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Guo J, Liu F, Yang X, Wang M, Yang S, Lan K, Yan L, Cao R, Chen X, Zhong W. TRPM4 channels contribute to Adriamycin chemoresistance in breast cancer cells. Eur J Pharmacol 2025; 998:177637. [PMID: 40250821 DOI: 10.1016/j.ejphar.2025.177637] [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: 11/24/2024] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/20/2025]
Abstract
Chemoresistance presents a critical challenge in breast cancer treatment. Here, we report that transient receptor potential melastatin 4 (TRPM4) plays a role in modulating doxorubicin (ADR) resistance in breast cancer cells. TRPM4 expression was significantly upregulated at both the mRNA and protein levels in MCF-7/ADR cells, a human breast cancer cell line resistant to the chemotherapy drug ADR. Pharmacological inhibition or knockdown of TRPM4 restored ADR sensitivity, while its overexpression in non-resistant MCF-7 cells diminished drug response, confirming the regulatory role of TRPM4 in resistance mechanisms. Western blot analyses confirmed that elevated TRPM4 expression drives P-glycoprotein (P-gp) upregulation in both MCF-7/ADR and KBv200 cells (KB vinblastine 200 resistant cell line), as well as in Huh7 (human hepatocellular carcinoma cell line) and HCT116 (human colorectal cancer cell line). In addition, we demonstrate that TRPM4 inhibition suppresses the level of NF-κB, a pivotal transcription factor regulating P-gp expression. Furthermore, we found that TRPM4-mediated cellular swelling, rather than membrane depolarization, is the primary driver of P-gp overexpression. Drug-resistant MCF-7/ADR cells exhibited significantly larger cell sizes compared to non-resistant MCF-7 cells, and this effect was reversed following TRPM4 inhibition. The swelling was induced by hypotonic stress rather than changes in membrane potential, further confirming the role of TRPM4 in P-gp regulation through volume changes. Analysis of the TCGA (The Cancer Genome Atlas) database revealed that elevated TRPM4 expression correlates with reduced patient survival, suggesting that TRPM4 plays a role in both drug resistance and tumor progression. Our findings provide new insights into the role of TRPM4 in resistance mechanisms and propose that targeting TRPM4 could represent an innovative therapeutic strategy to overcome chemoresistance and enhance drug efficacy in breast cancer.
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Affiliation(s)
- Juan Guo
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Fang Liu
- Department of Pathology, The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, Shaanxi, China
| | - Xinyue Yang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Mengyuan Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Shangze Yang
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Kun Lan
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Li Yan
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Ruiyuan Cao
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
| | - Xingjuan Chen
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
| | - Wu Zhong
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
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2
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Sogawa C, Shimada K, Nakano K. The Possibility of Plasma Membrane Transporters as Drug Targets in Oral Cancers. Int J Mol Sci 2025; 26:4310. [PMID: 40362545 PMCID: PMC12072478 DOI: 10.3390/ijms26094310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/25/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
Plasma membrane transporters are increasingly recognized as potential drug targets for oral cancer, particularly oral squamous cell carcinoma (OSCC). These transporters play crucial roles in cancer cell metabolism, drug resistance, and the tumor microenvironment, making them attractive targets for therapeutic intervention. Among the two main families of plasma membrane transporters, ATP-binding cassette (ABC) transporters have long been known to be involved in drug efflux and contribute to chemoresistance in cancer cells. On the other hand, solute carriers (SLCs) are also a family of transporters that facilitate the transport of various substrates, including nutrients and drugs, and have recently been shown to contribute to cancer chemosensitivity, metabolism, and proliferation. SLC transporters have been identified as potential cancer biomarkers and therapeutic targets, and their expression profiles suggest that they could be utilized in precision oncology approaches. We summarize previous reports on the expression and role of ABC and SLC transporters in oral cancer and discuss their potential as therapeutic targets.
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Affiliation(s)
- Chiharu Sogawa
- Department of Food and Health Sciences, Faculty of Environmental Studies, Hiroshima Institute of Technology, 2-1-1 Miyake, Saeki-ku, Hiroshima 731-5193, Japan
- Department of Clinical Engineering Faculty of Life Sciences, Hiroshima Institute of Technology, 2-1-1 Miyake, Saeki-ku, Hiroshima 731-5193, Japan
| | - Katsumitsu Shimada
- Department of Clinical Phathophysiology, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri 399-0781, Japan
| | - Keisuke Nakano
- Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama-city, Okayama 700-8558, Japan
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3
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Wang Y, Ding N, Zhao Y, Wang F, Liu W, Chen Z, Sun W, Gu L, Zhang Y. Design, synthesis, and biological evaluation of β-carboline derivatives as ABCB1 inhibitors for reversing multidrug resistance. Eur J Med Chem 2025; 288:117390. [PMID: 39965407 DOI: 10.1016/j.ejmech.2025.117390] [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: 12/20/2024] [Revised: 01/30/2025] [Accepted: 02/10/2025] [Indexed: 02/20/2025]
Abstract
The scarcity of ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp) inhibitors suitable for clinical application in improving multidrug resistance (MDR) promotes the development of drugs aimed at reversing MDR. In this work, we reported a comprehensive study for the first time about the reversal activity of β-carboline derivatives on ABCB1-mediated MDR. Among 48 synthesized derivatives, compound K27 significantly increased the sensitivity of ABCB1-mediated MDR SW620/AD300 cells to paclitaxel (PTX) (IC50 = 15.33 ± 5.4 nM, RF = 171.2) and hardly showed toxicity even at a high concentration of 20 μM when used alone. The in vitro studies indicated that compound K27 distinctly enhanced the arresting effect of PTX on the SW620/AD300 cell cycle, thereby inhibiting their proliferation. Mechanistically, compound K27 was confirmed to directly bind to ABCB1 to inhibit efflux function, reducing cellular efflux and ensuring stable intracellular concentration of PTX without affecting ABCB1's normal expression. Importantly, the combination of compound K27 and PTX exhibited potent tumor suppression in vivo without generating toxicity. These results demonstrated that β-carboline compounds represented by compound K27 may be potent ABCB1 inhibitors with considerable potential in effectively reversing ABCB1-mediated MDR, showing promising prospects.
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Affiliation(s)
- Yuanyuan Wang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Nanjin Ding
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yunpeng Zhao
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fengqing Wang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wen Liu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhe Chen
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiguang Sun
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Lianghu Gu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Yonghui Zhang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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4
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Jiang F, Yu M, Wang Y. Design, synthesis and biological evaluation of novel diaryl-substituted fused nitrogen heterocycles as tubulin polymerization inhibitors to overcome multidrug resistance in vitro and in vivo. Eur J Med Chem 2025; 283:117130. [PMID: 39662283 DOI: 10.1016/j.ejmech.2024.117130] [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: 09/18/2024] [Revised: 11/12/2024] [Accepted: 12/01/2024] [Indexed: 12/13/2024]
Abstract
Microtubule-targeting agents (MTAs) are considered as one of the most successful chemotherapy drugs for lung adenocarcinoma (LUAD). However, the clinical application of MTAs is often significantly plagued by multidrug resistance (MDR). To overcome this limitation in the quest of more effective MTAs for tumor therapy, a series of novel diaryl-substituted nitrogenous fused heterocycles were designed, synthesized and evaluated. Through four rounds of structure-activity relationship studies, the benzoimidazole derivative 37 was identified as a potent cytotoxic agent against both paclitaxel-sensitive and -resistant A549 (A549/T) cells, effectively overcoming multidrug resistance of A549/T cells against various MTAs. Mechanistic investigations revealed that 37 could disrupt microtubule assembly and induce cell cycle arrest at the G2/M phase, and hence trigger the cell apoptosis. Furthermore, 37 was found to be a poor substrate for P-glycoprotein (P-gp), a major contributor to multidrug resistance, and could reduce the level of P-gp in resistant cells, thereby effectively overcoming P-gp-mediated multidrug resistance. Notably, 37 exhibited higher liver microsomal stability and better water solubility than those of the reference combretastatin A-4 (CA-4). In vivo studies using an A549/T xenograft model demonstrated that 37 significantly inhibited tumor growth without obvious toxicity, outperforming the positive controls CA-4 and paclitaxel. As a novel tubulin polymerization inhibitor, compound 37 is marked by potent anticancer activity and remarkable anti-MDR properties. These salient features, coupled with the low toxicity of 37, would render it quite promising as a lead for further drug development towards clinical treatment of multidrug-resistant LUAD.
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MESH Headings
- Humans
- Drug Resistance, Multiple/drug effects
- Drug Design
- Drug Resistance, Neoplasm/drug effects
- Tubulin Modulators/pharmacology
- Tubulin Modulators/chemical synthesis
- Tubulin Modulators/chemistry
- Structure-Activity Relationship
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Animals
- Tubulin/metabolism
- Heterocyclic Compounds/chemistry
- Heterocyclic Compounds/pharmacology
- Heterocyclic Compounds/chemical synthesis
- Mice
- Drug Screening Assays, Antitumor
- Cell Proliferation/drug effects
- Polymerization/drug effects
- Molecular Structure
- Apoptosis/drug effects
- Dose-Response Relationship, Drug
- Nitrogen/chemistry
- Mice, Nude
- Cell Line, Tumor
- Mice, Inbred BALB C
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/metabolism
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Affiliation(s)
- Fuhao Jiang
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Min Yu
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Yang Wang
- School of Pharmacy, Fudan University, Shanghai, 201203, China; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, 453007, China.
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5
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Madrid MF, Mendoza EN, Padilla AL, Choquenaira-Quispe C, de Jesus Guimarães C, de Melo Pereira JV, Barros-Nepomuceno FWA, Lopes Dos Santos I, Pessoa C, de Moraes Filho MO, Rocha DD, Ferreira PMP. In vitro models to evaluate multidrug resistance in cancer cells: Biochemical and morphological techniques and pharmacological strategies. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2025; 28:1-27. [PMID: 39363148 DOI: 10.1080/10937404.2024.2407452] [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: 10/05/2024]
Abstract
The overexpression of ATP-binding cassette (ABC) transporters contributes to the failure of chemotherapies and symbolizes a great challenge in oncology, associated with the adaptation of tumor cells to anticancer drugs such that these transporters become less effective, a mechanism known as multidrug resistance (MDR). The aim of this review is to present the most widely used methodologies for induction and comprehension of in vitro models for detection of multidrug-resistant (MDR) modulators or inhibitors, including biochemical and morphological techniques for chemosensitivity studies. The overexpression of MDR proteins, predominantly, the subfamily glycoprotein-1 (P-gp or ABCB1) multidrug resistance, multidrug resistance-associated protein 1 (MRP1 or ABCCC1), multidrug resistance-associated protein 2 (MRP2 or ABCC2) and cancer resistance protein (ABCG2), in chemotherapy-exposed cancer lines have been established/investigated by several techniques. Amongst these techniques, the most used are (i) colorimetric/fluorescent indirect bioassays, (ii) rhodamine and efflux analysis, (iii) release of 3,30-diethyloxacarbocyanine iodide by fluorescence microscopy and flow cytometry to measure P-gp function and other ABC transporters, (iv) exclusion of calcein-acetoxymethylester, (v) ATPase assays to distinguish types of interaction with ABC transporters, (vi) morphology to detail phenotypic characteristics in transformed cells, (vii) molecular testing of resistance-related proteins (RT-qPCR) and (viii) 2D and 3D models, (ix) organoids, and (x) microfluidic technology. Then, in vitro models for detecting chemotherapy MDR cells to assess innovative therapies to modulate or inhibit tumor cell growth and overcome clinical resistance. It is noteworthy that different therapies including anti-miRNAs, antibody-drug conjugates (to natural products), and epigenetic modifications were also considered as promising alternatives, since currently no anti-MDR therapies are able to improve patient quality of life. Therefore, there is also urgency for new clinical markers of resistance to more reliably reflect in vivo effectiveness of novel antitumor drugs.
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Affiliation(s)
- Maria Fernanda Madrid
- Drug Research and Development Center (NPDM), Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | - Eleicy Nathaly Mendoza
- Drug Research and Development Center (NPDM), Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | - Ana Lizeth Padilla
- Pharmaceutical Sciences, Faculty of Pharmacy, Dentistry, and Nursing, Federal University of Ceará, Fortaleza, Brazil
| | - Celia Choquenaira-Quispe
- Pharmaceutical Sciences, Faculty of Pharmacy, Dentistry, and Nursing, Federal University of Ceará, Fortaleza, Brazil
- Catholic University of Santa María, Arequipa, Perú
| | - Celina de Jesus Guimarães
- Drug Research and Development Center (NPDM), Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | - João Victor de Melo Pereira
- Drug Research and Development Center (NPDM), Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | | | - Ingredy Lopes Dos Santos
- Laboratory of Experimental Cancerology (LabCancer), Department of Biophysics and Physiology, Federal University of Piauí, Teresina, Brazil
| | - Claudia Pessoa
- Drug Research and Development Center (NPDM), Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | - Manoel Odorico de Moraes Filho
- Drug Research and Development Center (NPDM), Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | - Danilo Damasceno Rocha
- Drug Research and Development Center (NPDM), Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | - Paulo Michel Pinheiro Ferreira
- Laboratory of Experimental Cancerology (LabCancer), Department of Biophysics and Physiology, Federal University of Piauí, Teresina, Brazil
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6
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Amiri R, Nabi PN, Fazilat A, Roshani F, Nouhi Kararoudi A, Hemmati-Dinarvand M, Valilo M. Crosstalk between miRNAs and signaling pathways in the development of drug resistance in breast cancer. Horm Mol Biol Clin Investig 2024:hmbci-2024-0066. [PMID: 39665256 DOI: 10.1515/hmbci-2024-0066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 11/28/2024] [Indexed: 12/13/2024]
Abstract
One of the biggest challenges of today's society is cancer, which imposes a significant financial, emotional and spiritual burden on human life. Breast cancer (BC) is one of the most common cancers that affects people in society, especially women, and due to advanced treatment strategies and primary prevention, it is still the second cause of cancer-related deaths in society. Various genetic and environmental factors are involved in the development of BC. MicroRNAs (miRNA)s are non-coding RNAs, that the degradation or inhibition of them plays an important role in the prevention or development of cancer by modulating many cellular pathways including apoptosis, drug resistance, and tumorigenesis. Drug resistance is one of the important defense mechanisms of cancer cells against anticancer drugs and is considered one of the main causes of cancer treatment failure. Different miRNAs, including mir-7, mir-21, mir-31, and mir-124 control different cell activities, including drug resistance, through different pathways, including PI3K/AKT/mTOR, TGF-β, STAT3, and NF-kB. Therefore, cell signaling pathways are one of the important factors that miRNAs control cellular activities. Hence, in this study, we decided to highlight an overview of the relationship between miRNAs and signaling pathways in the development of drug resistance in BC.
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Affiliation(s)
- Reza Amiri
- Nargund College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bengaluru, Karnataka, India
| | | | - Ahmad Fazilat
- Department of Genetics, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Fatemeh Roshani
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Alireza Nouhi Kararoudi
- Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Mohsen Hemmati-Dinarvand
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Valilo
- Department of Biochemistry, 37555 Faculty of Medicine, Urmia University of Medical Sciences , Urmia, Iran
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7
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Kang MJ, Lee KR, Choi YJ, Chae YJ. Identification of flavonol derivatives inhibiting MDR1: a strategy to overcome multidrug resistance in cancer. Nat Prod Res 2024:1-9. [PMID: 39497580 DOI: 10.1080/14786419.2024.2420333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/26/2024] [Accepted: 10/16/2024] [Indexed: 11/12/2024]
Abstract
Multidrug resistance is a crucial factor contributing to the failure of cancer treatment. Multidrug resistance protein 1 (MDR1) is the most relevant efflux transporter associated with multidrug resistance. The objective of this study was to identify potent MDR1 inhibitors from flavonols. Fifteen flavonols were identified as inhibitors of MDR1 in vitro, with four compounds exhibiting strong inhibitory activity, having IC50 values below 5 μM. These potent MDR1 inhibitors were found to enhance chemosensitivity to doxorubicin in MDR1-overexpressing cells. The results of the multiple-factor analysis indicated that the 3, 5, and 6-methoxy groups were crucial for enhancing the inhibitory effects on MDR1. Furthermore, the total number of methoxy groups in the flavonol backbone was found to be a significant factor in determining the potency of MDR1 inhibition. These observations provide fundamental insights into the structure-activity relationship between flavonol derivatives and MDR1 inhibition, potentially aiding in overcoming drug resistance in cancer.
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Affiliation(s)
- Min-Ji Kang
- College of Pharmacy, Woosuk University, Wanju, Republic of Korea
| | - Kyeong-Ryoon Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
- Department of Bioscience, University of Science and Technology, Daejeon, Republic of Korea
| | - You-Jin Choi
- College of Pharmacy, Daegu Catholic University, Gyeongsan, Republic of Korea
| | - Yoon-Jee Chae
- College of Pharmacy, Woosuk University, Wanju, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Woosuk University, Wanju, Republic of Korea
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8
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Amin MN, Abdelmohsen UR, Samra YA. Turkish coffee has an antitumor effect on breast cancer cells in vitro and in vivo. Nutr Metab (Lond) 2024; 21:73. [PMID: 39272080 PMCID: PMC11396339 DOI: 10.1186/s12986-024-00846-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND Breast cancer is the most diagnosed cancer in women. Its pathogenesis includes several pathways in cancer proliferation, apoptosis, and metastasis. Some clinical data have indicated the association between coffee consumption and decreased cancer risk. However, little data is available on the effect of coffee on breast cancer cells in vitro and in vivo. METHODS In our study, we assessed the effect of Turkish coffee and Fridamycin-H on different pathways in breast cancer, including apoptosis, proliferation, and oxidative stress. A human breast cancer cell line (MCF-7) was treated for 48 h with either coffee extract (5% or 10 v/v) or Fridamycin-H (10 ng/ml). Ehrlich solid tumors were induced in mice for in vivo modeling of breast cancer. Mice with Ehrlich solid tumors were treated orally with coffee extract in drinking water at a final concentration (v/v) of either 3%, 5%, or 10% daily for 21 days. Protein expression levels of Caspase-8 were determined in both in vitro and in vivo models using ELISA assay. Moreover, P-glycoprotein and peroxisome proliferator-activated receptor gamma (PPAR-γ) protein expression levels were analyzed in the in vitro model. β-catenin protein expression was analyzed in tumor sections using immunohistochemical analysis. In addition, malondialdehyde (MDA) serum levels were analyzed using colorimetry. RESULTS Both coffee extract and Fridamycin-H significantly increased Caspase-8, P-glycoprotein, and PPAR-γ protein levels in MCF-7 cells. Consistently, all doses of in vivo coffee treatment induced a significant increase in Caspase-8 and necrotic zones and a significant decrease in β- catenin, MDA, tumor volume, tumor weight, and viable tumor cell density. CONCLUSION These findings suggest that coffee extract and Fridamycin-H warrant further exploration as potential therapies for breast cancer.
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Affiliation(s)
- Mohamed N Amin
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Usama Ramadan Abdelmohsen
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
- Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, New Minia City, 61111, Egypt
| | - Yara A Samra
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
- Department of Basic Medical Sciences, Faculty of Oral and Dental Medicine, Ahram Canadian University, Giza, 12566, Egypt
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9
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Said AM, Mansour YE, Soliman RR, Islam R, Fatahala SS. Design, synthesis, molecular modeling, in vitro and in vivo biological evaluation of potent anthranilamide derivatives as dual P-glycoprotein and CYP3A4 inhibitors. Eur J Med Chem 2024; 273:116492. [PMID: 38762918 DOI: 10.1016/j.ejmech.2024.116492] [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: 03/09/2024] [Revised: 05/06/2024] [Accepted: 05/08/2024] [Indexed: 05/21/2024]
Abstract
Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition. Herein, we report the rational design and evaluation of novel dual potent inhibitors of P-gp and CYP3A4 using an anthranilamide derivative tariquidar as a starting point for their structural optimizations. Compound 14f, bearing N-imidazolylbenzyl side chain, was found to have potent and selective P-gp (EC50 = 28 nM) and CYP3A4 (IC50 = 223 nM) inhibitory activities with low absorption potential (Papp (A-to-B) <0.06). In vivo, inhibitor 14f improved the oral absorption of paclitaxel by 6 times in mice and by 30 times in rats as compared to vehicle, while 14f itself remained poorly absorbed. Compound 14f, possessing dual P-gp and CYP3A4 inhibitory activities, offered additional enhancement in paclitaxel oral absorption compared to tariquidar in mice. Evaluating the CYP effect of 14f on oral absorption of paclitaxel requires considering the variations in CYP expression between animal species. This study provides further medicinal chemistry advice on strategies for resolving concerns with the oral administration of chemotherapeutic agents.
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Affiliation(s)
- Ahmed M Said
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, BCC, Omaha, NE, 68198, USA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt; Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.
| | - Yara E Mansour
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt
| | - Radwa R Soliman
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA
| | - Ridwan Islam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, BCC, Omaha, NE, 68198, USA
| | - Samar S Fatahala
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo, 11795, Egypt.
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10
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Vences-Guzmán MÁ, Jiménez-Rodríguez M, Lozano L, Rojas-Juárez S, Ramírez-Estudillo JA, Hernández-Vázquez ÁY, Pita-Ortiz IY, Ramírez-Ceballos KG, Medina-Medina S, Sohlenkamp C. A clinical metagenomic study of biopsies from Mexican endophthalmitis patients reveals the presence of complex bacterial communities and a diversity of resistance genes. Access Microbiol 2024; 6:000639.v3. [PMID: 39045243 PMCID: PMC11261729 DOI: 10.1099/acmi.0.000639.v3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 05/13/2024] [Indexed: 07/25/2024] Open
Abstract
Infectious endophthalmitis is a severe ophthalmic emergency. This infection can be caused by bacteria and fungi. For efficient treatment, the administration of antimicrobial drugs to which the microbes are susceptible is essential. The aim of this study was to identify micro-organisms in biopsies of Mexican endophthalmitis patients using metagenomic next-generation sequencing and determine which antibiotic resistance genes were present in the biopsy samples. In this prospective case study, 19 endophthalmitis patients were recruited. Samples of vitreous or aqueous humour were extracted for DNA extraction for metagenomic next-generation sequencing. Analysis of the sequencing results revealed the presence of a wide variety of bacteria in the biopsies. Resistome analysis showed that homologues of antibiotic resistance genes were present in several biopsy samples. Genes possibly conferring resistance to ceftazidime and vancomycin were detected in addition to various genes encoding efflux pumps. Our findings contrast with the widespread opinion that only one or a few bacterial strains are present in the infected tissues of endophthalmitis patients. These diverse communities might host many of the resistance genes that were detected, which can further complicate the infections.
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Affiliation(s)
| | | | - Luis Lozano
- Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico
| | - Sergio Rojas-Juárez
- Departamento de Retina, Fundación Hospital Nuestra Señora de la Luz IAP, Mexico City, Mexico
| | | | | | | | | | - Silvia Medina-Medina
- Departamento de Retina, Fundación Hospital Nuestra Señora de la Luz IAP, Mexico City, Mexico
| | - Christian Sohlenkamp
- Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, Mexico
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11
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Yang Q, To KKW, Hu G, Fu K, Yang C, Zhu S, Pan C, Wang F, Luo K, Fu L. BI-2865, a pan-KRAS inhibitor, reverses the P-glycoprotein induced multidrug resistance in vitro and in vivo. Cell Commun Signal 2024; 22:325. [PMID: 38872211 PMCID: PMC11170860 DOI: 10.1186/s12964-024-01698-4] [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: 03/15/2024] [Accepted: 06/03/2024] [Indexed: 06/15/2024] Open
Abstract
BACKGROUND Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored. METHODS The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts' tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate's efflux were analyzed through the vanadate-sensitive ATPase assay, [125I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence. RESULTS We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What's more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity. CONCLUSIONS This study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers.
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MESH Headings
- Humans
- Animals
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Multiple/drug effects
- Mice
- Cell Line, Tumor
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- Xenograft Model Antitumor Assays
- Mice, Nude
- Doxorubicin/pharmacology
- Mice, Inbred BALB C
- Female
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Affiliation(s)
- Qihong Yang
- People's Hospital of Longhua, Shenzhen, 518109, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Kenneth Kin Wah To
- School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Guilin Hu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
| | - Kai Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Chuan Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Shuangli Zhu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Can Pan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Fang Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Kewang Luo
- People's Hospital of Longhua, Shenzhen, 518109, China.
| | - Liwu Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
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12
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Shchulkin AV, Abalenikhina YV, Kosmachevskaya OV, Topunov AF, Yakusheva EN. Regulation of P-Glycoprotein during Oxidative Stress. Antioxidants (Basel) 2024; 13:215. [PMID: 38397813 PMCID: PMC10885963 DOI: 10.3390/antiox13020215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/02/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
P-glycoprotein (Pgp, ABCB1, MDR1) is an efflux transporter protein that removes molecules from the cells (outflow) into the extracellular space. Pgp plays an important role in pharmacokinetics, ensuring the absorption, distribution, and excretion of drugs and its substrates, as well as in the transport of endogenous molecules (steroid and thyroid hormones). It also contributes to tumor cell resistance to chemotherapy. In this review, we summarize the mechanisms of Pgp regulation during oxidative stress. The currently available data suggest that Pgp has a complex variety of regulatory mechanisms under oxidative stress, involving many transcription factors, the main ones being Nrf2 and Nf-kB. These factors often overlap, and some can be activated under certain conditions, such as the deposition of oxidation products, depending on the severity of oxidative stress. In most cases, the expression of Pgp increases due to increased transcription and translation, but under severe oxidative stress, it can also decrease due to the oxidation of amino acids in its molecule. At the same time, Pgp acts as a protector against oxidative stress, eliminating the causative factors and removing its by-products, as well as participating in signaling pathways.
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Affiliation(s)
- Aleksey V. Shchulkin
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
| | - Yulia V. Abalenikhina
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
| | - Olga V. Kosmachevskaya
- Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia; (O.V.K.); (A.F.T.)
| | - Alexey F. Topunov
- Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia; (O.V.K.); (A.F.T.)
| | - Elena N. Yakusheva
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
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13
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de Almeida Gomes I, da Lima AB, da Silva Brito DM, Almeida Lima A, de Oliveira FL, Espino Zelaya EA, Magalhães Rebello Alencar L, Castelo Branco de Souza Collares Maia D, Amaral de Moraes ME, Pantoja Mesquita F, Noronha Souza PF, Montenegro RC. Recalculating the Route: Repositioning Antimicrobial Peptides for Cancer Treatment. Chem Biodivers 2024; 21:e202301840. [PMID: 38088493 DOI: 10.1002/cbdv.202301840] [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: 11/20/2023] [Accepted: 12/03/2023] [Indexed: 02/22/2024]
Abstract
Resistance to antimicrobial drugs has been considered a public health problem. Likewise, the increasing resistance of cancer cells to drugs currently used in therapy has also become a problem. Therefore, the research and development of synthetic peptides bring a new perspective on the emergence of new drugs for treating this resistance since bioinformatics provides a means to optimize these molecules and save time and costs in research. Peptides have several mechanisms of action, such as forming pores on the cell membrane and inhibiting protein synthesis. Some studies report the use of antimicrobial peptides with the potential for action against cancer cells, suggesting a repositioning of antimicrobial peptides to fight back cancer resistance. There is an alteration in the microenvironment, making its net charge negative for the survival and growth of cancer cells. The changes in glycoproteins favor the membrane to have a more negative charge, favoring the interaction between the cells and the peptide, thus making possible the repositioning of these antimicrobial peptides against cancer. Here, we will discuss the mechanism of action, targets and effects of peptides, comparison between microbial and cancer cells, and proteomic changes caused by the interaction of peptides and cells.
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Affiliation(s)
- Isadora de Almeida Gomes
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
| | - Ana Beatriz da Lima
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
| | - Daiane Maria da Silva Brito
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, 60020-181, CE, Brazil
| | - Arlene Almeida Lima
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
| | - Francisco Laio de Oliveira
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
| | - Elmer Adilson Espino Zelaya
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
| | | | | | - Maria Elisabete Amaral de Moraes
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
| | - Felipe Pantoja Mesquita
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
| | - Pedro Filho Noronha Souza
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
| | - Raquel C Montenegro
- Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Rua Coronel Nunes de Melo 1000, Fortaleza, CE, 60430-275, Brazil
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14
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Gewering T, Waghray D, Parey K, Jung H, Tran NNB, Zapata J, Zhao P, Chen H, Januliene D, Hummer G, Urbatsch I, Moeller A, Zhang Q. Tracing the substrate translocation mechanism in P-glycoprotein. eLife 2024; 12:RP90174. [PMID: 38259172 PMCID: PMC10945689 DOI: 10.7554/elife.90174] [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] [Indexed: 01/24/2024] Open
Abstract
P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs (Juliano and Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds (Loo and Clarke, 2000; Loo et al., 2009; Aller et al., 2009; Alam et al., 2019; Nosol et al., 2020; Chufan et al., 2015), but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.
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Affiliation(s)
- Theresa Gewering
- Osnabrück University, Department of Biology/Chemistry, Structural Biology SectionOsnabrückGermany
- Department of Structural Biology, Max Planck Institute of BiophysicsFrankfurtGermany
| | - Deepali Waghray
- Department of Integrative Structural and Computational Biology, The Scripps Research InstituteLa JollaUnited States
| | - Kristian Parey
- Osnabrück University, Department of Biology/Chemistry, Structural Biology SectionOsnabrückGermany
- Department of Structural Biology, Max Planck Institute of BiophysicsFrankfurtGermany
- Osnabrück University, Center of Cellular Nanoanalytic Osnabrück (CellNanOs)OsnabrückGermany
| | - Hendrik Jung
- Department of Theoretical Biophysics, Max Planck Institute of BiophysicsFrankfurtGermany
| | - Nghi NB Tran
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences CenterLubbockUnited States
| | - Joel Zapata
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences CenterLubbockUnited States
| | - Pengyi Zhao
- Department of Chemistry & Environmental Science, New Jersey Institute of TechnologyNewarkUnited States
| | - Hao Chen
- Department of Chemistry & Environmental Science, New Jersey Institute of TechnologyNewarkUnited States
| | - Dovile Januliene
- Osnabrück University, Department of Biology/Chemistry, Structural Biology SectionOsnabrückGermany
- Department of Structural Biology, Max Planck Institute of BiophysicsFrankfurtGermany
- Osnabrück University, Center of Cellular Nanoanalytic Osnabrück (CellNanOs)OsnabrückGermany
| | - Gerhard Hummer
- Department of Theoretical Biophysics, Max Planck Institute of BiophysicsFrankfurtGermany
- Institute for Biophysics, Goethe University FrankfurtFrankfurtGermany
| | - Ina Urbatsch
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences CenterLubbockUnited States
| | - Arne Moeller
- Osnabrück University, Department of Biology/Chemistry, Structural Biology SectionOsnabrückGermany
- Department of Structural Biology, Max Planck Institute of BiophysicsFrankfurtGermany
- Osnabrück University, Center of Cellular Nanoanalytic Osnabrück (CellNanOs)OsnabrückGermany
| | - Qinghai Zhang
- Department of Integrative Structural and Computational Biology, The Scripps Research InstituteLa JollaUnited States
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15
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Damiani D, Tiribelli M. ATP-Binding Cassette Subfamily G Member 2 in Acute Myeloid Leukemia: A New Molecular Target? Biomedicines 2024; 12:111. [PMID: 38255216 PMCID: PMC10813371 DOI: 10.3390/biomedicines12010111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/21/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Despite the progress in the knowledge of disease pathogenesis and the identification of many molecular markers as potential targets of new therapies, the cure of acute myeloid leukemia remains challenging. Disease recurrence after an initial response and the development of resistance to old and new therapies account for the poor survival rate and still make allogeneic stem cell transplantation the only curative option. Multidrug resistance (MDR) is a multifactorial phenomenon resulting from host-related characteristics and leukemia factors. Among these, the overexpression of membrane drug transporter proteins belonging to the ABC (ATP-Binding Cassette)-protein superfamily, which diverts drugs from their cellular targets, plays an important role. Moreover, a better understanding of leukemia biology has highlighted that, at least in cancer, ABC protein's role goes beyond simple drug transport and affects many other cell functions. In this paper, we summarized the current knowledge of ABCG2 (formerly Breast Cancer Resistance Protein, BCRP) in acute myeloid leukemia and discuss the potential ways to overcome its efflux function and to revert its ability to confer stemness to leukemia cells, favoring the persistence of leukemia progenitors in the bone marrow niche and justifying relapse also after therapy intensification with allogeneic stem cell transplantation.
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Affiliation(s)
- Daniela Damiani
- Division of Hematology and Stem Cell Transplantation, Udine Hospital, 33100 Udine, Italy;
- Department of Medicine, Udine University, 33100 Udine, Italy
| | - Mario Tiribelli
- Division of Hematology and Stem Cell Transplantation, Udine Hospital, 33100 Udine, Italy;
- Department of Medicine, Udine University, 33100 Udine, Italy
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16
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Fantone S, Piani F, Olivieri F, Rippo MR, Sirico A, Di Simone N, Marzioni D, Tossetta G. Role of SLC7A11/xCT in Ovarian Cancer. Int J Mol Sci 2024; 25:587. [PMID: 38203758 PMCID: PMC10779187 DOI: 10.3390/ijms25010587] [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: 11/18/2023] [Revised: 12/21/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Ovarian cancer is one of the most dangerous gynecologic cancers worldwide and has a high fatality rate due to diagnosis at an advanced stage of the disease as well as a high recurrence rate due to the occurrence of chemotherapy resistance. In fact, chemoresistance weakens the therapeutic effects, worsening the outcome of this pathology. Solute Carrier Family 7 Member 11 (SLC7A11, also known as xCT) is the functional subunit of the Xc- system, an anionic L-cystine/L-glutamate antiporter expressed on the cell surface. SLC7A11 expression is significantly upregulated in several types of cancers in which it can inhibit ferroptosis and favor cancer cell proliferation, invasion and chemoresistance. SLC7A11 expression is also increased in ovarian cancer tissues, suggesting a possible role of this protein as a therapeutic target. In this review, we provide an overview of the current literature regarding the role of SLC7A11 in ovarian cancer to provide new insights on SLC7A11 modulation and evaluate the potential role of SLC7A11 as a therapeutic target.
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Affiliation(s)
- Sonia Fantone
- Scientific Direction, IRCCS INRCA, 60124 Ancona, Italy; (S.F.); (F.O.)
| | - Federica Piani
- Hypertension and Cardiovascular Risk Research Center, Medical and Surgical Sciences Department, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy;
| | - Fabiola Olivieri
- Scientific Direction, IRCCS INRCA, 60124 Ancona, Italy; (S.F.); (F.O.)
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy;
| | - Maria Rita Rippo
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy;
| | - Angelo Sirico
- Obstetrics and Gynecology Unit, Sant’Anna e San Sebastiano Hospital, 81100 Caserta, Italy;
| | - Nicoletta Di Simone
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy;
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Daniela Marzioni
- Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy;
| | - Giovanni Tossetta
- Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy;
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17
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Zheng E, Madura P, Grandos J, Broncel M, Pawlos A, Woźniak E, Gorzelak-Pabiś P. When the same treatment has different response: The role of pharmacogenomics in statin therapy. Biomed Pharmacother 2024; 170:115966. [PMID: 38061135 DOI: 10.1016/j.biopha.2023.115966] [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: 09/17/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024] Open
Abstract
Statins, also known as HMG-CoA reductase inhibitors, are one of the most potently prescribed and thoroughly researched medications, predominantly utilized for managing cardiovascular diseases by modulating serum cholesterol levels. Despite the well-documented efficacy of statins in reducing overall mortality via attenuating the risk of cardiovascular diseases, notable interindividual variability in therapeutic responses persists as such variability could compromise the lipid-lowering efficacy of the drug, potentially increasing susceptibility to adverse effects or attenuating therapeutic outcomes.This phenomenon has catalysed a growing interest in the scientific community to explore common genetic polymorphisms within genes that encode for pivotal enzymes within the pharmacokinetic pathways of statins. In our review, we focus to provide insight into potentially clinically relevant polymorphisms associated with statins' pharmacokinetic participants and assess their consequent implications on modulating the therapeutic outcomes of statins among distinct genetic carrier.
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Affiliation(s)
- Edward Zheng
- Dept. of Internal Diseases and Clinical Pharmacology, The Laboratory of Tissue Immunopharmacology, Medical University of Lodz, Poland
| | - Paulina Madura
- Dept. of Internal Diseases and Clinical Pharmacology, The Laboratory of Tissue Immunopharmacology, Medical University of Lodz, Poland
| | - Jakub Grandos
- Dept. of Internal Diseases and Clinical Pharmacology, The Laboratory of Tissue Immunopharmacology, Medical University of Lodz, Poland
| | - Marlena Broncel
- Dept. of Internal Diseases and Clinical Pharmacology, The Laboratory of Tissue Immunopharmacology, Medical University of Lodz, Poland
| | - Agnieszka Pawlos
- Dept. of Internal Diseases and Clinical Pharmacology, The Laboratory of Tissue Immunopharmacology, Medical University of Lodz, Poland
| | - Ewelina Woźniak
- Dept. of Internal Diseases and Clinical Pharmacology, The Laboratory of Tissue Immunopharmacology, Medical University of Lodz, Poland
| | - Paulina Gorzelak-Pabiś
- Dept. of Internal Diseases and Clinical Pharmacology, The Laboratory of Tissue Immunopharmacology, Medical University of Lodz, Poland.
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18
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Jorgensen C, Ulmschneider MB, Searson PC. Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood-Brain Barrier. J Med Chem 2023; 66:16615-16627. [PMID: 38097510 PMCID: PMC12036829 DOI: 10.1021/acs.jmedchem.3c01069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
We report molecular dynamics simulations of rhodamine entry into the central binding cavity of P-gp in the inward open conformation. Rhodamine can enter the inner volume via passive transport across the luminal membrane or lateral diffusion in the lipid bilayer. Entry into the inner volume is determined by the aperture angle at the apex of the protein, with a critical angle of 27° for rhodamine. The central binding cavity has an aqueous phase with a few lipids, which significantly reduces substrate diffusion. Within the central binding cavity, we identified regions with relatively weak binding, suggesting that the combination of reduced mobility and weak substrate binding confines rhodamine to enable the completion of the efflux cycle. Tariquidar, a P-gp inhibitor, aggregates at the lower arms of the P-gp, suggesting that inhibition involves steric hindrance of entry into the inner volume and/or steric hindrance of access of ATP to the nucleotide-binding domains.
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Affiliation(s)
- Christian Jorgensen
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
| | | | - Peter C. Searson
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
- Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
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19
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Zhao H. Kinetic modelling of the P-glycoprotein mediated efflux with a large-scale matched molecular pair analysis. Eur J Med Chem 2023; 261:115830. [PMID: 37774507 DOI: 10.1016/j.ejmech.2023.115830] [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: 05/30/2023] [Revised: 09/19/2023] [Accepted: 09/21/2023] [Indexed: 10/01/2023]
Abstract
P-glycoprotein (Pgp) mediated efflux impacts on the drug absorption, distribution, metabolism and excretion, and confers multidrug resistance to cancer cells. Kinetic modelling provides mechanistic insights into the relationship between the substrate-Pgp interactions and efflux, and bridges the gap between the preference of polar compounds as Pgp substrates and the hydrophobic nature of its drug-binding site. Matched molecular pair analysis supports the guidelines of controlling H-bond donors and polar surface area in the efflux mitigation, but also reveals insufficiency of this type of rule-based approach. Contrary to the rule-of-five compliant compounds, proteolysis-targeting chimeras (PROTACs) have shown the opposite preference of physicochemical properties to evade efflux. Our analysis reiterates the critical role of intrinsic passive permeability in the efflux ratio, and indeed, its mitigation is often driven by increased passive permeability. It is thus useful to separate the passive permeability from the structural context-specific substrate-Pgp interactions in the design cycle.
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Affiliation(s)
- Hongtao Zhao
- Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
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20
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Paskas S, Stockmann P, Mijatović S, Kuhnert L, Honscha W, Hey-Hawkins E, Maksimović-Ivanić D. Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin. Pharmaceuticals (Basel) 2023; 16:1582. [PMID: 38004447 PMCID: PMC10674596 DOI: 10.3390/ph16111582] [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: 09/19/2023] [Revised: 11/01/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug resistance, has the ability to transport a broad spectrum of substrates out of the cell and is, therefore, considered as a potential target to improve cancer therapies or as an approach to combat drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein (BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently, with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa, DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480 cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly, co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However, a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition by the carborane derivatives emerges as a possible reason.
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Affiliation(s)
- Svetlana Paskas
- Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, Belgrade University, 11060 Belgrade, Serbia; (S.P.); (S.M.)
| | - Philipp Stockmann
- Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
| | - Sanja Mijatović
- Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, Belgrade University, 11060 Belgrade, Serbia; (S.P.); (S.M.)
| | - Lydia Kuhnert
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany; (L.K.); (W.H.)
| | - Walther Honscha
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany; (L.K.); (W.H.)
| | - Evamarie Hey-Hawkins
- Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
| | - Danijela Maksimović-Ivanić
- Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, Belgrade University, 11060 Belgrade, Serbia; (S.P.); (S.M.)
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21
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Sonam Dongsar T, Tsering Dongsar T, Molugulu N, Annadurai S, Wahab S, Gupta N, Kesharwani P. Targeted therapy of breast tumor by PLGA-based nanostructures: The versatile function in doxorubicin delivery. ENVIRONMENTAL RESEARCH 2023; 233:116455. [PMID: 37356522 DOI: 10.1016/j.envres.2023.116455] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/15/2023] [Accepted: 06/17/2023] [Indexed: 06/27/2023]
Abstract
Breast carcinoma is a molecularly diverse illness, and it is among the most prominent and often reported malignancies in female across the globe. Surgical intervention, chemotherapy, immunotherapy, gene therapy, and endocrine treatment are among the currently viable treatment options for the carcinoma of breast. Chemotherapy is among the most prevalent cancer management strategy. Doxorubicin (DOX) widely employed as a cytostatic medication for the treatment of a variety of malignancies. Despite its widespread acceptance and excellent efficacy against an extensive line up of neoplasia, it has a variety of shortcomings that limit its therapeutic potential in the previously mentioned indications. Employment of nanoparticulate systems has come up as a unique chemo medication delivery strategy and are being considerably explored for the amelioration of breast carcinoma. Polylactic-co-glycolic acid (PLGA)-based nano systems are being utilized in a number of areas within the medical research and medication delivery constitutes one of the primary functions for PLGA given their inherent physiochemical attributes, including their aqueous solubility, biocompatibility, biodegradability, versatility in formulation, and limited toxicity. Herein along with the different application of PLGA-based nano formulations in cancer therapy, the present review intends to describe the various research investigations that have been conducted to enumerate the effectiveness of DOX-encapsulated PLGA nanoparticles (DOX-PLGA NPs) as a feasible treatment option for breast cancer.
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Affiliation(s)
- Tenzin Sonam Dongsar
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Tenzin Tsering Dongsar
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Nagashekhara Molugulu
- School of Pharmacy, Monash University, Bandar Sunway, Jalan Lagoon Selatan, 47500, Malaysia
| | - Sivakumar Annadurai
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Neelima Gupta
- Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, 470003, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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22
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Gutay-Tóth Z, Gellen G, Doan M, Eliason JF, Vincze J, Szente L, Fenyvesi F, Goda K, Vecsernyés M, Szabó G, Bacso Z. Cholesterol-Depletion-Induced Membrane Repair Carries a Raft Conformer of P-Glycoprotein to the Cell Surface, Indicating Enhanced Cholesterol Trafficking in MDR Cells, Which Makes Them Resistant to Cholesterol Modifications. Int J Mol Sci 2023; 24:12335. [PMID: 37569709 PMCID: PMC10419235 DOI: 10.3390/ijms241512335] [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: 07/01/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
The human P-glycoprotein (P-gp), a transporter responsible for multidrug resistance, is present in the plasma membrane's raft and non-raft domains. One specific conformation of P-gp that binds to the monoclonal antibody UIC2 is primarily associated with raft domains and displays heightened internalization in cells overexpressing P-gp, such as in NIH-3T3 MDR1 cells. Our primary objective was to investigate whether the trafficking of this particular P-gp conformer is dependent on cholesterol levels. Surprisingly, depleting cholesterol using cyclodextrin resulted in an unexpected increase in the proportion of raft-associated P-gp within the cell membrane, as determined by UIC2-reactive P-gp. This increase appears to be a compensatory response to cholesterol loss from the plasma membrane, whereby cholesterol-rich raft micro-domains are delivered to the cell surface through an augmented exocytosis process. Furthermore, this exocytotic event is found to be part of a complex trafficking mechanism involving lysosomal exocytosis, which contributes to membrane repair after cholesterol reduction induced by cyclodextrin treatment. Notably, cells overexpressing P-gp demonstrated higher total cellular cholesterol levels, an increased abundance of stable lysosomes, and more effective membrane repair following cholesterol modifications. These modifications encompassed exocytotic events that involved the transport of P-gp-carrying rafts. Importantly, the enhanced membrane repair capability resulted in a durable phenotype for MDR1 expressing cells, as evidenced by significantly improved viabilities of multidrug-resistant Pgp-overexpressing immortal NIH-3T3 MDR1 and MDCK-MDR1 cells compared to their parents when subjected to cholesterol alterations.
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Affiliation(s)
- Zsuzsanna Gutay-Tóth
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Gabriella Gellen
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
- MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Department of Analytical Chemistry, Institute of Chemistry, ELTE Eötvös Loránd University, 1053 Budapest, Hungary
| | - Minh Doan
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
| | - James F. Eliason
- Great Lakes Stem Cell Innovation Center, Detroit, MI 48202, USA;
| | - János Vincze
- Department of Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Lajos Szente
- CycloLab Cyclodextrin Research & Development Laboratory, Ltd., 1097 Budapest, Hungary;
| | - Ferenc Fenyvesi
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (F.F.); (M.V.)
| | - Katalin Goda
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
| | - Miklós Vecsernyés
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (F.F.); (M.V.)
| | - Gábor Szabó
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
| | - Zsolt Bacso
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.G.-T.); (G.G.); (M.D.); (K.G.); (G.S.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (F.F.); (M.V.)
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23
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Gholizadeh Siahmazgi Z, Irani S, Ghiaseddin A, Fallah P, Haghpanah V. Xanthohumol hinders invasion and cell cycle progression in cancer cells through targeting MMP2, MMP9, FAK and P53 genes in three-dimensional breast and lung cancer cells culture. Cancer Cell Int 2023; 23:153. [PMID: 37533078 PMCID: PMC10394853 DOI: 10.1186/s12935-023-03009-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 07/28/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Despite recent advances in the treatment of lung and breast cancer, the mortality with these two types of cancer is high. Xanthohumol (XN) is known as a bioactive compound that shows an anticancer effect on cancer cells. Here, we intended to investigate the anticancer effects of XN on the breast and lung cancer cell lines, using the three-dimensional (3D) cell culture. METHODS XN was isolated from Humulus lupulus using Preparative-Thin Layer Chromatography (P-TLC) method and its authenticity was documented through Fourier Transform Infrared spectroscopy (FT-IR) and Hydrogen Nuclear Magnetic Resonance (H-NMR) methods. The spheroids of the breast (MCF-7) and lung (A549) cancer cell lines were prepared by the Hanging Drop (HD) method. Subsequently, the IC50s of XN were determined using the MTT assay in 2D and 3D cultures. Apoptosis was evaluated by Annexin V/PI flow cytometry and NFκB1/2, BAX, BCL2, and SURVIVIN expressions. Cell cycle progression was determined by P21, and P53 expressions as well as PI flow cytometry assays. Multidrug resistance was investigated through examining the expression of MDR1 and ABCG2. The invasion was examined by MMP2, MMP9, and FAK expression and F-actin labeling with Phalloidin-iFluor. RESULTS While the IC50s for the XN treatment were 1.9 µM and 4.74 µM in 2D cultures, these values were 12.37 µM and 31.17 µM in 3D cultures of MCF-7 and A549 cells, respectively. XN induced apoptosis in MCF-7 and A549 cell lines. Furthermore, XN treatment reduced cell cycle progression, multidrug resistance, and invasion at the molecular and/or cellular levels. CONCLUSIONS According to our results of XN treatment in 3D conditions, this bioactive compound can be introduced as an adjuvant anti-cancer agent for breast and lung cancer.
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Affiliation(s)
| | - Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ali Ghiaseddin
- Department of Biomedical Engineering Division, Chemical Engineering Faculty, Tarbiat Modares University, Tehran, Iran
| | - Parviz Fallah
- Laboratory Science Department, Allied Medicine Faculty, Alborz University of Medical Sciences, Karaj, Iran
| | - Vahid Haghpanah
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Endocrinology and Metabolism Research Center (EMRC), Dr. Shariati Hospital, North Kargar Ave, 14114, Tehran, Iran.
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24
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Ibrahim MAA, Abdeljawaad KAA, Abdelrahman AHM, Sidhom PA, Tawfeek AM, Mekhemer GAH, Abd El-Rahman MK, Dabbish E, Shoeib T. In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study. Pharmaceuticals (Basel) 2023; 16:1019. [PMID: 37513931 PMCID: PMC10384459 DOI: 10.3390/ph16071019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/11/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Multidrug resistance (MDR) is one of the most problematic issues in chemotherapeutic carcinoma therapy. The ABCB1 transporter, a drug efflux pump overexpressed in cancer cells, has been thoroughly investigated for its association with MDR. Thus, discovering ABCB1 inhibitors can reverse the MDR in cancer cells. In the current work, a molecular docking technique was utilized for hunting the most prospective ABCB1 inhibitors from the Toxin and Toxin-Target Database (T3DB). Based on the docking computations, the most promising T3DB compounds complexed with the ABCB1 transporter were subjected to molecular dynamics (MD) simulations over 100 ns. Utilizing the MM-GBSA approach, the corresponding binding affinities were computed. Compared to ZQU (calc. -49.8 kcal/mol), Emamectin B1a (T3D1043), Emamectin B1b (T3D1044), Vincristine (T3D4016), Vinblastine (T3D4017), and Vindesine (T3D2479) complexed with ABCB1 transporter demonstrated outstanding binding affinities with ΔGbinding values of -93.0, -92.6, -93.8, -92.2, and -90.8 kcal/mol, respectively. The structural and energetic investigations confirmed the constancy of the identified T3DB compounds complexed with the ABCB1 transporter during the 100 ns MD course. To mimic the physiological conditions, MD simulations were conducted for those identified inhibitors complexed with ABCB1 transporter in the presence of a POPC membrane. These findings revealed that Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse the MDR. Therefore, subjecting those compounds to further in-vitro and in-vivo investigations is worthwhile.
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Affiliation(s)
- Mahmoud A A Ibrahim
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt
- School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa
| | - Khlood A A Abdeljawaad
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt
| | - Alaa H M Abdelrahman
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt
| | - Peter A Sidhom
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
| | - Ahmed M Tawfeek
- Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Gamal A H Mekhemer
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt
| | - Mohamed K Abd El-Rahman
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
| | - Eslam Dabbish
- Department of Chemistry, The American University in Cairo, New Cairo 11835, Egypt
| | - Tamer Shoeib
- Department of Chemistry, The American University in Cairo, New Cairo 11835, Egypt
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25
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Kong X, Gao P, Wang J, Fang Y, Hwang KC. Advances of medical nanorobots for future cancer treatments. J Hematol Oncol 2023; 16:74. [PMID: 37452423 PMCID: PMC10347767 DOI: 10.1186/s13045-023-01463-z] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 05/31/2023] [Indexed: 07/18/2023] Open
Abstract
Early detection and diagnosis of many cancers is very challenging. Late stage detection of a cancer always leads to high mortality rates. It is imperative to develop novel and more sensitive and effective diagnosis and therapeutic methods for cancer treatments. The development of new cancer treatments has become a crucial aspect of medical advancements. Nanobots, as one of the most promising applications of nanomedicines, are at the forefront of multidisciplinary research. With the progress of nanotechnology, nanobots enable the assembly and deployment of functional molecular/nanosized machines and are increasingly being utilized in cancer diagnosis and therapeutic treatment. In recent years, various practical applications of nanobots for cancer treatments have transitioned from theory to practice, from in vitro experiments to in vivo applications. In this paper, we review and analyze the recent advancements of nanobots in cancer treatments, with a particular emphasis on their key fundamental features and their applications in drug delivery, tumor sensing and diagnosis, targeted therapy, minimally invasive surgery, and other comprehensive treatments. At the same time, we discuss the challenges and the potential research opportunities for nanobots in revolutionizing cancer treatments. In the future, medical nanobots are expected to become more sophisticated and capable of performing multiple medical functions and tasks, ultimately becoming true nanosubmarines in the bloodstream.
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Affiliation(s)
- Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Peng Gao
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Division of Breast Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
- Breast Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Yi Fang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Kuo Chu Hwang
- Department of Chemistry, National Tsing Hua University, Hsinchu, 30013, Taiwan ROC.
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26
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Schäfer J, Klösgen VJ, Omer EA, Kadioglu O, Mbaveng AT, Kuete V, Hildebrandt A, Efferth T. In Silico and In Vitro Identification of P-Glycoprotein Inhibitors from a Library of 375 Phytochemicals. Int J Mol Sci 2023; 24:10240. [PMID: 37373385 DOI: 10.3390/ijms241210240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Cancer therapy with clinically established anticancer drugs is frequently hampered by the development of drug resistance of tumors and severe side effects in normal organs and tissues. The demand for powerful, but less toxic, drugs is high. Phytochemicals represent an important reservoir for drug development and frequently exert less toxicity than synthetic drugs. Bioinformatics can accelerate and simplify the highly complex, time-consuming, and expensive drug development process. Here, we analyzed 375 phytochemicals using virtual screenings, molecular docking, and in silico toxicity predictions. Based on these in silico studies, six candidate compounds were further investigated in vitro. Resazurin assays were performed to determine the growth-inhibitory effects towards wild-type CCRF-CEM leukemia cells and their multidrug-resistant, P-glycoprotein (P-gp)-overexpressing subline, CEM/ADR5000. Flow cytometry was used to measure the potential to measure P-gp-mediated doxorubicin transport. Bidwillon A, neobavaisoflavone, coptisine, and z-guggulsterone all showed growth-inhibitory effects and moderate P-gp inhibition, whereas miltirone and chamazulene strongly inhibited tumor cell growth and strongly increased intracellular doxorubicin uptake. Bidwillon A and miltirone were selected for molecular docking to wildtype and mutated P-gp forms in closed and open conformations. The P-gp homology models harbored clinically relevant mutations, i.e., six single missense mutations (F336Y, A718C, Q725A, F728A, M949C, Y953C), three double mutations (Y310A-F728A; F343C-V982C; Y953A-F978A), or one quadruple mutation (Y307C-F728A-Y953A-F978A). The mutants did not show major differences in binding energies compared to wildtypes. Closed P-gp forms generally showed higher binding affinities than open ones. Closed conformations might stabilize the binding, thereby leading to higher binding affinities, while open conformations may favor the release of compounds into the extracellular space. In conclusion, this study described the capability of selected phytochemicals to overcome multidrug resistance.
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Affiliation(s)
- Julia Schäfer
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
| | - Vincent Julius Klösgen
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
- Institute of Bioinformatics, Johannes Gutenberg University, 55131 Mainz, Germany
| | - Ejlal A Omer
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
| | - Onat Kadioglu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
| | - Armelle T Mbaveng
- Department of Biochemistry, Faculty of Science, University of Dschang, Dschang P.O. Box 67, Cameroon
| | - Victor Kuete
- Department of Biochemistry, Faculty of Science, University of Dschang, Dschang P.O. Box 67, Cameroon
| | - Andreas Hildebrandt
- Institute of Bioinformatics, Johannes Gutenberg University, 55131 Mainz, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
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27
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Gao Y, Liu T, Liu J, Yang Y, Sun K, Li Z, Zhai X, Zuo D. ZYY-B-2, a novel ALK inhibitor, overcomes resistance to ceritinib by inhibiting P-gp function and induces apoptosis through mitochondrial pathway in ceritinib-resistant H2228 cells. Chem Biol Interact 2023; 379:110516. [PMID: 37116853 DOI: 10.1016/j.cbi.2023.110516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 04/04/2023] [Accepted: 04/25/2023] [Indexed: 04/30/2023]
Abstract
Targeting the Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene is a promising therapeutic strategy for non-small-cell lung cancer (NSCLC) patients. With the advent of the first- and second-generation ALK inhibitors, the mortality rate of lung cancer has shown a downward trend, but almost inevitably, patients will eventually develop resistance, which severely limits the clinical application. Hence, developing new ALK inhibitors which can overcome resistance is essential. Here, we synthesized a novel ALK inhibitor 1-[4-[[5-Chloro-4-[[2-[(1-methylethyl)sulfonyl]phenyl]amino]-2-pyrimidinyl]amino]-3-methoxyphenyl]-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-imidazolidinone (ZYY-B-2) based on the structure of the second-generation ALK inhibitor ceritinib. ZYY-B-2 exhibited impressive anti-proliferative effect in the EML4-ALK positive H2228 cells and ceritinib-resistant H2228 (H2228/Cer) cells. Meanwhile, ZYY-B-2 inhibited the activation of p-ALK in a concentration-dependent manner, and inactivated its downstream target proteins p-AKT and p-ERK to inhibit cell proliferation. Subsequently, we found that ZYY-B-2 blocked H2228 cells and H2228/Cer cells in G0/G1 phase and induced cells to undergo apoptosis through the mitochondrial pathway. The ability of its anti-proliferation and pro-apoptosis was significantly stronger than the second generation ALK inhibitor ceritinib. In addition, high expression of P-gp was found in H2228/Cer cells compared with H2228 cells. ZYY-B-2 could inhibit the expression of P-gp in a dose-dependent manner to overcome ceritinib resistance, and the suppression effect of ZYY-B-2 on P-gp might be related to its inhibition of PI3K/AKT signaling pathway. In summary, ZYY-B-2, a promising ALK inhibitor, shows potent activity against ceritinib-resistant cells, which provides experimental and theoretical basis for the further development of new ALK inhibitors.
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Affiliation(s)
- Ying Gao
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Tong Liu
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Jingang Liu
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Yuying Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Keyan Sun
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Zengqiang Li
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China
| | - Xin Zhai
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
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28
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Damiani D, Tiribelli M. ABCG2 in Acute Myeloid Leukemia: Old and New Perspectives. Int J Mol Sci 2023; 24:ijms24087147. [PMID: 37108308 PMCID: PMC10138346 DOI: 10.3390/ijms24087147] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/05/2023] [Accepted: 04/10/2023] [Indexed: 04/29/2023] Open
Abstract
Despite recent advances, prognosis of acute myeloid leukemia (AML) remains unsatisfactory due to poor response to therapy or relapse. Among causes of resistance, over-expression of multidrug resistance (MDR) proteins represents a pivotal mechanism. ABCG2 is an efflux transporter responsible for inducing MDR in leukemic cells; through its ability to extrude many antineoplastic drugs, it leads to AML resistance and/or relapse, even if conflicting data have been reported to date. Moreover, ABCG2 may be co-expressed with other MDR-related proteins and is finely regulated by epigenetic mechanisms. Here, we review the main issues regarding ABCG2 activity and regulation in the AML clinical scenario, focusing on its expression and the role of polymorphisms, as well as on the potential ways to inhibit its function to counteract drug resistance to, eventually, improve outcomes in AML patients.
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Affiliation(s)
- Daniela Damiani
- Division of Hematology and Stem Cell Transplantation, Udine Hospital, P.le Santa Maria della Misericordia, 5, 33100 Udine, Italy
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
| | - Mario Tiribelli
- Division of Hematology and Stem Cell Transplantation, Udine Hospital, P.le Santa Maria della Misericordia, 5, 33100 Udine, Italy
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
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29
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Yang B, Yan Y, Wang D, Zhang Y, Yin J, Zhu G. On-target inhibition of Cryptosporidium parvum by nitazoxanide (NTZ) and paclitaxel (PTX) validated using a novel MDR1-transgenic host cell model and algorithms to quantify the effect on the parasite target. PLoS Negl Trop Dis 2023; 17:e0011217. [PMID: 36972284 PMCID: PMC10079235 DOI: 10.1371/journal.pntd.0011217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 04/06/2023] [Accepted: 03/05/2023] [Indexed: 03/29/2023] Open
Abstract
Cryptosporidium parvum is a globally distributed zoonotic protozoan parasite that causes moderate to severe, sometime deadly, watery diarrhea in humans and animals, for which fully effective treatments are yet unavailable. In studying the mechanism of action of drugs against intracellular pathogens, it is important to validate whether the observed anti-infective activity is attributed to the drug action on the pathogen or host target. For the epicellular parasite Cryptosporidium, we have previously developed a concept that the host cells with significantly increased drug tolerance by transient overexpression of the multidrug resistance protein-1 (MDR1) could be utilized to evaluate whether and how much the observed anti-cryptosporidial activity of an inhibitor was attributed to the inhibitor’s action on the parasite target. However, the transient transfection model was only applicable to evaluating native MDR1 substrates. Here we report an advanced model using stable MDR1-transgenic HCT-8 cells that allows rapid development of novel resistance to non-MDR1 substrates by multiple rounds of drug selection. Using the new model, we successfully validated that nitazoxanide, a non-MDR1 substrate and the only FDA-approved drug to treat human cryptosporidiosis, killed C. parvum by fully (100%) acting on the parasite target. We also confirmed that paclitaxel acted fully on the parasite target, while several other inhibitors including mitoxantrone, doxorubicin, vincristine and ivermectin acted partially on the parasite targets. Additionally, we developed mathematical models to quantify the proportional contribution of the on-parasite-target effect to the observed anti-cryptosporidial activity and to evaluate the relationships between several in vitro parameters, including antiparasitic efficacy (ECi), cytotoxicity (TCi), selectivity index (SI) and Hill slope (h). Owning to the promiscuity of the MDR1 efflux pump, the MDR1-transgenic host cell model could be applied to assess the on-parasite-target effects of newly identified hits/leads, either substrates or non-substrates of MDR1, against Cryptosporidium or other epicellular pathogens.
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Affiliation(s)
- Bo Yang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, the Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yueyang Yan
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, the Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun, China
| | - Dongqiang Wang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, the Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ying Zhang
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, the Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jigang Yin
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, the Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun, China
| | - Guan Zhu
- State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, the Institute of Zoonosis, and the College of Veterinary Medicine, Jilin University, Changchun, China
- * E-mail:
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Al Bitar S, El-Sabban M, Doughan S, Abou-Kheir W. Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond. World J Gastroenterol 2023; 29:1395-1426. [PMID: 36998426 PMCID: PMC10044855 DOI: 10.3748/wjg.v29.i9.1395] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/12/2022] [Accepted: 11/16/2022] [Indexed: 03/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide. Despite advances in therapeutic regimens, the number of patients presenting with metastatic CRC (mCRC) is increasing due to resistance to therapy, conferred by a small population of cancer cells, known as cancer stem cells. Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC. Agents are being developed to target key molecules involved in drug-resistance and metastasis of CRC, and these include vascular endothelial growth factor, epidermal growth factor receptor, human epidermal growth factor receptor-2, mitogen-activated extracellular signal-regulated kinase, in addition to immune checkpoints. Currently, there are several ongoing clinical trials of newly developed targeted agents, which have shown considerable clinical efficacy and have improved the prognosis of patients who do not benefit from conventional chemotherapy. In this review, we highlight recent developments in the use of existing and novel targeted agents against drug-resistant CRC and mCRC. Furthermore, we discuss limitations and challenges associated with targeted therapy and strategies to combat intrinsic and acquired resistance to these therapies, in addition to the importance of implementing better preclinical models and the application of personalized therapy based on predictive biomarkers for treatment selection.
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Affiliation(s)
- Samar Al Bitar
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Marwan El-Sabban
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Samer Doughan
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
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Bhatia A, Upadhyay AK, Sharma S. miRNAs are now starring in "No Time to Die: Overcoming the chemoresistance in cancer". IUBMB Life 2023; 75:238-256. [PMID: 35678612 DOI: 10.1002/iub.2652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/04/2022] [Indexed: 12/24/2022]
Abstract
Cancer is a leading cause of death globally, with about 19.3 million new cases reported each year. Current therapies for cancer management include-chemotherapy, radiotherapy, and surgery. However, they are loaded with side effects and tend to cause toxicity in the patient's body posttreatment, ultimately hindering the response towards the treatment building up resistance. This is where noncoding RNAs such as miRNAs help provide us with a helping hand for taming the chemoresistance and providing potential holistic cancer management. MicroRNAs are promising targets for anticancer therapy as they perform critical regulatory roles in various signaling cascades related to cell proliferation, apoptosis, migration, and invasion. Combining miRNAs and anticancer drugs and devising a combination therapy has managed cancer well in various independent studies. This review aims to provide insights into how miRNAs play a mechanistic role in cancer development and progression and regulate drug resistance in various types of cancers. Furthermore, next-generation novel therapies using miRNAs in combination with anticancer treatments in multiple cancers have been put forth and how they improve the efficacy of the treatments. Exemplary studies currently in the preclinical and clinical models have been summarized. Ultimately, we briefly talk through the challenges that come forward with it and minimize them.
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Affiliation(s)
- Anmol Bhatia
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Atul Kumar Upadhyay
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Siddharth Sharma
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
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Özvegy-Laczka C, Ungvári O, Bakos É. Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox. Biochem Pharmacol 2023; 209:115448. [PMID: 36758706 DOI: 10.1016/j.bcp.2023.115448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/11/2023]
Abstract
In humans, approximately 70% of drugs are eliminated through the liver. This process is governed by the concerted action of membrane transporters and metabolic enzymes. Transporters mediating hepatocellular uptake of drugs belong to the SLC (Solute carrier) superfamily of transporters. Drug efflux either toward the portal vein or into the bile is mainly mediated by active transporters of the ABC (ATP Binding Cassette) family. Alteration in the function and/or expression of liver transporters due to mutations, disease conditions, or co-administration of drugs or food components can result in altered pharmacokinetics. On the other hand, drugs or food components interacting with liver transporters may also interfere with liver function (e.g., bile acid homeostasis) and may even cause liver toxicity. Accordingly, certain transporters of the liver should be investigated already at an early stage of drug development. Most frequently radioactive probes are applied in these drug-transporter interaction tests. However, fluorescent probes are cost-effective and sensitive alternatives to radioligands, and are gaining wider application in drug-transporter interaction tests. In our review, we summarize our current understanding about hepatocyte ABC and SLC transporters affected by drug interactions. We provide an update of the available fluorescent and fluorogenic/activable probes applicable in in vitro or in vivo testing of these ABC and SLC transporters, including near-infrared transporter probes especially suitable for in vivo imaging. Furthermore, our review gives a comprehensive overview of the available fluorescence-based methods, not directly relying on the transport of the probe, suitable for the investigation of hepatic ABC or SLC-type drug transporters.
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Affiliation(s)
- Csilla Özvegy-Laczka
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary.
| | - Orsolya Ungvári
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary; Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Éva Bakos
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary
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Tran NNB, Bui ATA, Jaramillo-Martinez V, Weber J, Zhang Q, Urbatsch IL. Lipid environment determines the drug-stimulated ATPase activity of P-glycoprotein. Front Mol Biosci 2023; 10:1141081. [PMID: 36911528 PMCID: PMC9995911 DOI: 10.3389/fmolb.2023.1141081] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
P-glycoprotein (Pgp) is a multidrug transporter that uses the energy from ATP binding and hydrolysis to export from cells a wide variety of hydrophobic compounds including anticancer drugs, and mediates the bioavailability and pharmacokinetics of many drugs. Lipids and cholesterol have been shown to modulate the substrate-stimulated ATPase activity of purified Pgp in detergent solution and the substrate transport activity after reconstitution into proteoliposomes. While lipid extracts from E. coli, liver or brain tissues generally support well Pgp's functionality, their ill-defined composition and high UV absorbance make them less suitable for optical biophysical assays. On the other hand, studies with defined synthetic lipids, usually the bilayer-forming phosphatidylcholine with or without cholesterol, are often plagued by low ATPase activity and low binding affinity of Pgp for drugs. Drawing from the lipid composition of mammalian plasma membranes, we here investigate how different head groups modulate the verapamil-stimulated ATPase activity of purified Pgp in detergent-lipid micelles and compare them with components of E. coli lipids. Our general approach was to assay modulation of verapamil-stimulation of ATPase activity by artificial lipid mixtures starting with the bilayer-forming palmitoyloyl-phosphatidylcholine (POPC) and -phosphatidylethanolamine (POPE). We show that POPC/POPE supplemented with sphingomyelin (SM), cardiolipin, or phosphatidic acid enhanced the verapamil-stimulated activity (Vmax) and decreased the concentration required for half-maximal activity (EC50). Cholesterol (Chol) and more so its soluble hemisuccinate derivative cholesteryl hemisuccinate substantially decreased EC50, perhaps by supporting the functional integrity of the drug binding sites. High concentrations of CHS (>15%) resulted in a significantly increased basal activity which could be due to binding of CHS to the drug binding site as transport substrate or as activator, maybe acting cooperatively with verapamil. Lastly, Pgp reconstituted into liposomes or nanodiscs displayed higher basal activity and sustained high levels of verapamil stimulated activity. The findings establish a stable source of artificial lipid mixtures containing either SM and cholesterol or CHS that restore Pgp functionality with activities and affinities similar to those in the natural plasma membrane environment and will pave the way for future functional and biophysical studies.
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Affiliation(s)
- Nghi N. B. Tran
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - A. T. A. Bui
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Valeria Jaramillo-Martinez
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Joachim Weber
- Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Qinghai Zhang
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, United States
| | - Ina L. Urbatsch
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, United States
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ATP-binding cassette efflux transporters and MDR in cancer. Drug Discov Today 2023; 28:103537. [PMID: 36801375 DOI: 10.1016/j.drudis.2023.103537] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 01/27/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023]
Abstract
Of the many known multidrug resistance (MDR) mechanisms, ATP-binding cassette (ABC) transporters expelling drug molecules out of cells is a major factor limiting the efficacy of present-day anticancer drugs. In this review, we highlights updated information on the structure, function, and regulatory mechanisms of major MDR-related ABC transporters, such as P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP), and the effect of modulators on their functions. We also provide focused information on different modulators of ABC transporters that could be utilized against the emerging MDR crisis in cancer treatment. Finally, we discuss the importance of ABC transporters as therapeutic targets in light of future strategic planning for translating ABC transporter inhibitors into clinical practice.
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Foglietta F, Macrì M, Panzanelli P, Francovich A, Durando G, Garello F, Terreno E, Serpe L, Canaparo R. Ultrasound boosts doxorubicin efficacy against sensitive and resistant ovarian cancer cells. Eur J Pharm Biopharm 2023; 183:119-131. [PMID: 36632905 DOI: 10.1016/j.ejpb.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/21/2022] [Accepted: 01/07/2023] [Indexed: 01/10/2023]
Abstract
Ovarian cancer (OC) is characterised by the highest mortality of all gynaecological malignancies, frequent relapses, and the development of resistance to drug therapy. Sonodynamic therapy (SDT) is an innovative anticancer approach that combines a chemical/drug (sonosensitizer) with low-intensity ultrasound (US), which are both harmless per sé, with the sonosensitizer being acoustically activated, thus yielding localized cytotoxicity often via reactive oxygen species (ROS) generation. Doxorubicin (Doxo) is a potent chemotherapeutic drug that has also been recommended as a first-line treatment against OC. This research work aims to investigate whether Doxo can be used at very low concentrations, in order to avoid its significant side effects, as a sonosensitiser under US exposure to promote cancer cell death in Doxo non-resistant (A2780/WT) and Doxo resistant (A2780/ADR) human OC cell lines. Moreover, since recurrence is an important issue in OC, we have also investigated whether the proposed SDT with Doxo induces immunogenic cell death (ICD) and thus hinders OC recurrence. Our results show that the sonodynamic anticancer approach with Doxo is effective in both A2780/WT and A2780/ADR cell lines, and that it proceeds via a ROS-dependent mechanism of action and immune sensitization that is based on the activation of the ICD pathway.
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Affiliation(s)
- Federica Foglietta
- Department of Drug Science and Technology, University of Torino, Via Pietro Giuria 13, 10125 Torino, Italy
| | - Manuela Macrì
- Department of Drug Science and Technology, University of Torino, Via Pietro Giuria 13, 10125 Torino, Italy
| | - Patrizia Panzanelli
- Department of Neuroscience Rita Levi Montalcini, University of Torino, Via Cherasco 15, 10126 Torino, Italy
| | - Andrea Francovich
- Institut de Physiologie, Université de Fribourg, Fribourg 1770, Switzerland
| | - Gianni Durando
- National Institute of Metrological Research (INRIM), Strada delle Cacce 91, 10135 Torino, Italy
| | - Francesca Garello
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy
| | - Enzo Terreno
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy
| | - Loredana Serpe
- Department of Drug Science and Technology, University of Torino, Via Pietro Giuria 13, 10125 Torino, Italy.
| | - Roberto Canaparo
- Department of Drug Science and Technology, University of Torino, Via Pietro Giuria 13, 10125 Torino, Italy
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Bakadlag R, Limniatis G, Georges G, Georges E. The anti-estrogen receptor drug, tamoxifen, is selectively Lethal to P-glycoprotein-expressing Multidrug resistant tumor cells. BMC Cancer 2023; 23:24. [PMID: 36609245 PMCID: PMC9824978 DOI: 10.1186/s12885-022-10474-x] [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: 04/02/2022] [Accepted: 12/22/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND P-glycoprotein (P-gp), a member of the ATP Binding Cassette B1 subfamily (ABCB1), confers resistance to clinically relevant anticancer drugs and targeted chemotherapeutics. However, paradoxically P-glycoprotein overexpressing drug resistant cells are "collaterally sensitive" to non-toxic drugs that stimulate its ATPase activity. METHODS Cell viability assays were used to determine the effect of low concentrations of tamoxifen on the proliferation of multidrug resistant cells (CHORC5 and MDA-Doxo400), expressing P-gp, their parental cell lines (AuxB1 and MDA-MB-231) or P-gp-CRISPR knockout clones of AuxB1 and CHORC5 cells. Western blot analysis was used to estimate P-gp expression in different cell lines. Apoptosis of tamoxifen-induced cell death was estimated by flow cytometry using Annexin-V-FITC stained cells. Oxidative stress of tamoxifen treated cells was determined by measuring levels of reactive oxygen species and reduced thiols using cell-permeant 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) and 5,5-dithio-bis-(2-nitrobenzoic acid) DTNB, respectively. RESULTS In this report, we show that P-gp-expressing drug resistant cells (CHORC5 and MDA-Doxo400) are collaterally sensitive to the anti-estrogen tamoxifen or its metabolite (4-hydroxy-tamoxifen). Moreover, P-gp-knockout clones of CHORC5 cells display complete reversal of collateral sensitivity to tamoxifen. Drug resistant cells exposed to low concentrations of tamoxifen show significant rise in reactive oxygen species, drop of reduced cellular thiols and increased apoptosis. Consistent with the latter, CHORC5 cells expressing high levels of human Bcl-2 (CHORC5-Bcl-2) show significant resistance to tamoxifen. In addition, the presence of the antioxidant N-acetylcysteine or P-gp ATPase inhibitor, PSC-833, reverse the collateral sensitivity of resistant cells to tamoxifen. By contrast, the presence of rotenone (specific inhibitor of mitochondria complex I) synergizes with tamoxifen. CONCLUSION This study demonstrates the use of tamoxifen as collateral sensitivity drug that can preferentially target multidrug resistant cells expressing P-gp at clinically achievable concentrations. Given the widespread use of tamoxifen in the treatment of estrogen receptor-positive breast cancers, this property of tamoxifen may have clinical applications in treatment of P-gp-positive drug resistant breast tumors.
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Affiliation(s)
- Rowa Bakadlag
- grid.14709.3b0000 0004 1936 8649Institute of Parasitology, Macdonald Campus, McGill University, Ste. Anne de Bellevue, Québec, H9X-3V9 Canada
| | - Georgia Limniatis
- grid.14709.3b0000 0004 1936 8649Institute of Parasitology, Macdonald Campus, McGill University, Ste. Anne de Bellevue, Québec, H9X-3V9 Canada
| | - Gabriel Georges
- grid.421142.00000 0000 8521 1798Department of Cardiac Surgery, Quebec Heart & Lung Institute, Université Laval, Québec, Canada
| | - Elias Georges
- grid.14709.3b0000 0004 1936 8649Institute of Parasitology, Macdonald Campus, McGill University, Ste. Anne de Bellevue, Québec, H9X-3V9 Canada
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Cai J, Cao YB, Leung ELH. Detection of Single Non-small Cell Lung Cancer Cell Multidrug Resistance with Single-Cell Bioanalyzer. Methods Mol Biol 2023; 2689:1-11. [PMID: 37430042 DOI: 10.1007/978-1-0716-3323-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death in the world. Despite the development of various lung cancer treatment methods, including surgery, radiation therapy, endocrine therapy, immunotherapy, and gene therapy, chemotherapy remains the most common approach for treating cancer. The risk of tumors acquiring resistance to chemotherapy remains a significant hurdle to the use of this approach for the successful treatment of various types of cancer. The majority of cancer-related deaths are related to metastasis. Circulating tumor cells (CTCs) are cells that have been detached from the primary tumor or have metastasized and entered the circulation. CTCs can cause metastases in various organs by reaching them through the bloodstream. The CTCs exist in peripheral blood as single cells or as oligoclonal clusters of tumor cells along with platelets and lymphocytes. The detection of CTCs is an important component of liquid biopsy which aids in the diagnosis, treatment, and prognosis of cancer. Here, we describe a method for extracting CTCs from the tumor of patients and using the microfluidic single-cell technique to study the inhibition of multidrug resistance due to drug efflux on a single cancer cell, to propose novel methods that can provide clinicians with more appropriate choices in their diagnostic and treatment approaches.
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Affiliation(s)
- Jun Cai
- Faculty of Pharmacy and Food Science, Zhuhai College of Science and Technology, Zhuhai, China
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, SAR, China
| | - Ya-Bing Cao
- Department of Oncology, Kiang Wu Hospital, Macau, SAR, China
| | - Elaine Lai-Han Leung
- Cancer Center, Faculty of Health Science, University of Macau, Macau, SAR, China.
- MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau, SAR, China.
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Shchulkin AV, Abalenikhina YV, Mylnikov PY, Chernykh IV, Yakusheva EN. Assessment of Malondialdehyde Belonging to Modulators and Substrates of the P-Glycoprotein Transporter Protein. DOKL BIOCHEM BIOPHYS 2022; 507:247-255. [PMID: 36786982 DOI: 10.1134/s1607672922060096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/15/2022] [Accepted: 07/18/2022] [Indexed: 02/15/2023]
Abstract
In the study on cells of the Caco-2 line, the affiliation of malondialdehyde (MDA) to modulators and substrates of P-glycoprotein (Pgp) was assessed, and the biological role of Pgp in conditions of oxidative stress (OS) was studied. MDA was used at concentrations of 10, 50, 100, and 150 μM; OS was simulated by incubation with hydrogen peroxide (H2O2) at concentrations of 0.1-100 μM for 24 h. The relative amount of Pgp was evaluated by the Western blot hybridization, and the activity was estimated by the transport of its substrate fexofenadine (HPLC with UV detection, HPLC MS/MS). In this study, it was shown that MDA at concentrations of 10 and 50 μM and exposure duration of 24 h increases the relative amount and activity of Pgp by acting through CAR and PXR, and MDA can be transported by Pgp. The induction of Pgp under the action of MDA during the development of OS can have a protective significance, ensuring the removal of the peroxidation product from cells into the extracellular space and thereby increasing the viability of cells.
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Zhu Y, Binder J, Yurgelonis I, Rai DK, Lazarro S, Costales C, Kobylarz K, McMonagle P, Steppan CM, Aschenbrenner L, Anderson AS, Cardin RD. Generation of a VeroE6 Pgp gene knock out cell line and its use in SARS-CoV-2 antiviral study. Antiviral Res 2022; 208:105429. [PMID: 36208677 PMCID: PMC9533647 DOI: 10.1016/j.antiviral.2022.105429] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/28/2022] [Accepted: 10/02/2022] [Indexed: 11/25/2022]
Abstract
Vero cells are widely used for antiviral tests and virology research for SARS-CoV-2 as well as viruses from various other families. However, Vero cells generally express high levels of multi-drug resistance 1 (MDR1) or Pgp protein, the efflux transporter of foreign substances including many antiviral compounds, affecting the antiviral activity as well as interpretation of data. To address this, a Pgp gene knockout VeroE6 cell line (VeroE6-Pgp-KO) was generated using CRISPR-CAS9 technology. These cells no longer expressed the Pgp protein as indicated by flow cytometry analysis following staining with a Pgp-specific monoclonal antibody. They also showed significantly reduced efflux transporter activity in the calcein acetoxymethyl ester (calcein AM) assay. The VeroE6-Pgp-KO cells and the parental VeroE6 cells were each infected with SARS-CoV-2 to test antiviral activities of remdesivir and nirmatrelvir, two known Pgp substrates, in the presence or absence of a Pgp inhibitor. The compounds showed antiviral activities in VeroE6-Pgp-KO cells similar to that observed in the presence of the Pgp inhibitor. Thus, the newly established VeroE6-Pgp-KO cell line adds a new in vitro virus infection system for SARS-CoV-2 and possibly other viruses to test antiviral therapies without a need to control the Pgp activity. Removal of the Pgp inhibitor for antiviral assays will lead to less data variation and prevent failed assays.
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Affiliation(s)
- Yuao Zhu
- Pfizer Inc, 401 N Middletown Rd, Pearl River, NY, 10965, USA,Corresponding author
| | - Joe Binder
- Pfizer Inc, 401 N Middletown Rd, Pearl River, NY, 10965, USA
| | | | - Devendra K. Rai
- Pfizer Inc, 401 N Middletown Rd, Pearl River, NY, 10965, USA
| | - Sarah Lazarro
- Pfizer Inc, 445 Eastern Point Rd, Groton, CT, 06333, USA
| | | | - Keith Kobylarz
- Pfizer Inc, 401 N Middletown Rd, Pearl River, NY, 10965, USA
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Wada M. Role of ABC Transporters in Cancer Development and Malignant Alteration. YAKUGAKU ZASSHI 2022; 142:1201-1225. [DOI: 10.1248/yakushi.22-00108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Tamari S, Menju T, Toyazaki T, Miyamoto H, Chiba N, Noguchi M, Ishikawa H, Miyata R, Kayawake H, Tanaka S, Yamada Y, Yutaka Y, Nakajima D, Ohsumi A, Hamaji M, Date H. Nrf2/p‑Fyn/ABCB1 axis accompanied by p‑Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non‑small cell lung cancer. Oncol Rep 2022; 48:171. [PMID: 35959810 DOI: 10.3892/or.2022.8386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/19/2022] [Indexed: 11/05/2022] Open
Abstract
Adjuvant cisplatin‑vinorelbine is a standard therapy for stage II/III lung cancer. However, a poor survival rate of patients with lung cancer is attributed to vinorelbine resistance arising from ATP‑binding cassette (ABC) sub‑family B member 1 (ABCB1) and phosphorylated Fyn (p‑Fyn) overexpression. However, the underlying mechanisms remain unclear. NF‑E2‑related factor 2 (Nrf2) regulates the ABC family and activates the nuclear transport of Fyn. The present study evaluated the roles of the Nrf2/p‑Fyn/ABCB1 axis in vinorelbine‑resistant (VR) cells and clinical samples. To establish VR cells, H1299 cells were exposed to vinorelbine, and the intracellular reactive oxygen species (ROS) level in the H1299 cells was determined using a DCFH‑DA assay. The total and subcellular expression of Nrf2, ABCB1 and p‑Fyn in VR cells was evaluated. Immunofluorescence was used to detect the subcellular localization of p‑Fyn in VR cells. A cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine is dependent on Nrf2 activity. Immunohistochemistry was performed on 104 tissue samples from patients with lung cancer who underwent surgery followed by cisplatin‑vinorelbine treatment. The results revealed that persistent exposure to vinorelbine induced intracellular ROS formation in H1299 cells. p‑Fyn was localized in the nucleus, and ABCB1 and Nrf2 were overexpressed in VR cells. ABCB1 expression was dependent on Nrf2 downstream activation. The decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the surgical samples, Nrf2 and ABCB1 were associated with disease‑free survival, and p‑Fyn was associated with overall survival (P<0.05). On the whole, the present study demonstrates that Nrf2 upregulates ABCB1 and, accompanied by the nuclear accumulation of p‑Fyn, induces vinorelbine resistance. These findings may facilitate the development of drug resistance prevention strategies or new drug targets against non‑small cell lung cancer.
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Affiliation(s)
- Shigeyuki Tamari
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Toshi Menju
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Toshiya Toyazaki
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Hideaki Miyamoto
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Naohisa Chiba
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Misa Noguchi
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Hiroaki Ishikawa
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Ryo Miyata
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Hidenao Kayawake
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Satona Tanaka
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Yoshito Yamada
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Yojiro Yutaka
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Daisuke Nakajima
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Akihiro Ohsumi
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Masatsugu Hamaji
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
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Qiu J, Ghaffari S. Mitochondrial Deep Dive into Hematopoietic Stem Cell Dormancy: Not Much Glycolysis but Plenty of Sluggish Lysosomes. Exp Hematol 2022; 114:1-8. [PMID: 35908627 PMCID: PMC9949493 DOI: 10.1016/j.exphem.2022.07.299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 01/16/2023]
Abstract
The discovery of hematopoietic stem cells (HSCs) heterogeneity has had major implications for investigations of hematopoietic stem cell disorders, clonal hematopoiesis, and HSC aging. More recent studies of the heterogeneity of HSCs' organelles have begun to provide additional insights into HSCs' behavior with far-reaching ramifications for the mechanistic understanding of aging of HSCs and stem cell-derived diseases. Mitochondrial heterogeneity has been explored to expose HSC subsets with distinct properties and functions. Here we review some of the recent advances in these lines of studies that challenged the classic view of glycolysis in HSCs and led to the identification of lysosomes as dynamic pivotal switches in controlling HSC quiescence versus activation beyond their function in autophagy.
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Affiliation(s)
- Jiajing Qiu
- Department of Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Saghi Ghaffari
- Department of Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY; Developmental and Stem Cell Biology Multidisciplinary Training, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
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Yu KH, Park J, Mittal A, Abou-Alfa GK, Dika IE, Epstein AS, Ilson DH, Kelsen DP, Ku GY, Li J, Park W, Varghese AM, Chou JFL, Capanu M, Cooper B, Bartlett A, McCarthy D, Sangar V, McCarthy B, O’Reilly EM. Circulating tumor and invasive cell expression profiling predicts effective therapy in pancreatic cancer. Cancer 2022; 128:2958-2966. [PMID: 35647938 PMCID: PMC10131181 DOI: 10.1002/cncr.34269] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/06/2022] [Accepted: 05/02/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy. METHODS The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results. RESULTS Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS. CONCLUSIONS Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).
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Affiliation(s)
- Kenneth H. Yu
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Jennifer Park
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Avni Mittal
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Imane El Dika
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Andrew S. Epstein
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - David H. Ilson
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - David P. Kelsen
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Geoffrey Y. Ku
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Jia Li
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Wungki Park
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Anna M. Varghese
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | | | | | | | | | | | | | | | - Eileen M. O’Reilly
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
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Drug Resistance in Colorectal Cancer: From Mechanism to Clinic. Cancers (Basel) 2022; 14:cancers14122928. [PMID: 35740594 PMCID: PMC9221177 DOI: 10.3390/cancers14122928] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
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ChemoSensitivity Assay Guided Metronomic Chemotherapy Is Safe and Effective for Treating Advanced Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14122906. [PMID: 35740571 PMCID: PMC9220997 DOI: 10.3390/cancers14122906] [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: 05/07/2022] [Revised: 06/09/2022] [Accepted: 06/11/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Innovative chemotherapy regimens and tools to guide therapy in advanced pancreatic cancer are greatly needed. We present results of a study combining an innovative, metronomic chemotherapy strategy together with a blood-based pharmacogenomic tool to guide effective drug therapy. This study provides proof of principle that guided, metronomic chemotherapy for treatment of pancreatic cancer is a promising approach. Abstract Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients treated with standard chemotherapy. The current study combines these concepts for a highly personalized treatment approach. This was a retrospective analysis; a pilot (n = 50) and validation cohort (n = 45) were studied. The ChemoSensitivity Assay was performed at baseline and during therapy; results were correlated to drugs administered and patient outcomes. MCT was administered based on the assay results at the treating physician′s discretion. Patients in the pilot cohort experienced favorable survival compared with historical controls (median overall survival (mOS) 16.8 mo). Patients whose treatment closely matched the ChemoSensitivity Assay predictions experienced longer median time on lines of therapy (5.3 vs. 3.3 mo, p = 0.02) and showed a trend for longer mOS (20.9 vs. 12.5 mo, p = 0.055) compared with those not closely matched. These findings were confirmed in the validation cohort. Overall, patients treated with MCT closely matching Assay results experienced a remarkable mOS of 27.7 mo. ChemoSensitivity profiling-guided MCT is a promising approach for personalized therapy in advanced PDAC.
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Inoue Y, Yamaguchi T, Otsuka T, Utsunomiya Y, Pan D, Ogawa H, Kato H. Structure-based alteration of tryptophan residues of the multidrug transporter CmABCB1 to assess substrate binding using fluorescence spectroscopy. Protein Sci 2022; 31:e4331. [PMID: 35634783 PMCID: PMC9123602 DOI: 10.1002/pro.4331] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/01/2022] [Accepted: 04/06/2022] [Indexed: 09/17/2023]
Abstract
ABCB1, also known as P-glycoprotein, is an essential component of many physiological barriers and extrudes a variety of hydrophobic chemicals out of the cell. Structures of ABCB1 provided insights into the structural changes that occur upon ATP binding and the characteristic architecture of the substrate binding site. Yet, the structure-function relationship between substrate binding and transporting still remains largely obscured because there is no robust method for accurately measuring substrate binding constants. The methods currently used cannot identify whether the bound substrates are located in the inner chamber of the molecule in the transmembrane region or not because of the low spatial resolution. Here, we report a system for measuring the affinity of substrate binding to the Cyanidioschyzon merolae ABCB1 (CmABCB1) using site-specific tryptophan (Trp) fluorescence quenching. We designed a CmABCB1 mutant with an extrinsic Trp residue introduced into the inner chamber. Trp fluorescence was quenched by three substrates and one inhibitor, including rhodamine 6G, in a saturable fashion, allowing for accurate estimation of the dissociation constant (KD ) for each molecule. The KD for rhodamine 6G is similar to that determined using a reciprocal fluorescence quenching assay using rhodamine 6G fluorescence, suggesting that Trp fluorescence of the mutant was quenched by the interaction between the extrinsic Trp and substrates bound in the inner chamber. Structural comparison of the ABCB1 structures suggests that the system presented in this study could be ideal method of choice to determine the substrate binding affinities of compounds bound to the chamber of mammalian ABCB1.
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Affiliation(s)
- Yoshiki Inoue
- Department of Structural Biology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
| | - Tomohiro Yamaguchi
- Department of Structural Biology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
| | - Tetsuo Otsuka
- Department of Structural Biology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
| | - Yuto Utsunomiya
- Department of Structural Biology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
| | - Dongqing Pan
- Department of Structural Biology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
| | - Haruo Ogawa
- Department of Structural Biology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
| | - Hiroaki Kato
- Department of Structural Biology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
- Advanced Photon Technology DivisionRIKEN Harima Institute at SPring‐8Sayo‐gunHyogoJapan
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Pouya FD, Gazouli M, Rasmi Y, Lampropoulou DI, Nemati M. MicroRNAs and drug resistance in colorectal cancer with special focus on 5-fluorouracil. Mol Biol Rep 2022; 49:5165-5178. [PMID: 35212928 DOI: 10.1007/s11033-022-07227-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 02/03/2022] [Indexed: 02/08/2023]
Abstract
Colorectal cancer is globally one of the most common cancers in all age groups. The current chemotherapy combinations for colorectal cancer treatment include 5-fluorouracil-based regimens; however, drug resistance remains one of the main reasons for chemotherapy failure and disease recurrence. Many studies have determined colorectal cancer chemoresistance mechanisms such as drug efflux, cell cycle arrest, DNA damage repair, apoptosis, autophagy, vital enzymes, epigenetic, epithelial-mesenchymal transition, stem cells, and immune system suppression. Several microRNAs affect drug resistance by regulating the drug resistance-related target genes in colorectal cancer. These drug resistance-related miRNAs may be used as promising biomarkers for predicting drug response or as potential therapeutic targets for treating patients with colorectal cancer. This work reviews and discuss the role of selected microRNAs in 5-fluorouracil resistance and their molecular mechanisms in colorectal cancer.
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Affiliation(s)
- Fahima Danesh Pouya
- Department of Biochemistry, Faculty of Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Maria Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Yousef Rasmi
- Department of Biochemistry, Faculty of Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran.
| | - Dimitra Ioanna Lampropoulou
- Second Department of Medical Oncology, General Oncology Hospital of Kifissia "Agioi Anargiroi", Nea Kifissia, Athens, Greece
| | - Mohadeseh Nemati
- Department of Biochemistry, Faculty of Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Liang XL, Ji MM, Liao ZG, Zhao GW, Tang XL, Dong W. Chemosensitizing effect and mechanism of imperatorin on the anti-tumor activity of doxorubicin in tumor cells and transplantation tumor model. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY 2022; 26:145-155. [PMID: 35477542 PMCID: PMC9046893 DOI: 10.4196/kjpp.2022.26.3.145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 11/07/2021] [Accepted: 02/02/2022] [Indexed: 11/15/2022]
Abstract
Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the anti-tumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy.
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Affiliation(s)
- Xin-li Liang
- Key Laboratory of Modern Preparation of Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Miao-miao Ji
- Key Laboratory of Modern Preparation of Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Zheng-gen Liao
- Key Laboratory of Modern Preparation of Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Guo-wei Zhao
- Key Laboratory of Modern Preparation of Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Xi-lan Tang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Nanchang 330013, China
| | - Wei Dong
- Key Laboratory of Modern Preparation of Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China
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49
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Nanoparticle-based drug delivery systems to overcome gastric cancer drug resistance. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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50
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Pavlíková L, Šereš M, Breier A, Sulová Z. The Roles of microRNAs in Cancer Multidrug Resistance. Cancers (Basel) 2022; 14:cancers14041090. [PMID: 35205839 PMCID: PMC8870231 DOI: 10.3390/cancers14041090] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/16/2022] [Accepted: 02/20/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary The resistance of neoplastic cells to multiple drugs is a serious problem in cancer chemotherapy. The molecular causes of multidrug resistance in cancer are largely known, but less is known about the mechanisms by which cells deliver phenotypic changes that resist the attack of anticancer drugs. The findings of RNA interference based on microRNAs represented a breakthrough in biology and pointed to the possibility of sensitive and targeted regulation of gene expression at the post-transcriptional level. Such regulation is also involved in the development of multidrug resistance in cancer. The aim of the current paper is to summarize the available knowledge on the role of microRNAs in resistance to multiple cancer drugs. Abstract Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed.
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Affiliation(s)
- Lucia Pavlíková
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
| | - Mário Šereš
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Albert Breier
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Zdena Sulová
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
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