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1.
Biomed Pharmacother ; 139: 111632, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243600

RESUMO

P-glycoprotein, encoded by ATP-binding cassette transporters B1 gene (ABCB1), renders multidrug resistance (MDR) during cancer chemotherapy. Several synthetic small molecule inhibitors affect P-glycoprotein (P-gp) transport function in MDR tumor cells. However, inhibition of P-gp transport function adversely accumulates chemotherapeutic drugs in non-target normal tissues. Moreover, most small-molecule P-gp inhibitors failed in the clinical trials due to the low therapeutic window at the maximum tolerated dose. Therefore, downregulation of ABCB1-gene expression (P-gp) in tumor tissues seems to be a novel approach rather than inhibiting its transport function for the reversal of multidrug resistance (MDR). Several plant-derived phytochemicals modulate various signal transduction pathways and inhibit translocation of transcription factors, thereby reverses P-gp mediated MDR in tumor cells. Therefore, phytochemicals may be considered an alternative to synthetic small molecule P-gp inhibitors for the reversal of MDR in cancer cells. This review discussed the role of natural phytochemicals that modulate ABCB1 expression through various signal transduction pathways in MDR cancer cells. Therefore, modulating the cell signaling pathways by phytochemicals might play crucial roles in modulating ABCB1 gene expression and the reversal of MDR.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Humanos
2.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071136

RESUMO

In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. We also observed an increase in the level of polyubiquitinated proteins (via K48-linkage) and a decrease in the gene expression of some deubiquitinases after treatment with bortezomib. Resistant cells expressed higher levels of genes encoding 26S proteasome components and the chaperone HSP90, which is involved in 26S proteasome assembly. After 4 h of preincubation, bortezomib induced a more pronounced depression of proteasome activity in S cells than in R or T cells. However, none of these changes alone or in combination sufficiently suppressed the sensitivity of R or T cells to bortezomib, which remained at a level similar to that of S cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Linfoide/patologia , Proteínas de Neoplasias/metabolismo , Inibidores de Proteases/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular , Linhagem Celular Tumoral , Enzimas Desubiquitinantes , Fluoresceínas/metabolismo , Genes cdc/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leucemia Linfoide/genética , Leucemia Linfoide/metabolismo , Camundongos , Proteínas de Neoplasias/genética , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Proteínas Recombinantes/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteínas Ubiquitinadas/metabolismo , Vincristina/farmacologia
3.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065600

RESUMO

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Plaquetas/efeitos dos fármacos , Curcumina/farmacologia , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Monofosfato de Adenosina/metabolismo , Plaquetas/metabolismo , Curcuma/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Piperazinas/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
Chem Biol Interact ; 344: 109510, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33974899

RESUMO

The problem of chemoresistance development is an inescapable flipside of modern oncotherapy, in particular for сolorectal cancer patients. The search for or development of drugs effective against resistant tumors involves the use of model resistant cell lines in vitro. To obtain such lines, we reproduced the development of chemoresistance of human colon adenocarcinoma cells under the treatment with drugs of different mechanisms, a cytostatic (paclitaxel) and a targeted agent (Nutlin-3a, an inhibitor of p53-Mdm2 protein-protein interaction). In each case, we gradually increased the content of the substance in the medium, starting from effective concentrations that do not cause total cell death. When studying the lines resistant to the corresponding drug, we noted a reduced sensitivity to the drug of another mechanism of action. Analysis of the original and resistant lines showed that the cells use the universal efflux defense mechanism. The observed effect can be partially neutralized using inhibitors of the ABC transport proteins, including P-glycoprotein, known for its oncoprotective function. The role of the latter was confirmed by real-time RT-PCR and Western blotting.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imidazóis/farmacologia , Paclitaxel/farmacologia , Piperazinas/farmacologia , Quinolinas/farmacologia , Vanadatos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HCT116 , Humanos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores
5.
Turk Neurosurg ; 31(3): 447-459, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33978213

RESUMO

AIM: To analyze the Glutathione S-transferase (GST)-P, GST-M, cytochrome p450 (CYP)1-A1, CYP1-B1, and multidrug resistance (MDR)-1 expressions in malignant intracranial tumor (ICT)s, and to elicit their role on patient survival. MATERIAL AND METHODS: GST-P, GST-M, CYP1-A1, CYP1-B1, and MDR-1 expressions were analyzed using immunostaining in 149 samples from 141 patients with preoperative ICT diagnosis. The case characteristics were reviewed, and the enzyme expressions were equated based on the age, gender, and tumor type. Then, 77 of 141 patients with malignant ICT and complete medical records postoperative were also investigated in detail for the relationship between the diagnosis, enzyme expression, and overall survival. RESULTS: The average age was 49.44 years, with 83 (58.45%) male patients. Among the 77 malignant ICTs, 38 (49.3%) and 29 were glial tumors and metastases, respectively, with a 13.35-month overall survival. Patients with metastatic tumor have approximately threefold higher GSTP level than those with glial tumors. MDR-1 expression was approximately twofold higher in > 60-year-old patients. No statistically significant association was found between patients? smoking behaviors, alcohol consumption, and overall survival. Only MDR-1 expression was correlated with overall survival. Better overall survival was observed in patients with a negative MDR-1 expression than those with a positive one. CONCLUSION: MDR-1 is an important indicator of survival in malignant intracranial tumor patients. Longer survival is associated with negative MDR-1 expression.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glutationa Transferase/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Adulto Jovem
6.
J Med Chem ; 64(9): 6179-6197, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33938746

RESUMO

Overexpression of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), is an important factor leading to multidrug resistance (MDR) in cancer treatments. Three subclasses of dual inhibitors of P-gp and BCRP were designed based on the active moieties of BCRP inhibitors, tyrosine kinase inhibitors, and P-gp inhibitors, of which compound 21 possessed low cytotoxicity, high reversal potency, and good lipid distribution coefficient. 21 also increased the accumulation of Adriamycin (ADM) and Mitoxantrone (MX), blocked Rh123 efflux, and made no change in the protein expression of P-gp and BCRP. Importantly, coadministration of 21 can significantly improve the oral bioavailability of paclitaxel (PTX). It was also demonstrated that 21 significantly inhibited the growth of K562/A02 xenograft tumors by increasing the sensitivity of ADM in vivo. In summary, 21 has the potential to overcome MDR caused by P-gp and BCRP and to improve the oral bioavailability of PTX.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzeno/química , Benzeno/farmacologia , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Pirimidinas/química , Administração Oral , Animais , Benzeno/administração & dosagem , Disponibilidade Biológica , Interações Medicamentosas , Humanos , Células K562 , Camundongos , Paclitaxel/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Yakugaku Zasshi ; 141(4): 447-462, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33790111

RESUMO

The blood-brain barrier (BBB) consists of brain capillary endothelial cells linked by tight junctions and serves to regulate the transfer of endogenous compounds and xenobiotics between the circulating blood and brain interstitial fluid. We have developed a methodology to characterize brain-to-blood efflux transport in vivo, using the Brain Efflux Index and an in vitro culture model of the BBB, i.e., a conditionally immortalized cell line of the neurovascular unit. Employing these methods, we showed that the BBB plays an important role in protecting the brain by transporting neurotransmitters, neuromodulators, metabolites, uremic toxins, and xenobiotics together with atrial natriuretic peptide from the brain interstitial fluid to the circulating blood. We also developed a highly selective, sensitive LC-MS/MS method for simultaneous protein quantification. We found significant species differences in the expression amounts of various BBB transporter proteins among mice, rats, marmosets, cynomolgus monkeys, and humans. Among transporter proteins at the BBB, multidrug resistance protein 1 (Mdr1/Abcb1) is known to generate a concentration gradient of unbound substrate drugs between the blood and brain. Based on measurements of the intrinsic efflux transport rate of Mdr1 and the protein expression amounts of Mdr1 in mouse brain capillaries and Mdr1-expressing cell lines, we predicted the unbound drug concentration gradients of 7 drugs in the mouse brain in vivo. This was the first successful prediction of in vivo drug transport activity from in vitro experimental data and transporter protein concentration in tissues. This methodology and findings should greatly advance central nervous system barrier research.


Assuntos
Transporte Biológico/fisiologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Proteômica/métodos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular , Cromatografia Líquida/métodos , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Neurotransmissores/metabolismo , Proteômica/tendências , Ratos , Espectrometria de Massas em Tandem/métodos , Xenobióticos/metabolismo
8.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805044

RESUMO

Chemo-resistance hinders treatment of patients with hepatocellular carcinoma. Although there are many models that can be found in the literature, the root mechanism to explain chemo-resistance is still not fully understood. To gain a better understanding of this phenomenon, a chemo-resistant line, R-HepG2, was developed from a chemo-sensitive HepG2 line through an exposure of doxorubicin (DOX). The R-HepG2 exhibited a cancer stem cell (CSC) phenotype with an over-expression of P-glycoprotein (P-gp), conferring it a significant enhancement in drug efflux and survival. With these observations, we hypothesize that metabolic alteration in this drug-resistant CSC is the root cause of chemo-resistance. Our results show that, unlike other metabolic-reprogrammed CSCs that exhibit glycolytic phenotype described by the "Warburg effect", the R-HepG2 was metabolically quiescent with glucose independence, high metabolic plasticity, and relied on glutamine metabolism via the mitochondria for its chemo-resistance Intriguingly, drug efflux by P-gp in R-HepG2 depended on the mitochondrial ATP fueled by glutamine instead of glycolytic ATP. Armed with these observations, we blocked the glutamine metabolism in the R-HepG2 and a significant reduction of DOX efflux was obtained. We exploited this metabolic vulnerability using a combination of DOX and metformin in a glutamine-free condition to target the R-HepG2, resulting in a significant DOX sensitization. In conclusion, our findings highlight the metabolic modulation of chemo-resistance in CSCs. We delineate the altered metabolism that drives chemo-resistance and offer a new approach to target this CSC through metabolic interventions.


Assuntos
Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glutamina/farmacologia , Neoplasias Hepáticas/metabolismo , Mitocôndrias/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Antibióticos Antineoplásicos/farmacologia , Sobrevivência Celular , Doxorrubicina/farmacologia , Glucose/metabolismo , Células Hep G2 , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Fosforilação Oxidativa , Fenótipo
9.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917090

RESUMO

In the present paper, new pyrimidine derivatives were designed, synthesized and analyzed in terms of their anticancer properties. The tested compounds were evaluated in vitro for their antitumor activity. The cytotoxic effect on normal human dermal fibroblasts (NHDF) was also determined. According to the results, all the tested compounds exhibited inhibitory activity on the proliferation of all lines of cancer cells (colon adenocarcinoma (LoVo), resistant colon adenocarcinoma (LoVo/DX), breast cancer (MCF-7), lung cancer (A549), cervical cancer (HeLa), human leukemic lymphoblasts (CCRF-CEM) and human monocytic (THP-1)). In particular, their feature stronger influence on the activity of P-glycoprotein of cell cultures resistant to doxorubicin than doxorubicin. Tested compounds have more lipophilic character than doxorubicin, which determines their affinity for the molecular target and passive transport through biological membranes. Moreover, the inhibitory potential against topoisomerase II and DNA intercalating properties of synthesized compounds were analyzed via molecular docking.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
10.
Phytomedicine ; 85: 153528, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33735724

RESUMO

BACKGROUND: P-glycoprotein (P-gp) over-expression plays a vital role in not only systemic drug bioavailability but also cancer multi-drug resistance (MDR). Develop functional inhibitors of P-gp can conquer both problems. PURPOSE AND STUDY DESIGN: The aim of the present study was to research the P-gp modulating effects and MDR reversing ability of a novel flavonoid from Fissistigma cupreonitens, the underlying inhibitory mechanisms were further elucidated as well. METHODS: Calcein-AM, rhodamine 123, and doxorubicin were fluorescent substrates for the evaluation of P-gp inhibitory function and detailed drug binding modes. Docking simulation was performed to reveal the in silico molecular bonding. ATPase assay and MDR1 shift assay were adopted to reveal the ATP consumption and conformational change of P-gp. The MDR reversing effects were demonstrated through cytotoxicity, cell cycle, and apoptosis analyses. RESULTS: 5­hydroxy­7,8­dimethoxyflavanone inhibited the efflux of rhodamine 123 and doxorubicin in a competitive manner, and increased the intracellular fluorescence of calcein at a concentration as low as 2.5 µg/ml. 5­hydroxy­7,8­dimethoxyflavanone slightly changed P-gp's conformation and only stimulated ATPase at very high concentration (100 µg/ml). The docking results showed that 5­hydroxy­7,8­dimethoxyflavanone and verapamil exhibited similar binding affinity to P-gp. The MDR reversing effects were prominent in the vincristine group, the reversal folds were 23.01 and 13.03 when combined with 10 µg/ml 5­hydroxy­7,8­dimethoxyflavanone in the P-gp over-expressing cell line (ABCB1/Flp-In™-293) and MDR cancer cell line (KB/VIN), respectively. CONCLUSION: The present study demonstrated that 5­hydroxy­7,8­dimethoxyflavanone was a novel effective flavonoid in the P-gp efflux inhibition and in vitro cancer MDR reversion.


Assuntos
Annonaceae/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Flavonoides/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/metabolismo , Fluoresceínas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/farmacologia , Rodamina 123/metabolismo , Verapamil/farmacologia
11.
Eur J Med Chem ; 216: 113317, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33706147

RESUMO

The P-glycoprotein (Pgp) is a major transporter involved in multidrug resistance (MDR) of cancer cells leading to chemotherapy failure. In our previous study, we demonstrated that the amide derivatives of pyxinol are promising modulators against Pgp-mediated MDR in cancer. In the present study, we designed and synthesized novel pyxinol derivatives linked to amino acid residues. We evaluated MDR (paclitaxel (Ptx) resistance) reversal potency of forty pyxinol derivatives in KBV cells and analyzed their structure-activity relationships. Half of our derivatives sensitized KBV cells to Ptx at non-toxic concentrations, among which the pyxinol compound bearing a methionine residue (3c) exhibited the best activity in MDR reversal. Compound 3c was found to possess high selectivity toward Pgp and sensitize the KBV cells to Pgp substrates by blocking the efflux function of Pgp. This manifestation may be attributed to its high binding affinity with Pgp, as suggested by docking studies. Overall, the biological profile and ease of synthesizing these pyxinol derivatives render them promising lead compounds for further development for Pgp-mediated MDR.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Aminoácidos/química , Antineoplásicos/química , Resistencia a Medicamentos Antineoplásicos , Sapogeninas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Domínio Catalítico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Paclitaxel/farmacologia , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 216: 113336, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33725657

RESUMO

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 0.73 µM, RF = 69.6 with 5 µM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure-activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Furanos/metabolismo , Furanos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Paclitaxel/farmacologia , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologia
13.
J Med Chem ; 64(6): 3350-3366, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33724808

RESUMO

Based on literature reports of the last two decades, a computer-aided pattern analysis (C@PA) was implemented for the discovery of novel multitarget ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) inhibitors. C@PA included basic scaffold identification, substructure search and statistical distribution, as well as novel scaffold extraction to screen a large virtual compound library. Over 45,000 putative and novel broad-spectrum ABC transporter inhibitors were identified, from which 23 were purchased for biological evaluation. Our investigations revealed five novel lead molecules as triple ABCB1, ABCC1, and ABCG2 inhibitors. C@PA is the very first successful computational approach for the discovery of promiscuous ABC transporter inhibitors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Descoberta de Drogas/métodos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Cães , Desenho de Fármacos , Humanos , Células Madin Darby de Rim Canino , Modelos Moleculares , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Reconhecimento Automatizado de Padrão/métodos
14.
Expert Opin Drug Metab Toxicol ; 17(5): 555-580, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33703995

RESUMO

Introduction: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.Areas covered: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.Expert opinion: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica , Humanos , Absorção Intestinal , Lipídeos/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Solubilidade
15.
J Vet Med Sci ; 83(3): 473-477, 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33518631

RESUMO

In canine lymphoma, drug resistance is the major factor hindering treatment. In this study, we performed immunohistochemical examination of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which are considered as transporters related to multidrug resistance in three recurrent canine lymphomas. All cases were negative for both transporters before anticancer drug administration, but became positive after this administration. The expression was confirmed in capillary endothelial cells, such as in brain capillaries acting as the blood-brain barrier (BBB). It is suggested that both transporters expressed on capillary endothelial cells in lymphoma tissue may inhibit the spread of anticancer drugs into tumor tissues from blood, the same as the BBB. Therefore, capillary endothelial cells could act as a blood-tumor barrier, which might be involved in drug resistance in canine lymphoma.


Assuntos
Neoplasias da Mama , Doenças do Cão , Linfoma , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Barreira Hematoencefálica , Neoplasias da Mama/veterinária , Doenças do Cão/tratamento farmacológico , Cães , Resistência a Múltiplos Medicamentos , Células Endoteliais/metabolismo , Feminino , Linfoma/tratamento farmacológico , Linfoma/veterinária , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/veterinária
16.
Int Immunopharmacol ; 94: 107443, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33581579

RESUMO

BACKGROUND: Programmed cell death receptor 1 (PD-1) is an immunosuppressive molecule expressed on T cells, and its ligand (PD-L1) which expressed on tumor cells play pivotal roles in regulating host immune responses. However, little is known whether PD-1/PD-L1 axis could directly activates intracellular oncogenic signaling pathways in tumor cells, leading to tumor resistance. METHODS: In the present study, the expression of PD-1 and PD-L1 in the tissues of gastric cancer was detected by western blot and immunofluorescence. The effect of PD-L1-Fc and cisplatin on resistant gastric cancer cells was examined by MTT assay and Flow Cytometry. In addition. The effect of PD-L1-Fc on the expression of P-gp in gastric cancer cells and resistant gastric cancer cells was detected by quantitative real-time reverse-transcription PCR (qRT-PCR) and western blot. The molecular mechanisms of the regulation of cisplatin and PD-L1-Fc treatment were evaluated by western blot. RESULTS: We found that the level of PD-1 was significantly increased in human gastric cancer tissues and drug-resistant gastric cancer cells and P-gp was the same result. The PD-L1 could reduce the level of cell damage caused by cisplatin. In addition, we found PD-L1 can also up-regulate the expression of P-gp. Mechanistically, PD-L1 activated the PI3K/AKT signaling pathway in which PI3K/AKT pathway inhibition attenuated the upregulation of P-gp. CONCLUSION: PD-1/PD-L1 enhanced cisplatin resistance in gastric cancer through PI3K/AKT mediated P-gp expression.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Gástricas/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
17.
Int J Pharm ; 597: 120349, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33545293

RESUMO

The purpose of this study was to evaluate the impact of P-glycoprotein (P-gp) efflux on edoxaban absorption in gastrointestinal tracts quantitatively by a physiologically based pharmacokinetic (PBPK) model constructed with clinical and non-clinical observations (using GastroPlus™ software). An absorption process was described by the advanced compartmental absorption and transit model with the P-gp function. A human PBPK model was constructed by integrating the clinical and non-clinical observations. The constructed model was demonstrated to reproduce the data observed in the mass-balance study. Thus, elimination pathways can be quantitatively incorporated into the model. A constructed model successfully described the difference in slopes of plasma concentration (Cp)-time curve at around 8 - 24 hr post-dose between intravenous infusion and oral administration. Furthermore, the model without P-gp efflux activity can reproduce the Cp-time profile in the absence of P-gp activity observed from the clinical DDI study results. Since the difference of slopes between intravenous infusion and oral administration also disappeared by the absence of P-gp efflux activity, P-gp must be a key molecule to govern edoxaban's PK behavior. The constructed PBPK model will help us to understand the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts quantitatively.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Piridinas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico , Humanos , Modelos Biológicos , Tiazóis
18.
Toxicol Appl Pharmacol ; 416: 115442, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33609514

RESUMO

Cathinone derivatives are the most representative group within new drugs market, which have been described as neurotoxic. Since cathinones, as pentedrone and methylone, are available as racemates, it is our aim to study the neuronal cytotoxicity induced by each enantiomer. Therefore, a dopaminergic SH-SY5Y cell line was used to evaluate the hypothesis of enantioselectivity of pentedrone and methylone enantiomers on cytotoxicity, oxidative stress, and membrane efflux transport (confirmed by in silico studies). Our study demonstrated enantioselectivity of these cathinones, being the S-(+)-pentedrone and R-(+)-methylone the most oxidative enantiomers and also the most cytotoxic, suggesting the oxidative stress as main cytotoxic mechanism, as previously described in in vitro studies. Additionally, the efflux transporter multidrug resistance associated protein 1 (MRP1) seems to play, together with GSH, a selective protective role against the cytotoxicity induced by R-(-)-pentedrone enantiomer. It was also observed an enantioselectivity in the binding to P-glycoprotein (P-gp), another efflux protein, being the R-(-)-pentedrone and S-(-)-methylone the most transported enantiomeric compounds. These results were confirmed, in silico, by docking studies, revealing that R-(-)-pentedrone is the enantiomer with highest affinity to MRP1 and S-(-)-methylone and R-(-)-pentedrone are the enantiomers with highest affinity to P-gp. In conclusion, our data demonstrated that pentedrone and methylone present enantioselectivity in their cytotoxicity, which seems to involve different oxidative reactivity as well as different affinity to the P-gp and MRP1 that together with GSH play a protective role.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Alcaloides/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Metanfetamina/análogos & derivados , Metilaminas/toxicidade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pentanonas/toxicidade , Alcaloides/química , Alcaloides/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Humanos , Metanfetamina/química , Metanfetamina/metabolismo , Metanfetamina/toxicidade , Metilaminas/química , Metilaminas/metabolismo , Simulação de Acoplamento Molecular , Pentanonas/química , Pentanonas/metabolismo , Ligação Proteica , Estereoisomerismo
19.
J Med Chem ; 64(4): 2272-2290, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33560845

RESUMO

The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached clinical trials for this indication. In this work, we designed and synthesized novel blood-brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in Xenopus laevis oocytes, and in interleukin 1ß release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound 6 (2-(6-chloro-9H-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound 6 can be considered as a first non-nucleotide purine hit for future drug optimizations.


Assuntos
Anti-Inflamatórios/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Purinas/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Células HEK293 , Humanos , Interleucina-1beta/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Oócitos/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/metabolismo , Purinas/síntese química , Purinas/metabolismo , Xenopus laevis
20.
J Med Chem ; 64(5): 2725-2738, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33619967

RESUMO

Developing in silico models to predict the brain penetration of drugs remains a challenge owing to the intricate involvement of multiple transport systems in the blood brain barrier, and the necessity to consider a combination of multiple pharmacokinetic parameters. P-glycoprotein (P-gp) is one of the most important transporters affecting the brain penetration of drugs. Here, we developed an in silico prediction model for P-gp efflux potential in brain capillary endothelial cells (BCEC). Using the representative values of P-gp net efflux ratio in BCEC, we proposed a novel prediction system for brain-to-plasma concentration ratio (Kp,brain) and unbound brain-to-plasma concentration ratio (Kp,uu,brain) of P-gp substrates. We validated the proposed prediction system using newly acquired experimental brain penetration data of 28 P-gp substrates. Our system improved the predictive accuracy of brain penetration of drugs using only chemical structure information compared with that of previous studies.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/fisiologia , Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Compostos Orgânicos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Linhagem Celular , Simulação por Computador , Técnicas de Inativação de Genes , Humanos , Ratos Transgênicos
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