fish compared to mammals.
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Affiliation(s)
| | - Christina U Johnston
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada
| | - Christopher J Kennedy
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada.
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47
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Kundu A, Ghosh P, Bishayi B. Vitexin along with verapamil downregulates efflux pump P-glycoprotein in macrophages and potentiate M1 to M2 switching via TLR4-NF-κB-TNFR2 pathway in lipopolysaccharide treated mice. Immunobiology 2024; 229:152767. [PMID: 38103391 DOI: 10.1016/j.imbio.2023.152767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/22/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023]
Abstract
The lipopolysaccharide, a microbial toxin, is one of the major causative agents of sepsis. P-gp expression and its functions are altered during inflammation. LPS has been known to impair the functions of P-gp, an efflux transporter. But the effect of LPS on P-gp expression in murine peritoneal macrophages is poorly understood. Molecular docking studies reveal that vitexin is a potent substrate and verapamil a potent inhibitor of P-gp. In the present experimental study, the curative potential of vitexin as a fruit component and verapamil treated as a control inhibitor of P-gp was examined in a murine LPS sepsis model. The effects of vitexin and verapamil on P-gp expression in macrophages correlating with changes in macrophage polarization and associated functional responses during LPS induced sepsis were studied. Peritoneal macrophages of LPS (10 mg/kg body weight) challenged mice exhibited elevated levels of H2O2, superoxide, and NO in parallel with lower antioxidant activity. LPS treatment increased P-gp expression through increased TLR4/expression. However, LPS challenged mice treated with vitexin (5 mg/kg body weight) + verapamil (5 mg/kg body weight) showed higher anti-oxidant enzyme activity (SOD, CAT and GRx) resulting in reduced oxidative stress. This combination treatment also elevated TNFR2, concomitant with down-regulation of TLR4, NF-κB and P-gp expression in murine peritoneal macrophages, resulting in a switch from M1 to M2 polarisation of macrophages and reduced inflammatory responses. In conclusion, combined vitexin and verapamil treatment could be used as a promising therapy to regulate P-gp expression and protection against LPS mediated sepsis and inflammatory damages.
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Affiliation(s)
- Ayantika Kundu
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India
| | - Pratiti Ghosh
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
| | - Biswadev Bishayi
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
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48
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Gil M, Knetki-Wróblewska M, Niziński P, Strzemski M, Krawczyk P. Effectiveness of ALK inhibitors in treatment of CNS metastases in NSCLC patients. Ann Med 2023; 55:1018-1028. [PMID: 36896848 PMCID: PMC10795653 DOI: 10.1080/07853890.2023.2187077] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
Metastases to the central nervous system (CNS) in patients with non-small cell lung cancer constitute an extremely difficult clinical problem, and their occurrence is associated with a poor prognosis. Due to the existence of the blood-brain barrier (BBB) and the action of proteins responsible for the transport of drugs, e.g. P-glycoprotein (P-gp), the penetration of drugs into the CNS is insufficient. Until recently, the only method of CNS metastases treatment was radiotherapy and neurosurgery. The advancement of molecular biology allowed discover targets for molecularly targeted therapies. One of targets is abnormal anaplastic lymphoma kinase, which results from the rearrangement of the ALK gene in patients with non-small cell lung cancer (NSCLC). ALK rearrangement occurs in only about 4.5% of NSCLC patients, but its presence favors brain metastases. The ALK inhibitors (ALKi) were modified to obtain molecules with high ability to penetrate into the CNS. This was achieved by modifying the structure of individual molecules, which became, inter alia, less substrates for P-gp. These modifications caused that less than 10% of patients experience progression in CNS during new ALK inhibitors treatment. This review summarizes the knowledge about the action of BBB, the pharmacodynamics and pharmacokinetics of ALKi, with particular emphasis on their ability to penetrate the CNS and the intracranial activity of individual drugs from different generations of ALK inhibitors.
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Affiliation(s)
- Michał Gil
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Magdalena Knetki-Wróblewska
- Department of Lung Cancer and Chest Tumors, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Maciej Strzemski
- Department of Analytical Chemistry, Medical University of Lublin, Lublin, Poland
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
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49
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Adams S, Stapleton PA. Nanoparticles at the maternal-fetal interface. Mol Cell Endocrinol 2023; 578:112067. [PMID: 37689342 PMCID: PMC10591848 DOI: 10.1016/j.mce.2023.112067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/25/2023] [Accepted: 09/05/2023] [Indexed: 09/11/2023]
Abstract
The increasing production of intentional and unintentional nanoparticles (NPs) has led to their accumulation in the environment as air and ground pollution. The heterogeneity of these particles primarily relies on the NP physicochemical properties (i.e., chemical composition, size, shape, surface chemistry, etc.). Pregnancy represents a vulnerable life stage for both the woman and the developing fetus. The ubiquitous nature of these NPs creates a concern for developmental fetal exposures. At the maternal-fetal interface lies the placenta, a temporary endocrine organ that facilitates nutrient and waste exchange as well as communication between maternal and fetal tissues. Recent evidence in human and animal models identifies that gestational exposure to NPs results in placental translocation leading to local effects and endocrine disruption. Currently, the mechanisms underlying placental translocation and cellular uptake of NPs in the placenta are poorly understood. The purpose of this review is to assess the current understanding of the physiochemical factors influencing NP translocation, cellular uptake, and endocrine disruption at the maternal-fetal interface within the available literature.
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Affiliation(s)
- S Adams
- Department of Pharmacology and Toxicology, USA
| | - P A Stapleton
- Department of Pharmacology and Toxicology, USA; Environmental Occupational and Health Sciences Institute, Rutgers University, Piscataway, NJ, 08854, USA.
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50
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Guo Q, Li J, Mao J, Chen W, Yang M, Yang Y, Hua Y, Qiu L. Hollow MIL-125 Nanoparticles Loading Doxorubicin Prodrug and 3-Methyladenine for Reversal of Tumor Multidrug Resistance. J Funct Biomater 2023; 14:546. [PMID: 37998115 PMCID: PMC10671911 DOI: 10.3390/jfb14110546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/13/2023] [Accepted: 11/10/2023] [Indexed: 11/25/2023] Open
Abstract
Multidrug resistance (MDR) is a key factor in chemotherapy failure and tumor recurrence. The inhibition of drug efflux and autophagy play important roles in MDR therapy. Herein, a multifunctional delivery system (HA-MIL-125@DVMA) was prepared for synergistically reverse tumor MDR. Tumor-targeted hollow MIL-125-Ti nanoparticles were used to load the doxorubicin-vitamin E succinate (DV) prodrug and 3-methyladenine (3-MA) to enhance reverse MDR effects. The pH-sensitive DV can kill tumor cells and inhibit P-gp-mediated drug efflux, and 3-MA can inhibit autophagy. HA-MIL-125@DVMA had uniformly distributed particle size and high drug-load content. The nanoparticles could effectively release the drugs into tumor microenvironment due to the rapid hydrazone bond-breaking under low pH conditions, resulting in a high cumulative release rate. In in vitro cellular experiments, the accumulation of HA-MIL-125@DVMA and HA-MIL-125@DV in MCF-7/ADR cells was significantly higher than that in the control groups. Moreover, the nanoparticles significantly inhibited drug efflux in the cells, ensuring the accumulation of the drugs in cell cytoplasm and causing drug-resistant cells' death. Importantly, HA-MIL-125@DVMA effectively inhibited tumor growth without changes in body weight in tumor-bearing mice. In summary, the combination of the acid-sensitive prodrug DV and autophagy inhibitor 3-MA in a HA-MIL-125 nanocarrier can enhance the antitumor effect and reverse tumor MDR.
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Affiliation(s)
- Qingfeng Guo
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Jiangnan University, Wuxi 214122, China;
| | - Jie Li
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; (J.L.); (J.M.); (W.C.); (M.Y.); (Y.Y.)
| | - Jing Mao
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; (J.L.); (J.M.); (W.C.); (M.Y.); (Y.Y.)
| | - Weijun Chen
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; (J.L.); (J.M.); (W.C.); (M.Y.); (Y.Y.)
| | - Meiyang Yang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; (J.L.); (J.M.); (W.C.); (M.Y.); (Y.Y.)
| | - Yang Yang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; (J.L.); (J.M.); (W.C.); (M.Y.); (Y.Y.)
| | - Yuming Hua
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Jiangnan University, Wuxi 214122, China;
| | - Lipeng Qiu
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China; (J.L.); (J.M.); (W.C.); (M.Y.); (Y.Y.)
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