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1.
Pharm Res ; 37(10): 194, 2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32918191

RESUMEN

PURPOSE: We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. METHOD: hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (Kp,uu). RESULTS: MDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration. CONCLUSION: cP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Proteínas de Neoplasias/metabolismo , Farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células CACO-2 , Permeabilidad de la Membrana Celular , Dibenzocicloheptenos/farmacología , Dicetopiperazinas/farmacología , Perros , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Células de Riñón Canino Madin Darby , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Prazosina/farmacocinética , Quinidina/farmacocinética , Quinolinas/farmacología , Especificidad por Sustrato , Transfección
2.
Toxicol Appl Pharmacol ; 401: 115080, 2020 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-32497533

RESUMEN

Upregulation of ABCB1/MDR1 (P-gp) and BIRC5/Survivin promotes multidrug resistance in a variety of human cancers. LCL161 is an anti-cancer DIABLO/SMAC mimetic currently being tested in patients with solid tumors, but the molecular mechanism of action of LCL161 in cancer cells is still incompletely understood. It is still unclear whether LCL161 is therapeutically applicable for patients with ABCB1-overexpressing multidrug resistant tumors. In this study, we found that the potency of LCL161 is not affected by the expression of ABCB1 in KB-TAX50, KB-VIN10, and NTU0.017 cancer cells. Besides, LCL161 is equally potent towards the parental MCF7 breast cancer cells and its BIRC5 overexpressing, hormone therapy resistance subline MCF7-TamC3 in vitro. Mechanistically, we found that LCL161 directly modulates the ABCB1-ATPase activity and inhibits ABCB1 multi-drug efflux activity at low cytotoxic concentrations (i.e. 0.5xIC50 or less). Further analysis revealed that LCL161 also decreases intracellular ATP levels in part through BIRC5 downregulation. Therapeutically, co-treatment with LCL161 at low cytotoxic concentrations restored the sensitivity to the known ABCB1 substrate, paclitaxel, in ABCB1-expressing cancer cells and increased the sensitivity to tamoxifen in MCF7-TamC3 cells. In conclusion, LCL161 has the potential for use in the management of cancer patients with ABCB1 and BIRC5-related drug resistance. The findings of our study provide important information to physicians for designing a more "patient-specific" LCL161 clinical trial program in the future.


Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/farmacología , Proteínas Mitocondriales/farmacología , Survivin/antagonistas & inhibidores , Tiazoles/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfatasas/metabolismo , Antineoplásicos/química , Proteínas Reguladoras de la Apoptosis/química , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Proteínas Mitocondriales/química , Estructura Secundaria de Proteína , Survivin/biosíntesis , Survivin/genética , Tiazoles/química
3.
Phytomedicine ; 71: 153239, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32447245

RESUMEN

BACKGROUND AND PURPOSE: Multidrug resistance (MDR) remains the main obstacle in cancer treatment and overexpression of P-glycoprotein (P-gp) is one of the most common causes of chemoresistance. The development of novel P-gp inhibitors from natural products is a prospective strategy to combat MDR cancers. Among the natural sesquiterpene compounds, sesquiterpene pyridine alkaloids exhibit various biological properties. Therefore, in the present study, we evaluated the modulatory effects of wilforine on P-gp expression and function. The molecular mechanisms and kinetic models of wilforine-mediated P-gp inhibition were further investigated. METHODS: The human P-gp stable expression cells (ABCB1/Flp-InTM-293) and human cervical cancer cells (sensitive: HeLaS3; MDR: KBvin) were used. The cell viability was assessed by SRB assay. The inhibitory effect of wilforine on P-gp efflux and the underlying mechanism were evaluated by assays for calcein-AM uptake, rhodamine123 and doxorubicin efflux, ATPase activity, real-time quantitative RT-PCR, apoptosis, and cell cycle analysis. Molecular docking was performed by the docking software CDOCKER with BIOVIA Discovery Studio 4.5 (D.S. 4.5). RESULTS: We found that wilforine significantly inhibited the efflux activity of P-gp in a concentration-dependent manner. Further kinetic analysis demonstrated that wilforine significantly inhibited P-gp efflux function by competitive inhibition and stimulated the basal P-gp ATPase activity. In addition, wilforine re-sensitized MDR cancer cells to chemotherapeutic drugs. The docking model indicated that wilforine was bound to residues of P-gp such as LEU884, LYS887, THR176 and ASN172. CONCLUSION: These results suggest a novel future therapeutic strategy for MDR cancer using wilforine as an adjuvant treatment with chemotherapy.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Lactonas/farmacología , Piridinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/fisiología , Células HeLa , Humanos , Cinética , Lactonas/química , Simulación del Acoplamiento Molecular , Estudios Prospectivos , Piridinas/química
4.
PLoS One ; 15(5): e0227844, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32470043

RESUMEN

Morroniside is a biologically active polyphenol found in Cornus officinalis Sieb. et Zucc (CO) that exhibits a broad spectrum of pharmacological activities, such as protecting nerves, and preventing diabetic liver damage and renal damage. However, little data are available regarding the mechanism of its intestinal absorption. Here, an in vitro human intestinal epithelial cell model of cultured Caco-2 cells was applied to study the absorption and transport of morroniside. The effects of donor concentration, pH and inhibitors were investigated. The bidirectional permeability of morroniside from the apical (AP) to the basolateral (BL) side and in the reverse direction was studied. When administered at three tested concentrations (5, 25 and 100 µM), the apparent permeability coefficient (Papp) values in the AP-to-BL direction ranged from 1.59 × 10-6 to 2.66 × 10-6 cm/s. In the reverse direction, BL-to-AP, the value was ranged from 2.67 × 10-6 to 4.10 × 10-6 cm/s. The data indicated that morroniside transport was pH-dependent. The permeability of morroniside was affected by treatment with various inhibitors, such as multidrug resistance protein inhibitors MK571 and indomethacin, as well as the breast cancer resistance protein inhibitor apigenin. The mechanisms of the intestinal absorption of morroniside may involve multiple transport pathways, such as the passive diffusion and efflux protein-mediated active transport especially involving multidrug resistance protein 2 and breast cancer resistance protein. After the addition of CO, the Papp values in the AP-to-BL direction increased significantly, therefore, it can be assumed that some ingredients in the CO promote morroniside absorption in the small intestine.


Asunto(s)
Cornus/química , Glicósidos/farmacología , Absorción Intestinal/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Indometacina/farmacología , Absorción Intestinal/genética , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Neoplasias/patología , Permeabilidad/efectos de los fármacos , Propionatos/farmacología , Quinolinas/farmacología
5.
J Med Chem ; 63(10): 5458-5476, 2020 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-32329342

RESUMEN

SIS3 is a specific inhibitor of Smad3 that inhibits the TGFß1-induced phosphorylation of Smad3. In this article, a variety of SIS3 derivatives were designed and synthesized to discover potential inhibitors against P-glycoprotein-mediated multidrug resistance aided by late-stage functionalization of a 2-(4-(pyridin-2-yl)phenoxy)pyridine analogue. A novel class of potent P-gp reversal agents were investigated, and a lead compound 37 was identified as a potent P-gp reversal agent with strong bioactivity and outstanding affinity for P-gp.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Descubrimiento de Drogas/métodos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Isoquinolinas/química , Isoquinolinas/farmacología , Piridinas/química , Piridinas/farmacología , Pirroles/química , Pirroles/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Resistencia a Múltiples Medicamentos/fisiología , Humanos , Isoquinolinas/metabolismo , Células K562 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular/métodos , Piridinas/metabolismo , Pirroles/metabolismo , Proteína smad3/antagonistas & inhibidores , Proteína smad3/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
6.
Sci Rep ; 10(1): 6524, 2020 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-32300151

RESUMEN

Glioblastoma, the most lethal primary brain cancer, is extremely proliferative and invasive. Tumor cells at tumor/brain-interface often exist behind a functionally intact blood-brain barrier (BBB), and so are shielded from exposure to therapeutic drug concentrations. An ideal glioblastoma treatment needs to engage targets that drive proliferation as well as invasion, with brain penetrant therapies. One such target is the mitotic kinesin KIF11, which can be inhibited with ispinesib, a potent molecularly-targeted drug. Although, achieving durable brain exposures of ispinesib is critical for adequate tumor cell engagement during mitosis, when tumor cells are vulnerable, for efficacy. Our results demonstrate that the delivery of ispinesib is restricted by P-gp and Bcrp efflux at BBB. Thereby, ispinesib distribution is heterogeneous with concentrations substantially lower in invasive tumor rim (intact BBB) compared to glioblastoma core (disrupted BBB). We further find that elacridar-a P-gp and Bcrp inhibitor-improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Cinesina/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Quinazolinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Acridinas/química , Acridinas/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Glioblastoma/genética , Glioblastoma/patología , Humanos , Cinesina/genética , Ratones , Terapia Molecular Dirigida , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Pharm Res ; 37(3): 58, 2020 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-32086630

RESUMEN

PURPOSE: S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) is routinely used at concentrations of 0.10 µM and 0.10 mM to specifically inhibit transport of nucleosides mediated by equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), respectively. We recently showed that NBMPR (0.10 mM) might also inhibit placental active efflux of [3H]zidovudine and [3H]tenofovir disoproxil fumarate. Here we test the hypothesis that NBMPR abolishes the activity of P-glycoprotein (ABCB1) and/or breast cancer resistance protein (ABCG2). METHODS: We performed accumulation assays with Hoechst 33342 (a model dual substrate of ABCB1 and ABCG2) and bi-directional transport studies with the ABCG2 substrate [3H]glyburide in transduced MDCKII cells, accumulation studies in choriocarcinoma-derived BeWo cells, and in situ dual perfusions of rat term placenta with glyburide. RESULTS: NBMPR inhibited Hoechst 33342 accumulation in MDCKII-ABCG2 cells (IC50 = 53 µM) but not in MDCKII-ABCB1 and MDCKII-parental cells. NBMPR (0.10 mM) also inhibited bi-directional [3H]glyburide transport across monolayers of MDCKII-ABCG2 cells and blocked ABCG2-mediated [3H]glyburide efflux by rat term placenta in situ. CONCLUSION: NBMPR at a concentration of 0.10 mM abolishes ABCG2 activity. Researchers using NBMPR to evaluate the effect of ENTs on pharmacokinetics must therefore interpret their results carefully if studying compounds that are substrates of both ENTs and ABCG2.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transporte Biológico/efectos de los fármacos , Proteínas de Neoplasias/antagonistas & inhibidores , Tioinosina/análogos & derivados , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Antivirales/metabolismo , Antivirales/farmacocinética , Línea Celular , Perros , Femenino , Humanos , Células de Riñón Canino Madin Darby , Proteínas de Neoplasias/metabolismo , Placenta/efectos de los fármacos , Placenta/metabolismo , Embarazo , Ratas , Ratas Wistar , Tioinosina/farmacología
8.
Biochem Pharmacol ; 175: 113848, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32044354

RESUMEN

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Antineoplásicos/farmacología , Chalconas/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Neoplasias/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Antineoplásicos/química , Línea Celular Tumoral , Chalconas/química , Humanos , Simulación del Acoplamiento Molecular , Proteínas de Neoplasias/genética
9.
Sci Rep ; 10(1): 1970, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32029822

RESUMEN

Chemotherapy, a major cancer treatment approach, suffers seriously from multidrug resistance (MDR), generally caused by innate DNA repair proteins that reverse the DNA modification by anti-cancer therapeutics or trans-membrane efflux proteins that pump anti-cancer therapeutics out of the cytosol. This project focused on finding microRNAs that can regulate MDR proteins by managing corresponding mRNA levels through post-transcriptional regulation based on nucleotide sequence matching. Screening was done with bioinformatics databases for unpublished/unexplored microRNAs with high nucleotide sequence correspondence to two representative MDR proteins, MGMT (a DNA repair protein) and ABCB1 (an efflux protein), revealing microRNA-4539 and microRNA-4261 respectively. To investigate the enhancement of chemotherapeutics in cancer cells, high MGMT expressing glioblastoma (T98G) and a high ABCB1 expressing triple-negative breast cancer cell line (MDA-MB-231-luc) were treated with varying concentrations of chemotherapeutics and corresponding miRNAs. Newly identified MDR-related miRNAs (MDRmiRs) enhanced the response to anti-cancer therapeutics and resulted in effective cell death. In this study, we demonstrated that therapeutic miRNAs could be identified based on the nucleotide sequence matching of miRNAs to targeted mRNA and the same approach could be employed for the screening of therapeutic candidates to regulate specific target proteins in diverse diseases.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , MicroARNs/análisis , Neoplasias/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Biología Computacional , Reparación del ADN/efectos de los fármacos , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , MicroARNs/genética , Neoplasias/genética , Oligonucleótidos/genética , Oligonucleótidos/farmacología
10.
Biochem Pharmacol ; 171: 113733, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31783010

RESUMEN

Taxol-based chemotherapy is widely used as the first-line treatment for non-small cell lung cancer (NSCLC), however, the subsequent development of taxol-resistance is a major concern and challenge, resulting in tumor relapse and poor prognosis. Given the complex nature of taxol-resistance, we further delved into its mechanisms and demonstrated that CYP1B1 was associated to taxol response in taxol-resistant A549/Taxol cells. Compared to its parent A549 counterpart, A549/Taxol presented much higher level of CYP1B1, which was paralleled by increased aryl hydrocarbon receptor (AhR) expressions likely due to the long term taxol exposure and thereby allowed a subsequent up-regulation of CYP1B1. Inhibition of CYP1B1 by TMS [(E)-2,3',4,5'-tetramethoxystilbene], the specific CYP1B1 inhibitor, remarkably enhanced the sensitivity of A549/Taxol to taxol. Moreover, pre-incubation of taxol with human recombinant CYP1B1 did not affect drug toxicity in A549 cells, precluding the possibility of drug resistance ascribed to CYP1B1 due to directly inactivating taxol. Indeed, CYP1B1 is responsible for bio-transforming estrogen (E2) into the carcinogenetic metabolite that would inhibit microtubule stabilization induced by taxol and thereby compromising treatment efficacy. Remarkably, our data revealed potent CYP1B1 inhibition efficacy of 4-hydroxyemodin (HEM) as reflected by both molecular docking simulations and EROD assay, which posed HEM the advantage of breaking the vicious circle between E2 and CYP1B1, not only favoring to overcome taxol-resistance, but also offering long term benefit via circumventing carcinogenesis and tumor progression induced by E2. In addition to CYP1B1 inhibition, HEM notably inhibited P-gp activity and expression, a common feature of drug resistance, as well as significantly inactivated AKT/ERK pathways that contributed to the cell proliferation, migration, and drug resistance. Thus, HEM may act in concert to overcome taxol-resistance through comprehensive targeting three considered arms of drug-resistance mechanisms. Moreover, HEM profoundly resisted E2-stimulated cell migration in both A549 and A549/Taxol cells, a primary reason for tumor patients' mortality, as well as inflicted selective injury to A549/Taxol cells rather than normal lung cells, supporting HEM to be a promising agent for overcoming taxol-resistance in A549 cells.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Emodina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Paclitaxel/farmacología , Proteínas/antagonistas & inhibidores , Células A549 , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocromo P-450 CYP1B1/antagonistas & inhibidores , Citocromo P-450 CYP1B1/metabolismo , Emodina/química , Emodina/metabolismo , Emodina/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo
11.
Int J Cancer ; 146(6): 1631-1642, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31304590

RESUMEN

Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-ß) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type mice, but not in single Abcg2-/- mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a-/- mice showed a 1.9-fold higher plasma AUC0-1 hr than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.


Asunto(s)
Encéfalo/metabolismo , Pirazoles/farmacocinética , Quinolinas/farmacocinética , Factor de Crecimiento Transformador beta/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Acridinas/farmacología , Animales , Encéfalo/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Perros , Femenino , Interacciones de Hierba-Droga , Humanos , Células de Riñón Canino Madin Darby , Ratones , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Transportadores de Anión Orgánico/metabolismo , Pirazoles/sangre , Pirazoles/farmacología , Quinolinas/sangre , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Distribución Tisular
12.
Anticancer Res ; 39(12): 6499-6505, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810914

RESUMEN

BACKGROUND/AIM: Development of new potential drugs to overcome multidrug resistance to chemotherapy is a big challenge for cancer treatment. Attention is also given to the natural compounds and their derivatives. The study aimed at evaluating the impact of a new chalcone derivative (1C) on multidrug resistant cell lines, focusing on P-glycoprotein (P-gp, ABCB1) inhibition, as well as 1C-doxorubicin interaction in vitro. MATERIALS AND METHODS: Cytotoxic and antiproliferative effects of the 1C compound were assessed by thiazolyl blue tetrazolium bromide (MTT) method in mouse T-cell lymphoma and human colon adenocarcinoma cells expressing ABCB1. Alterations in ABCB1 activity were evaluated by rhodamine 123 accumulation assay using flow cytometry. Drug-drug interaction was studied using combination assay. RESULTS: Our results confirmed antiproliferative, cytotoxic, as well as ABCB1 inhibitory potential of 1C in both tested ABCB1-expressing cancer cell lines. Furthermore, 1C displayed synergistic interaction with doxorubicin. CONCLUSION: Our results suggest the 1C chalcone derivative as a promising compound against resistant lymphoma and colon cancer, which could be used in monotherapy or in combination with other chemotherapeutics.


Asunto(s)
Adenocarcinoma/metabolismo , Chalconas/farmacología , Neoplasias del Colon/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Linfoma de Células T/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Regulación hacia Abajo , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células T/tratamiento farmacológico
13.
Biomed Res Int ; 2019: 1269532, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31871929

RESUMEN

Multidrug resistance is the main obstacle to current chemotherapies. In this study, we evaluated the reversing effect of matrine, the principal alkaloid derived from Sophora alopecuroides, on chemoresistant leukemia K562/ADR cells. Matrine in a range of the nontoxic concentration was employed in the whole study. IC50s of cancer medicines were tested using WST-8 assay. Drug export and apoptotic rates were examined using flow cytometry. The mRNA and protein expressions were quantified by quantitative real-time PCR and western blotting, respectively. Our data indicated that matrine had potent reversal properties augmenting cytotoxicity of cancer medicines on K562/ADR cells as well as apoptotic rates induced by doxorubicin. Moreover, matrine inhibited drug-exporting activity and expression of ATP-binding cassette subfamily B member 1 (ABCB1) on both mRNA and protein levels. That might result from inhibited NF-kappa B activation, which also led to restored intrinsic apoptosis. These findings suggest that matrine in the nontoxic concentration can suppress ABCB1 drug transport and facilitate the intrinsic apoptosis pathway through the inhibiting effect on NF-kappa B and has the potential to become an efficient sensitizer for anticancer drug resistance.


Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Células K562/efectos de los fármacos , Quinolizinas/farmacología , Sophora/química , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Humanos , Concentración 50 Inhibidora , Leucemia/tratamiento farmacológico , FN-kappa B/antagonistas & inhibidores
14.
Pharmacol Res Perspect ; 7(6): e00540, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31832203

RESUMEN

Dimethylfumarate (DMF) has long been used as part of a fixed combination of fumaric acid esters (FAE) in some European countries and is now available as an oral monotherapy for psoriasis. The present investigation determined whether DMF and its main metabolite monomethylfumarate (MMF) interact with hepatic cytochrome P450 (CYP) enzymes and the P-glycoprotein (P-gp) transporter, and was performed as part of DMF's regulatory commitments. Although referred to in the available product labels/summary of product characteristics, the actual data have not yet been made publicly available. In vitro inhibition experiments using CYP-selective substrates with human liver microsomes showed 50% inhibitory concentrations (IC50) of >666 µmol/L for DMF and >750 µmol/L for MMF. MMF (≤250 µmol/L; 72 hours) was not cytotoxic in cultured human hepatocyte experiments and mRNA expression data indicated no CYP induction by MMF (1-250 µmol/L). DMF (≤6.66 mmol/L) showed moderate-to-high absorption (apparent permeability [Papp] ≥2.3-29.7 x 10-6 cm/s) across a Caucasian colon adenocarcinoma (Caco-2) cell monolayer, while MMF (≤7.38 mmol/L) demonstrated low-to-moderate permeability (Papp 1.2-8.9 × 10-6 cm/s). DMF was not a substrate for P-gp (net efflux ratios ≤1.22) but was a weak inhibitor of P-gp at supratherapeutic concentrations (estimated IC50 relative to solvent control of 1.5 mmol/L; [3H]digoxin efflux in Caco-2 cells). This inhibition is unlikely to be clinically relevant. MMF was not a substrate or inhibitor of P-gp. Thus, DMF and MMF should not affect the absorption, distribution, metabolism or excretion of coadministered drugs that are CYP and P-gp substrates.


Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Dimetilfumarato/farmacología , Fumaratos/farmacología , Maleatos/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Células CACO-2 , Permeabilidad de la Membrana Celular , Dimetilfumarato/uso terapéutico , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fumaratos/uso terapéutico , Hepatocitos , Humanos , Concentración 50 Inhibidora , Hígado/metabolismo , Maleatos/uso terapéutico , Microsomas Hepáticos , Psoriasis/tratamiento farmacológico
15.
Drug Metab Dispos ; 47(10): 1040-1049, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31399508

RESUMEN

Rhinacanthin-C is a major active constituent in Rhinacanthus nasutus (L.) Kurz, a plant widely used in herbal remedies. Its potential for pharmacokinetic herb-drug interaction may exist with drug transporters and drug metabolizing enzymes. This study assessed the possibility for rhinacanthin-C-mediated drug interaction by determining its inhibitory effects against major human efflux and influx drug transporters as well as various human cytochrome P450(CYP) isoforms. Rhinacanthin-C demonstrated a moderate permeability through the Caco-2 monolayers [Papp (AP-to-BL) = 1.26 × 10-6 cm/s]. It significantly inhibited transport mediated by both P-glycoprotein (P-gp) (IC50 = 5.20 µM) and breast cancer resistance protein (BCRP) (IC50 = 0.83 µM) across Caco-2 and BCRP-overexpressing Madin-Darby canine kidney II cells (MDCKII) cells. This compound also strongly inhibited uptake mediated by organic anion-transporting polypeptide 1B1 (OATP1B1) (IC50 = 0.70 µM) and OATP1B3 (IC50 = 3.95 µM) in OATP1B-overexpressing HEK cells. In addition to its inhibitory effect on these drug transporters, rhinacanthin-C significantly inhibited multiple human CYP isoforms including CYP2C8 (IC50 = 4.56 µM), 2C9 (IC50 = 1.52 µM), 2C19 (IC50 = 28.40 µM), and 3A4/5 (IC50 = 53 µM for midazolam and IC50 = 81.20 µM for testosterone), but not CYP1A2, 2A6, 2B6, 2D6, and 2E1. These results strongly support a high propensity for rhinacanthin-C as a perpetrator of clinical herb-drug interaction via inhibiting various influx and efflux drug transporters (i.e., P-gp, BCRP, OATP1B1, and OATP1B3) and CYP isoforms (i.e., CYP2C8, CYP2C9, and CYP2C19). Thus, the potential for significant pharmacokinetic herb-drug interaction should be addressed when herbal products containing rhinacanthin-C are to be used in conjunction with other prescription drugs.


Asunto(s)
Acanthaceae/química , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Interacciones de Hierba-Droga , Naftoquinonas/farmacología , Medicamentos bajo Prescripción/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Células HEK293 , Humanos , Concentración 50 Inhibidora , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Células de Riñón Canino Madin Darby , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Proteínas Recombinantes/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/antagonistas & inhibidores , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo
16.
Mol Pharm ; 16(8): 3361-3373, 2019 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-31265310

RESUMEN

P-glycoprotein (Pgp) is highly expressed on blood-brain barrier (BBB) and glioblastoma (GB) cells, particularly on cancer stem cells (SC). Pgp recognizes a broad spectrum of substrates, limiting the therapeutic efficacy of several chemotherapeutic drugs in eradicating GB SC. Finding effective and safe inhibitors of Pgp that improve drug delivery across the BBB and target GB SC is open to investigation. We previously identified a series of thiosemicarbazone compounds that inhibit Pgp with an EC50 in the nanomolar range, and herein, we investigate the efficacy of three of them in bypassing Pgp-mediated drug efflux in primary human BBB and GB cells. At 10 nM, the compounds were not cytotoxic for the brain microvascular endothelial hCMEC/D3 cell line, but they markedly enhanced the permeability of the Pgp-substrate doxorubicin through the BBB. Thiosemicarbazone derivatives increased doxorubicin uptake in GB, with greater effects in the Pgp-rich SC clones than in the differentiated clones derived from the same tumor. All compounds increased intratumor doxorubicin accumulation and consequent toxicity in GB growing under competent BBB, producing significant killing of GB SC. The compounds crossed the BBB monolayer. The most stable derivative, 10a, had a half-life in serum of 4.2 h. The coadministration of doxorubicin plus 10a significantly reduced the growth of orthotopic GB-SC xenografts, without eliciting toxic side effects. Our work suggests that the thiosemicarbazone compounds are able to transform doxorubicin, a prototype BBB-impermeable drug, into a BBB-permeable drug. Bypassing Pgp-mediated drug efflux in both BBB and GB SC, thiosemicarbazones might increase the success of chemotherapy in targeting GB SC, which represent the most aggressive and difficult components to eradicate.


Asunto(s)
Antineoplásicos/farmacocinética , Barrera Hematoencefálica/efectos de los fármacos , Portadores de Fármacos/farmacología , Glioblastoma/tratamiento farmacológico , Tiosemicarbazonas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos/administración & dosificación , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/metabolismo , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Femenino , Glioblastoma/patología , Semivida , Humanos , Masculino , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Permeabilidad/efectos de los fármacos , Cultivo Primario de Células , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Biomed Pharmacother ; 117: 109059, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31207578

RESUMEN

Jervine is a natural teratogenic compound isolated from Veratrum californicum. In this study, for the first time, we revealed a novel activity of jervine in sensitizing the anti-proliferation effect of doxorubicin (DOX). We demonstrated that the synergistic mechanism was related to the intracellular accumulation of DOX via modulating ABCB1 transportation. Jervine did not affect the expression of ABCB1 in mRNA nor protein levels. However, jervine increased the ATPase activity of ABCB1 and possibly served as a substrate of ABCB1. The molecular docking results indicated that jervine was bound to a closed ABCB1 conformation and blocked drug entrance to the central binding site at the transmembrane domain. The present study identifies jervine acts as a substrate of ABCB1, and has potential to be developed as a novel and potent chemotherapy sensitizer used for patients developing multidrug resistance.


Asunto(s)
Doxorrubicina/farmacología , Teratógenos/toxicidad , Alcaloides de Veratrum/toxicidad , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Células MCF-7 , Estructura Secundaria de Proteína , Especificidad por Sustrato/efectos de los fármacos , Teratógenos/química , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacología
19.
Drug Metab Dispos ; 47(7): 715-723, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31048454

RESUMEN

Although overexpression of multiple ATP-binding cassette transporters has been reported in clinical samples, few studies have examined how coexpression of multiple transporters affected resistance to chemotherapeutic drugs. We therefore examined how coexpression of ABCB1 (P-glycoprotein) and ABCG2 contributes to drug resistance in a cell line model. HEK293 cells were transfected with vector-encoding full-length ABCB1, ABCG2, or a bicistronic vector containing both genes, each under the control of a separate promoter. Cells transfected with both transporters (B1/G2 cells) demonstrated high levels of both transporters, and uptake of both the ABCB1-specific substrate rhodamine 123 and the ABCG2-specific substrate pheophorbide a was reduced when examined by flow cytometry. B1/G2 cells were also cross-resistant to the ABCB1 substrate doxorubicin, the ABCG2 substrate topotecan, as well as mitoxantrone and the cell cycle checkpoint kinase 1 inhibitor prexasertib, both of which were found to be substrates of both ABCB1 and ABCG2. When B1/G2 cells were incubated with both rhodamine 123 and pheophorbide a, transport of both compounds was observed, suggesting that ABCB1 and ABCG2, when coexpressed, can function independently to transport substrates. ABCB1 and ABCG2 also functioned additively to transport the common fluorescent substrates mitoxantrone and BODIPY-prazosin, as it was necessary to inhibit both transporters to prevent efflux from B1/G2 cells. ABCG2 expression was also found to decrease the efficacy of the ABCB1 inhibitor tariquidar in B1/G2 cells. Thus, ABCB1 and ABCG2 can independently and additively confer resistance to substrates, underscoring the need to inhibit multiple transporters when they are coexpressed.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Proteínas de Neoplasias/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Antineoplásicos/farmacología , Transporte Biológico , Supervivencia Celular/efectos de los fármacos , Células HEK293 , Humanos , Modelos Biológicos , Proteínas de Neoplasias/genética , Quinolinas/farmacología
20.
Talanta ; 201: 309-316, 2019 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-31122428

RESUMEN

Two different colors of water-soluble core-shell quantum dots CdTe/CdS (green and orange red) have been synthesized and characterized in this paper. The formation of core-shell quantum dots not only improves the fluorescence quantum yield, but also reduces the biological toxicity of quantum dots, and improves the fluorescence lifetime. Two novel fluorescent bioprobes, CdTe/CdS (λem = 545 nm)-5-Fu and Bio-CdTe/CdS (λem = 600 nm)-TAM, have been synthesized via the interaction of these two core-shell quantum dots with anticancer drugs (5-Fu) and P-gp inhibitors (TAM), respectively. These two fluorescent probes have been simultaneously used in fluorescence imaging of human breast cancer cells MDA-MB-231/MDR. It can be observed that under the action of P-gp inhibitors distributed on the cell membrane, anticancer drugs can be retained in cancer cells. According to the color of quantum dots on the probe, the visualization results of the action of anticancer drugs and P-gp inhibitors can be obtained. This study shows that to prepare functional bioprobes using core-shell quantum dots CdTe/CdS has great potential in the field of biomedical research such as anticancer drugs.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Colorantes Fluorescentes/química , Puntos Cuánticos/química , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Cadmio/química , Cadmio/toxicidad , Compuestos de Cadmio/química , Compuestos de Cadmio/toxicidad , Línea Celular Tumoral , Fluorescencia , Colorantes Fluorescentes/toxicidad , Fluorouracilo/farmacología , Humanos , Puntos Cuánticos/toxicidad , Solubilidad , Espectrometría de Fluorescencia/métodos , Sulfuros/química , Sulfuros/toxicidad , Tamoxifeno/farmacología , Telurio/química , Telurio/toxicidad , Agua/química
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