RESUMEN
A major obstacle to chemotherapeutic success in cancer treatment is the development of drug resistance. This occurs when a tumour fails to reduce in size after treatment or when there is clinical relapse after an initial positive response to treatment. A unique and serious type of resistance is multidrug resistance (MDR). MDR causes the simultaneous cross resistance to unrelated drugs used in chemotherapy. MDR can be acquired through genetic alterations following drug exposure, or as discovered by us, through alternative pathways mediated by the transfer of functional MDR proteins and nucleic acids by extracellular vesicles (M Bebawy V Combes E Lee R Jaiswal J Gong A Bonhoure GE Grau, 23 9 1643 1649, 2009).Multiple myeloma is an incurable cancer of bone marrow plasma cells. Treatment involves high dose combination chemotherapy and patient response is unpredictable and variable due to the presence of multisite clonal tumour infiltrates. This clonal heterogeneity can contribute to the development of MDR. There is currently no approved clinical test for the minimally invasive testing of MDR in myeloma.Extracellular vesicles comprise a group of heterogeneous cell-derived membranous structures which include; exosomes, microparticles (microvesicles), migrasomes and apoptotic bodies. Extracellular vesicles serve an important role in cellular communication through the intercellular transfer of cellular protein, nucleic acid and lipid cargo. Of these, microparticles (MPs) originate from the cell plasma membrane and vary in size from 0.1-1um. We have previously shown that MPs confer MDR through the transfer of resistance proteins and nucleic acids. A test for the early detection of MDR would benefit clinical decision making, improve survival and support rational drug use. This review focuses on microparticles as novel clinical biomarkers for the detection of MDR in Myeloma and discusses their role in the therapeutic management of the disease.
Asunto(s)
Mieloma Múltiple , Ácidos Nucleicos , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/diagnóstico , Resistencia a Antineoplásicos/fisiología , Recurrencia Local de Neoplasia , Resistencia a Múltiples Medicamentos/fisiologíaRESUMEN
Lyn, a tyrosine kinase that is activated by double-stranded DNAdamaging agents, is involved in various signaling pathways, such as proliferation, apoptosis, and DNA repair. Ribosomal protein S3 (RpS3) is involved in protein biosynthesis as a component of the ribosome complex and possesses endonuclease activity to repair damaged DNA. Herein, we demonstrated that rpS3 and Lyn interact with each other, and the phosphorylation of rpS3 by Lyn, causing ribosome heterogeneity, upregulates the translation of p-glycoprotein, which is a gene product of multidrug resistance gene 1. In addition, we found that two different regions of the rpS3 protein are associated with the SH1 and SH3 domains of Lyn. An in vitro immunocomplex kinase assay indicated that the rpS3 protein acts as a substrate for Lyn, which phosphorylates the Y167 residue of rpS3. Furthermore, by adding various kinase inhibitors, we confirmed that the phosphorylation status of rpS3 was regulated by both Lyn and doxorubicin, and the phosphorylation of rpS3 by Lyn increased drug resistance in cells by upregulating p-glycoprotein translation. [BMB Reports 2023; 56(5): 302-307].
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Subfamilia B de Transportador de Casetes de Unión a ATP , Resistencia a Múltiples Medicamentos , Proteínas Ribosómicas , Familia-src Quinasas , Humanos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Reparación del ADN/efectos de los fármacos , Resistencia a Múltiples Medicamentos/genética , Resistencia a Múltiples Medicamentos/fisiología , Fosforilación , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismoRESUMEN
BACKGROUND: Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1/P-gp) is a major cause of cancer chemotherapy failure, but the regulation mechanisms are largely unknown. METHODS: Based on single gene knockout, we studied the regulation of CDK6-PI3K axis on ABCB1-mediated MDR in human cancer cells. CRISPR/Cas9 technique was performed in KB-C2 cells to knockout cdk6 or cdk4 gene. Western blot, RT-PCR and transcriptome analysis were performed to investigate target gene deletion and expression of critical signaling factors. The effect of cdk4 or cdk6 deficiency on cell apoptosis and the cell cycle was analyzed using flow cytometry. In vivo studies were performed to study the sensitivity of KB-C2 tumors to doxorubicin, tumor growth and metastasis. RESULTS: Deficiency of cdk6 led to remarkable downregulation of ABCB1 expression and reversal of ABCB1-mediated MDR. Transcriptomic analysis revealed that CDK6 knockout regulated a series of signaling factors, among them, PI3K 110α and 110ß, KRAS and MAPK10 were downregulated, and FOS-promoting cell autophagy and CXCL1-regulating multiple factors were upregulated. Notably, PI3K 110α/110ß deficiency in-return downregulated CDK6 and the CDK6-PI3K axis synergizes in regulating ABCB1 expression, which strengthened the regulation of ABCB1 over single regulation by either CDK6 or PI3K 110α/110ß. High frequency of alternative splicing (AS) of premature ABCB1 mRNA induced by CDK6, CDK4 or PI3K 110α/110ß level change was confirmed to alter the ABCB1 level, among them 10 common skipped exon (SE) events were found. In vivo experiments demonstrated that loss of cdk6 remarkably increased the sensitivity of KB-C2 tumors to doxorubicin by increasing drug accumulation of the tumors, resulting in remarkable inhibition of tumor growth and metastasis, as well as KB-C2 survival in the nude mice. CONCLUSIONS: CDK6-PI3K as a new target signaling axis to reverse ABCB1-mediated MDR is reported for the first time in cancers. Pathways leading to inhibition of cancer cell proliferation were revealed to be accompanied by CDK6 deficiency.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Antineoplásicos , Quinasa 6 Dependiente de la Ciclina , Neoplasias , Fosfatidilinositol 3-Quinasas , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/genética , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/fisiología , Humanos , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.
Asunto(s)
Resistencia a Múltiples Medicamentos/fisiología , Melatonina/metabolismo , Priones/metabolismo , Animales , Resistencia a Múltiples Medicamentos/genética , Humanos , Peroxidación de Lípido , Melatonina/farmacología , Melatonina/fisiología , Microdominios de Membrana/metabolismo , Neoplasias/metabolismo , Proteínas Priónicas/metabolismo , Priones/química , Priones/genética , Transducción de Señal , Microambiente Tumoral/fisiologíaRESUMEN
Global reports on multidrug resistance (MDR) and life-threatening pathogens such as SARS-CoV-2 and Candida cruris have stimulated researchers to explore new antimicrobials that are eco-friendly and economically viable. In this context, biodegradable polymers such as nisin, chitin, and pullulan play an important role in solving the problem. Pullulan is an important edible, biocompatible, water-soluble polymer secreted by Aureobasidium pullulans that occurs ubiquitously. It consists of maltotriose units linked with α-1,6 glycosidic bonds and is classed as Generally Regarded as Safe (GRAS) by the Food and Drug Administration (FDA) in the USA. Pullulan is known for its antibacterial, antifungal, antiviral, and antitumor activities when incorporated with other additives such as antibiotics, drugs, nanoparticles, and so on. Considering the importance of its antimicrobial activities, this polymer can be used as a potential antimicrobial agent against various pathogenic microorganisms including the multidrug-resistant (MDR) pathogens. Moreover, pullulan has ability to synthesize biogenic silver nanoparticles (AgNPs), which are remarkably efficacious against pathogenic microbes. The pullulan-based nanocomposites can be applied for wound healing, food packaging, and also enhancing the shelf-life of fruits and vegetables. In this review, we have discussed biosynthesis of pullulan and its role as antibacterial, antiviral, and antifungal agent. Pullulan-based films impregnated with different antimicrobials such as AgNPs, chitosan, essential oils, and so on, forming nanocomposites have also been discussed as natural alternatives to combat the problems posed by pathogens.
Asunto(s)
Antiinfecciosos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Glucanos/biosíntesis , Antibacterianos , Antiinfecciosos/química , Antifúngicos , COVID-19 , Quitina/farmacología , Quitosano/química , Resistencia a Múltiples Medicamentos/fisiología , Embalaje de Alimentos , Glucanos/metabolismo , Glucanos/farmacología , Humanos , Nanopartículas del Metal/química , Nanocompuestos/química , Nisina/farmacología , Polímeros/química , SARS-CoV-2RESUMEN
The expression of ATP-binding cassette transporter (ABC transporters) has been reported in various tissues such as the lung, liver, kidney, brain and intestine. These proteins account for the efflux of different compounds and metabolites across the membrane, thus decreasing the concentration of the toxic compounds. ABC transporter genes play a vital role in the development of multidrug resistance, which is the main obstacle that hinders the success of chemotherapy. Preclinical and clinical trials have investigated the probability of overcoming drug-associated resistance and substantial toxicities. The focus has been put on several strategies to overcome multidrug resistance. These strategies include the development of modulators that can modulate ABC transporters. This knowledge can be translated for clinical oncology treatment in the future.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/fisiología , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
Hepatocellular carcinoma (HCC) is one of the most difficult cancer types to treat. Liver cancer is often diagnosed at late stages and therapeutic treatment is frequently accompanied by development of multidrug resistance. This leads to poor outcomes for cancer patients. Understanding the fundamental molecular mechanisms leading to liver cancer development is crucial for developing new therapeutic approaches, which are more efficient in treating cancer. Mice with a liver specific UDP-glucose ceramide glucosyltransferase (UGCG) knockout (KO) show delayed diethylnitrosamine (DEN)-induced liver tumor growth. Accordingly, the rationale for our study was to determine whether UGCG overexpression is sufficient to drive cancer phenotypes in liver cells. We investigated the effect of UGCG overexpression (OE) on normal murine liver (NMuLi) cells. Increased UGCG expression results in decreased mitochondrial respiration and glycolysis, which is reversible by treatment with EtDO-P4, an UGCG inhibitor. Furthermore, tumor markers such as FGF21 and EPCAM are lowered following UGCG OE, which could be related to glucosylceramide (GlcCer) and lactosylceramide (LacCer) accumulation in glycosphingolipid-enriched microdomains (GEMs) and subsequently altered signaling protein phosphorylation. These cellular processes lead to decreased proliferation in NMuLi/UGCG OE cells. Our data show that increased UGCG expression itself does not induce pro-cancerous processes in normal liver cells, which indicates that increased GlcCer expression leads to different outcomes in different cancer types.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Metabolismo Energético/fisiología , Glucosilceramidas/metabolismo , Hígado/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular , Resistencia a Múltiples Medicamentos/fisiología , Glucosiltransferasas/metabolismo , Glucólisis/fisiología , Glicoesfingolípidos/metabolismo , Neoplasias Hepáticas/metabolismo , Ratones , Mitocondrias/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Triple-negative metaplastic breast carcinoma (MBC) poses a significant treatment challenge due to lack of targeted therapies and chemotherapy resistance. We isolated a novel MBC cell line, BAS, which showed a molecular and phenotypic profile different from the only other metaplastic cell model, HS578T cells. To gain insight behind chemotherapeutic resistance, we generated doxorubicin (HS-DOX, BAS-DOX) and paclitaxel (HS-TX, BAS-TX) resistant derivatives of both cell lines. Drug sensitivity assays indicated a truly multidrug resistant (MDR) phenotype. Both BAS-DOX and BAS-TX showed up-regulation of FOXC1 and its experimental down-regulation re-sensitized cells to doxorubicin and paclitaxel. Experimental modulation of FOXC1 expression in MCF-7 and MDA-MB-231 cells corroborated its role in MDR. Genome-wide expression analyses identified gene expression signatures characterized by up-regulation of TGFB2, which encodes cytokine TGF-ß2, in both BAS-DOX and BAS-TX cells. Pharmacological inhibition of the TGF-ß pathway with galunisertib led to down-regulation of FOXC1 and increase in drug sensitivity in both BAS-DOX and BAS-TX cells. MicroRNA (miR) expression analyses identified high endogenous miR-495-3p levels in BAS cells that were downregulated in both BAS MDR cells. Transient expression of miR-495-3p mimic in BAS-DOX and BAS-TX cells caused downregulation of TGFB2 and FOXC1 and re-sensitized cells to doxorubicin and paclitaxel, whereas miR-495-3p inhibition in BAS cells led to increase in resistance to both drugs and up-regulation of TGFB2 and FOXC1. Together, these data suggest interplay between miR-495-3p, TGF-ß2 and FOXC1 regulating MDR in MBC and open the exploration of novel therapeutic strategies.
Asunto(s)
Neoplasias de la Mama/metabolismo , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/fisiología , Factores de Transcripción Forkhead/metabolismo , MicroARNs/metabolismo , Factor de Crecimiento Transformador beta2/metabolismo , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , Células Tumorales CultivadasRESUMEN
ATP-binding cassette (ABC) transporter C10 (ABCC10), also named multidrug resistance protein 7 (MRP7), is a member of ABC transporter superfamily and has been revealed to transport a wide range of chemotherapeutic agents including taxanes, epothilone B, Vinca alkaloids, and anthracyclines. In our previous study, a 5-cyano-6-phenylpyrimidin derivative CP55 was synthesized and found significantly reversal effect of multidrug resistance (MDR) mediated by ABCB1. In this study, we found CP55 also efficiently reversed MDR mediated by ABCC10. Our in vitro study showed that co-treatment with CP55 significantly increased the efficacy of ABCC10-substrate anticancer drugs in MDR cells overexpressing ABCC10. Furthermore, we showed that treatment with CP55 increased the intracellular accumulation of [3H]-labeled anticancer drugs and in-turn decreasing drug efflux by inhibiting the transport activity, without altering ABCC10 protein ex-pression level or cellular localization. Potential CP55-ABCC10 interactions were predicted via docking analysis using human ABCC10 homology model and obtained high docking score. Therefore, CP55 represents a promising therapeutic agent in the combinational treatment of chemo-resistant cancer related to ABCC10.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfato/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Múltiples Medicamentos/fisiología , Humanos , Proteínas de Neoplasias/metabolismo , Sensibilidad y EspecificidadRESUMEN
ABCG2 is an ABC membrane protein reverse transport pump, which removes toxic substances such as medicines out of cells. As a result, drug bioavailability is an unexpected change and negatively influences the ADMET (absorption, distribution, metabolism, excretion, and toxicity), leading to multi-drug resistance (MDR). Currently, in spite of promising studies, screening for ABCG2 inhibitors showed modest results. The aim of this study was to search for small molecules that could inhibit the ABCG2 pump. We first used the WISS MODEL automatic server to build up ABCG2 homology protein from 655 amino acids. Pharmacophore models, which were con-structed based on strong ABCG2 inhibitors (IC50 < 1 µM), consist of two hydrophobic (Hyd) groups, two hydrogen bonding acceptors (Acc2), and an aromatic or conjugated ring (Aro|PiR). Using molecular docking method, 714 substances from the DrugBank and 837 substances from the TCM with potential to inhibit the ABCG2 were obtained. These chemicals maybe favor synthesized or extracted and bioactivity testing.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/química , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/química , Transportadoras de Casetes de Unión a ATP/metabolismo , Resistencia a Múltiples Medicamentos/fisiología , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Simulación del Acoplamiento Molecular/métodos , Simulación de Dinámica Molecular , Unión Proteica/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
Multidrug and toxic compound extrusion (MATE) transport proteins confer multidrug resistance on pathogenic microorganisms and affect pharmacokinetics in mammals. Our understanding of how MATE transporters work, has mostly relied on protein structures and MD simulations. However, the energetics of drug transport has not been studied in detail. Many MATE transporters utilise the electrochemical H+ or Na+ gradient to drive substrate efflux, but NorM-VC from Vibrio cholerae can utilise both forms of metabolic energy. To dissect the localisation and organisation of H+ and Na+ translocation pathways in NorM-VC we engineered chimaeric proteins in which the N-lobe of H+-coupled NorM-PS from Pseudomonas stutzeri is fused to the C-lobe of NorM-VC, and vice versa. Our findings in drug binding and transport experiments with chimaeric, mutant and wildtype transporters highlight the versatile nature of energy coupling in NorM-VC, which enables adaptation to fluctuating salinity levels in the natural habitat of V. cholerae.
Asunto(s)
Antiportadores/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Vibrio cholerae/metabolismo , Antiportadores/fisiología , Proteínas Bacterianas/fisiología , Sitios de Unión , Transporte Biológico , Resistencia a Múltiples Medicamentos/genética , Resistencia a Múltiples Medicamentos/fisiología , Hidrógeno/química , Hidrógeno/metabolismo , Iones/metabolismo , Proteínas de Transporte de Catión Orgánico/fisiología , Unión Proteica , Sodio/química , Sodio/metabolismo , Vibrio cholerae/fisiologíaRESUMEN
Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfato/metabolismo , Resistencia a Antineoplásicos/fisiología , Mitocondrias/metabolismo , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Línea Celular Tumoral , Respiración de la Célula/efectos de los fármacos , Respiración de la Célula/fisiología , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/fisiología , Femenino , Proteínas del Choque Térmico HSP40/deficiencia , Proteínas del Choque Térmico HSP40/metabolismo , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Consumo de Oxígeno/efectos de los fármacosRESUMEN
Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/ß-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/ß-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/biosíntesis , Neoplasias de la Mama/metabolismo , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/fisiología , Molécula de Adhesión Celular Epitelial/biosíntesis , Transición Epitelial-Mesenquimal/fisiología , Proteínas de Neoplasias/biosíntesis , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Molécula de Adhesión Celular Epitelial/antagonistas & inhibidores , Molécula de Adhesión Celular Epitelial/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , Mitoxantrona/farmacología , Proteínas de Neoplasias/genética , ARN Interferente Pequeño/administración & dosificaciónRESUMEN
The outer membrane (OM) of Gram-negative bacteria provides an efficient barrier against external noxious compounds such as antimicrobial agents. Associated with drug target modification, it contributes to the overall failure of chemotherapy. In the complex OM architecture, Lipid A plays an essential role by anchoring the lipopolysaccharide in the membrane and ensuring the spatial organization between lipids, proteins, and sugars. Currently, the targets of almost all antibiotics are intracellularly located and require translocation across membranes. We report herein an integrated view of Lipid A synthesis, membrane assembly, a structure comparison at the molecular structure level of numerous Gram-negative bacterial species, as well as its recent use as a target for original antibacterial molecules. This review paves the way for a new vision of a key membrane component that acts during bacterial adaptation to environmental stresses and for the development of new weapons against microbial resistance to usual antibiotics.
Asunto(s)
Adaptación Biológica/fisiología , Bacterias Gramnegativas/metabolismo , Lípido A/metabolismo , Secuencia de Aminoácidos , Animales , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/fisiología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Múltiples Medicamentos/fisiología , Inhibidores Enzimáticos/farmacología , Bacterias Gramnegativas/química , Bacterias Gramnegativas/efectos de los fármacos , Humanos , Lípido A/biosíntesis , Lípido A/químicaRESUMEN
Multidrug-resistant Pseudomonas aeruginosa is one of the main opportunistic pathogens causing severe infection. One of the mechanisms involved in the resistance to imipenem in clinical isolates is the loss of the OprD porin. Changes like substitutions, deletions, insertions, or mutations in the oprD gene can modify the conformation of OprD porin or inhibit its presence and generate resistance to carbapenems. The aim of this work was to obtain anti-OprD polyclonal antibodies and to determine by both immunofluorescence microscopy (IFI) and Western blot assays, the presence of the OprD porin in resistant-carbapenem P. aeruginosa strains with different changes in the oprD gene. Changes in the gene oprD were identified in clinical isolates of P. aeruginosa. When proteins were translated, several polymorphisms were found; however, these did not affect the presence of OprD porin (PCM25, PCM36, and PCM78). Also it was detected an insertion sequence ISPa1328 (PCM52) and a premature stop codon (PCM91), which inhibited the presence of the OprD porin. This study shows how changes in the oprD gene of P. aeruginosa clinical isolates affect the presence of the OprD porin detected by Western blot and indirect immunofluorescence assays using specific polyclonal anti-OprD antibodies generated in this work.
Asunto(s)
Farmacorresistencia Microbiana/fisiología , Porinas/genética , Porinas/metabolismo , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Animales , Resistencia a Múltiples Medicamentos/fisiología , Humanos , ConejosRESUMEN
Multidrug resistance (MDR) is the main obstacle in cancer chemotherapy. ATP-binding cassette (ABC) transporters can transport a wide range of antitumor drugs out of cells, which is the most common reason in the development of resistance to drugs. Currently, various therapeutic strategies are used to reverse MDR, among which CRISPR/Cas9 gene editing technique is expected to be an effective way. Here, we reviewed the research progress of reversing ABC-mediated drug resistance by CRISPR/Cas9 system.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/fisiología , Sistemas CRISPR-Cas , Resistencia a Múltiples Medicamentos/fisiología , Animales , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Múltiples Medicamentos/genética , Edición Génica , HumanosRESUMEN
Multidrug resistance (MDR) is a serious challenge in chemotherapy and also a major threat to breast cancer treatment. As an intracellular energy factory, mitochondria provide energy for drug efflux and are deeply involved in multidrug resistance. Mitochondrial targeted delivery of doxorubicin can overcome multidrug resistance by disrupting mitochondrial function. By incorporating a reactive oxygen species (ROS)-responsive hydrophobic group into the backbone structure of hyaluronic acid - a natural ligand for the highly expressed CD44 receptor on tumor surfaces, a novel ROS-responsive and CD44-targeting nano-carriers was constructed. In this study, mitochondria-targeted triphenylphosphine modified-doxorubicin (TPP-DOX) and amphipathic ROS-responsive hyaluronic acid derivatives (HA-PBPE) were synthesized and confirmed by 1H NMR. The nanocarriers TPP-DOX @ HA-PBPE was prepared in a regular shape and particle size of approximately 200 nm. Compared to free DOX, its antitumor activity in vitro and tumor passive targeting in vivo has been enhanced. The ROS-responsive TPP-DOX@HA-PBPE nanocarriers system provide a promising strategy for the reverse of MDR and efficient delivery of doxorubicin derivatives into drug-resistant cancer cells.
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Antineoplásicos/metabolismo , Neoplasias de la Mama/metabolismo , Doxorrubicina/metabolismo , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Nanopartículas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Nanopartículas/administración & dosificación , Nanopartículas/química , Especies Reactivas de Oxígeno/químicaRESUMEN
The purpose of our study is to identify the efficacy of ruxolitinib in human leukocyte antigen (HLA) haploidentical hematopoietic stem cell transplantation (haplo-HSCT) recipients with multidrug-resistant (MDR)-graft-versus-host disease (GVHD, n = 34). MDR-GVHD was defined as GVHD showing no improvement after at least 3 types of treatments. The median number of previous GVHD-therapies was 4 for both MDR-acute GVHD (aGVHD) and MDR-chronic GVHD (cGVHD). For MDR-aGVHD (n = 15), the median time to response was 10 days (range 2 to 65), and the overall response rate (ORR) was 60.0% (9/15), including 40.0% (6/15) complete response (CR) and 20.0% (3/15) partial response (PR). The 1-year probability of overall survival after ruxolitinib was 66.7%. The rates of hematologic and infectious toxicities were 73.3% and 46.7% after ruxolitinib treatment. For MDR-cGVHD (n = 19), the median time to response was 29 days (range 6 to 175), and the ORR was 89.5% (17/19), including 26.3% (5/19) CR and 63.2% (12/19) PR. All patients remained alive until our last follow-up. The rates of hematologic and infectious toxicities were 36.8% and 47.4% after ruxolitinib treatment. Ruxolitinib is an effective salvage treatment for MDR-GVHD in haplo-HSCT recipients.
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Ciclofosfamida , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas , Pirazoles/uso terapéutico , Terapia Recuperativa , Trasplante Haploidéntico , Adolescente , Adulto , Niño , Preescolar , Resistencia a Múltiples Medicamentos/fisiología , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/diagnóstico , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Pirimidinas , Estudios Retrospectivos , Terapia Recuperativa/tendencias , Trasplante Haploidéntico/tendencias , Trasplante Homólogo/tendencias , Resultado del Tratamiento , Adulto JovenRESUMEN
P-glycoprotein (P-gp), also known as ABCB1, is a cell membrane transporter that mediates the efflux of chemically dissimilar amphipathic drugs and confers resistance to chemotherapy in most cancers. Homologous transmembrane helices (TMHs) 6 and 12 of human P-gp connect the transmembrane domains with its nucleotide-binding domains, and several residues in these TMHs contribute to the drug-binding pocket. To investigate the role of these helices in the transport function of P-gp, we substituted a group of 14 conserved residues (seven in both TMHs 6 and 12) with alanine and generated a mutant termed 14A. Although the 14A mutant lost the ability to pump most of the substrates tested out of cancer cells, surprisingly, it acquired a new function. It was able to import four substrates, including rhodamine 123 (Rh123) and the taxol derivative flutax-1. Similar to the efflux function of wild-type P-gp, we found that uptake by the 14A mutant is ATP hydrolysis-, substrate concentration-, and time-dependent. Consistent with the uptake function, the mutant P-gp also hypersensitizes HeLa cells to Rh123 by 2- to 2.5-fold. Further mutagenesis identified residues from both TMHs 6 and 12 that synergistically form a switch in the central region of the two helices that governs whether a given substrate is pumped out of or into the cell. Transforming P-gp or an ABC drug exporter from an efflux transporter into a drug uptake pump would constitute a paradigm shift in efforts to overcome cancer drug resistance.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transporte Biológico/fisiología , Resistencia a Múltiples Medicamentos/fisiología , Preparaciones Farmacéuticas/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Sustitución de Aminoácidos/fisiología , Animales , Sitios de Unión/fisiología , Línea Celular , Línea Celular Tumoral , Resistencia a Antineoplásicos/fisiología , Células HeLa , Humanos , Insectos , Simulación del Acoplamiento Molecular/métodos , Rodamina 123/metabolismo , Especificidad por Sustrato/fisiologíaRESUMEN
Imatinib-resistance is a significant concern for Bcr-Abl-positive chronic myelogenous leukemia (CML) treatment. Emodin, the predominant compound of traditional medicine rhubarb, was reported to inhibit the multidrug resistance by downregulating P-glycoprotein of K562/ADM cells with overexpression of P-glycoprotein in our previous studies. In the present study, we found that emodin can be a potential inhibitor for the imatinib-resistance in K562/G01 cells which are the imatinib-resistant subcellular line of human chronic myelogenous leukemia cells with overexpression of breakpoint cluster region-abelson (Bcr-Abl) oncoprotein. Emodin greatly enhanced cell sensitivity to imatinib, suppressed resistant cell proliferation and increased potentiated apoptosis induced by imatinib in K562/G01 cells. After treatment of emodin and imatinib together, the levels of p-Bcr-Abl and Bcr-Abl were significantly downregulated. Moreover, Bcr-Abl important downstream target, STAT5 and its phosphorylation were affected. Furthermore, the expression of Bcr-Abl and signal transducers and activators of transcription 5 (STAT5) related molecules, including c-MYC, MCL-1, poly(ADP-ribose)polymerase (PARP), Bcl-2 and caspase-3, were changed. Emodin also decreased Src expression and its phosphorylation. More importantly, emodin simultaneously targeted both the ATP-binding and allosteric sites on Bcr-Abl by molecular docking, with higher affinity with the myristoyl-binding site for enhanced Bcr-Abl kinase inhibition. Overall, these data indicated emodin might be an effective therapeutic agent for inhibiting resistance to imatinib in CML treatment.