ABSTRACT
OBJECTIVES: Multidrug resistance mediated by P-glycoprotein is a potential obstacle to cancer treatment. This phase 1 trial determined the safety of paclitaxel with valspodar, a P-glycoprotein inhibitor, in patients with advanced solid tumors. METHODS: Patients were treated with single-agent paclitaxel Q3W 175 mg/m 2 (or 135 mg/m 2 if heavily pretreated) as a 3-hour infusion. If their disease was stable (SD) or progressive (PD), paclitaxel at 30% (52.5 mg/m 2 ), 40% (70 mg/m 2 ), or 50% (87.5 mg/m 2 ) of 175 mg/m 2 (full dose) was administered with valspodar 5 mg/kg orally 4 times daily for 12 doses. Pharmacokinetic sampling (PK) for paclitaxel and valspodar was performed during single-agent and combination therapy. RESULTS: Sixteen patients had SD/PD after one cycle of paclitaxel and then received paclitaxel at 30% (n=3), 40% (n=3), and 50% (n=10) with valspodar. Hematologic adverse events (AEs) including myelosuppression at paclitaxel 40% were comparable to those of full-dose paclitaxel. Non-hematologic AEs consisted of reversible hepatic (hyperbilirubinemia and transaminitis) and neurologic AEs (ataxia and paresthesias). Eleven patients experienced SD with a median of 12.7 weeks (range, 5.4 to 36.0), 4 patients progressed, and 1 was inevaluable. Reduced dose paclitaxel with valspodar resulted in lower plasma peak concentrations of paclitaxel; otherwise, concentrations were similar to single-agent paclitaxel. CONCLUSION: Paclitaxel at 70 mg/m 2 was administered safely with valspodar. Limited efficacy in hematologic and solid tumors resulted in discontinuation of its clinical development and other transporter inhibitors. Recently, the development of ATP-binding cassette transporter inhibitors has been reconsidered to mitigate resistance to antibody-drug conjugates.
Subject(s)
Cyclosporins , Neoplasms , Humans , Paclitaxel , Neoplasms/chemically induced , Cyclosporins/adverse effects , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Ovarian cancer (OC) has the worst prognosis among gynecological malignancies. Cisplatin (CDDP) is one of the most commonly used treatments for OC, but recurrence and metastasis are common due to endogenous or acquired resistance. High expression of ATP-binding cassette (ABC) transporters is an important mechanism of resistance to OC chemotherapy, but targeting ABC transporters in OC therapy remains a challenge. The expression of sortilin-related receptor 1 (SORL1; SorLA) in the response of OC to CDDP was determined by analysis of TCGA and GEO public datasets. Immunohistochemistry and western blotting were utilized to evaluate the expression levels of SORL1 in OC tissues and cells that were sensitive or resistant to CDDP treatment. The in vitro effect of SORL1 on OC cisplatin resistance was proven by CCK-8 and cell apoptosis assays. The subcutaneous xenotransplantation model verified the in vivo significance of SORL1 in OC. Finally, the molecular mechanism by which SORL1 regulates OC cisplatin resistance was revealed by coimmunoprecipitation, gene set enrichment analysis and immunofluorescence analysis. This study demonstrated that SORL1 is closely related to CDDP resistance and predicts a poor prognosis in OC. In vivo xenograft experiments showed that SORL1 knockdown significantly enhanced the effect of CDDP on CDDP-resistant OC cells. Mechanistically, silencing of SORL1 inhibits the early endosomal antigen 1 (EEA1) pathway, which impedes the stability of ATP-binding cassette B subfamily member 1 (ABCB1), sensitizing CDDP-resistant OC cells to CDDP. The findings of this study suggest that targeting SORL1 may represent a promising therapeutic approach for overcoming CDDP resistance in OC.
Subject(s)
Cisplatin , Ovarian Neoplasms , Humans , Female , Cisplatin/pharmacology , Cisplatin/therapeutic use , Cisplatin/metabolism , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , ATP-Binding Cassette Transporters/genetics , Adenosine Triphosphate , LDL-Receptor Related Proteins/metabolism , LDL-Receptor Related Proteins/pharmacology , LDL-Receptor Related Proteins/therapeutic use , Membrane Transport Proteins , ATP Binding Cassette Transporter, Subfamily B/pharmacology , ATP Binding Cassette Transporter, Subfamily B/therapeutic useABSTRACT
BACKGROUND: Deregulation of the apoptotic process underlies the pathogenesis of many cancers, including leukemia, but is also very important for the success of chemotherapy treatment. Therefore, the gene expression profile of main apoptotic factors, such as anti-apoptotic BCL2 (B-cell lymphoma protein 2) and pro-apoptotic BAX (BCL2-associated X), as well as genes involved in the multi-drug resistance (ABCB1), could have significant impact on the prognosis and could be used as targets for specific therapy. PATIENTS AND METHODS: We analyzed the expression of BCL2, BAX, and ABCB1 in bone-marrow samples collected at diagnosis from 51 adult patients with acute myeloid leukemia with normal karyotype (AML-NK) using real-time polymerase chain reaction method, and examined their prognostic potential. RESULTS: Increased expression of BCL2 (BCL2 +) was associated with the presence of chemoresistance (p = 0.024), while patients with low BAX expression were more prone to relapse (p = 0.047). Analysis of the combined effect of BCL2 and BAX expression showed that 87% of patients with BAX/BCL2 low status were resistant to therapy (p = 0.044). High expression of ABCB1 was associated with BCL2 + status (p < 0.001), and with absence FLT3-ITD mutations (p = 0.019). CONCLUSIONS: The present analysis of BCL2, BAX, and ABCB1 gene expression profiles is the first study focusing solely on AML-NK patients. Preliminary results showed that patients with high BCL2 expression are likely to experience resistance to chemotherapy, and may benefit from specific anti-BCL2 treatment. Further investigations conducted on a larger number of patients could elucidate actual prognostic significance of these genes in AML-NK patients.
Subject(s)
Leukemia, Myeloid, Acute , Humans , Adult , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism , bcl-2-Associated X Protein/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Prognosis , Karyotype , Gene Expression , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/therapeutic useABSTRACT
Memory impairment is a result of multiple factors including amyloid-beta (Aß) accumulation. Several receptors are mediated for Aß transport and signaling. Moreover, blood lipids are involved in Aß signaling pathway through these receptors. Mediated blood lipid level by statins aims to regulate Aß signaling cascade. First, the structure of receptors was taken from the RCSB PDB database and prepared with MGLTools and AutoDock tool 4. Second, the ligand was prepared for docking through AutoDock Vina. The binding affinity was calculated, and the binding sites were determined through LigPlot+ software. Besides, pharmacokinetic properties were calculated through multiple software. Finally, a molecular dynamics (MD) simulation was conducted to evaluate ligands stability along with clustering analysis to evaluate proteins connection. Our molecular docking and dynamic analyses revealed silymarin as a potential inhibitor of acetylcholinesterase (AChE), P-glycoprotein, and angiotensin-converting enzyme 2 (ACE2) with 0.704, 0.85, and 0.83 Å for RMSD along with -114.27, -107.44, and -122.51 kcal/mol for free binding energy, respectively. Moreover, rosuvastatin and quercetin have more stability compared to silymarin and donepezil in complex with P-glycoprotein and ACE2, respectively. Eventually, based on clustering and pharmacokinetics analysis, silymarin, rosuvastatin, and quercetin are suggested to be involved in peripheral clearance of Aß. The bioactivity effects of mentioned statins and antioxidants are predicted to be helpful in treating memory impairment in Alzheimer's disease (AD). Nevertheless, mentioned drug effect could be improved by nanoparticles to facilitate penetration of the blood-brain barrier (BBB).
Subject(s)
Alzheimer Disease , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Silymarin , Humans , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/therapeutic use , Molecular Docking Simulation , Acetylcholinesterase/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Rosuvastatin Calcium/therapeutic use , Quercetin/therapeutic use , Amyloid beta-Peptides/metabolism , Silymarin/therapeutic use , ATP Binding Cassette Transporter, Subfamily B/therapeutic useABSTRACT
The failure of chemotherapy in the treatment of carcinoma is mainly due to the development of multidrug resistance (MDR), which is largely caused by the overexpression of P-glycoprotein (P-gp/ABCB1/MDR1). Until recently, the 3D structure of the P-gp transporter has not been experimentally resolved, which restricted the discovery of prospective P-gp inhibitors utilizing in silico techniques. In this study, the binding energies of 512 drug candidates in clinical or investigational stages were assessed as potential P-gp inhibitors employing in silico methods. On the basis of the available experimental data, the performance of the AutoDock4.2.6 software to predict the drug-P-gp binding mode was initially validated. Molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy computations were subsequently conducted to screen the investigated drug candidates. Based on the current results, five promising drug candidates, namely valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus, showed promising binding energies against P-gp transporter with ΔGbinding values of -126.7, -112.1, -111.9, -102.9, and -101.4 kcal/mol, respectively. The post-MD analyses revealed the energetical and structural stabilities of the identified drug candidates in complex with the P-gp transporter. Furthermore, in order to mimic the physiological conditions, the potent drugs complexed with the P-gp were subjected to 100 ns MD simulations in an explicit membrane-water environment. The pharmacokinetic properties of the identified drugs were predicted and demonstrated good ADMET characteristics. Overall, these results indicated that valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus hold promise as prospective P-gp inhibitors and warrant further invitro/invivo investigations.
Subject(s)
Drug Resistance, Multiple , Neoplasms , Humans , Molecular Docking Simulation , Dactinomycin/therapeutic use , Prospective Studies , Neoplasms/drug therapy , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Sirolimus , Drug Discovery , Drug Resistance, NeoplasmABSTRACT
BACKGROUND AND AIM: Different studies have shown pharmacogenetic variants related to drug toxicity in acute myeloid leukemia (AML) patients. Our aim was to identify the association between ABCB1, CDA, DCK, GSTT1, and GSTM1 variants with clinical outcomes and toxicity in pediatric patients with AML. METHODS: Fifty-one confirmed de novo AML pediatric patients were included. A SNaPshot™ assay and conventional PCR were used to evaluate ABCB1, CDA, DCK, GSTT1, and GSTM1 variants. Clinical outcomes and toxicity associations were evaluated using odds ratios and Chi-square analysis. RESULTS: Patients carrying ABCB1 (1236C > T, rs1128503) GG genotype in had a 6.8 OR (CI 95% 1.08-42.73, p = .044) for cardiotoxicity as compared to patients carrying either AA or GA genotypes 0.14 OR (CI 95% 0.023-0.92, p = .044). For ABCB1 (1236G > A rs1128503/2677C > A/T rs2032582/3435G > A rs1045642) AA/AA/AA combined genotypes had a strong association with death after HSTC OR 13.73 (CI 95% 1.94-97.17, p = .009). Combined genotypes GG/CC/GG with CDA (79A > C, rs2072671) CA genotype or CDA (-451G > A, rs532545) CT genotype, had a 4.11 OR (CI 95% 2.32-725, p = .007) and 3.8 OR (CI 95% 2.23-6.47, p = .027) with MRD >0.1% after first chemotherapy cycle, respectively. CONCLUSION: Our results highlight the importance of pharmacogenetic analysis in pediatric AML, particularly in populations with a high degree of admixture, and might be useful as a future tool for patient stratification for treatment.
Subject(s)
Leukemia, Myeloid, Acute , Pharmacogenetics , Humans , Child , Colombia/epidemiology , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Genotype , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/therapeutic useABSTRACT
BACKGROUND: Intracellular levels of cyclic nucleotides can also be controlled by the action of multidrug resistance protein types 4 (MRP4) and 5 (MRP5). To date, no studies evaluated the role of their inhibition in an animal model of erectile dysfunction (ED). OBJECTIVES: To evaluate the effect of a 2-week treatment with MK571, an inhibitor of the efflux of cyclic nucleotides in the ED of obese mice. MATERIALS AND METHODS: Mice were divided in three groups: (i) lean, (ii) obese, and (iii) obese + MK571. The corpus cavernosum (CC) were isolated, and concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), and tadalafil in addition to electrical field stimulation (EFS) were carried out in phenylephrine pre-contracted tissues. Expression of ABCC4 and ABCC5, intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), the protein levels for pVASPSer157 and pVASPSer239 , and the intracavernous pressure (ICP) were also determined. The intracellular and extracellular (supernatant) ratios in CC from obese and lean stimulated with a cGMP-increasing substance (BAY 58-2667) in the absence and presence of MK571 (20 µM, 30 min) were also assessed. RESULTS: The treatment with MK571 completely reversed the lower relaxing responses induced by EFS, ACh, SNP, and tadalafil observed in obese mice CC in comparison with untreated obese mice. Cyclic GMP and p-VASPSer239 expression were significantly reduced in CC from obese groups. MK571 promoted a sixfold increase in cGMP without interfering in the protein expression of p-VASPSer239 . Neither the cAMP levels nor p-VASPSer157 were altered in MK571-treated animals. The ICP was â¼50% lower in obese than in the lean mice; however, the treatment with MK571 fully reversed this response. Expressions of ABCC4 and ABCC5 were not different between groups. The intra/extracellular ratio of cGMP was similar in CC from obese and lean mice stimulated with BAY 58-2667. CONCLUSIONS: The MRPs inhibition by MK571 favored the accumulation of cGMP in the smooth muscle cells, thus improving the smooth muscle relaxation and the erectile function in obese mice.
Subject(s)
Erectile Dysfunction , Male , Humans , Mice , Animals , Erectile Dysfunction/drug therapy , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Tadalafil/pharmacology , Tadalafil/therapeutic use , Mice, Obese , Nitroprusside/pharmacology , Nitroprusside/metabolism , Nitroprusside/therapeutic use , Cyclic GMP/metabolism , Acetylcholine/pharmacology , Acetylcholine/therapeutic use , ObesityABSTRACT
BACKGROUND: Tuberculosis (TB) is the leading opportunistic infection of people living with human immunodeficiency virus (HIV; PLWH). Cytochrome P450 (CYP) 2B6 and ATP-binding cassette sub-family B member 1 (ABCB1) are involved in the metabolism and transportation of efavirenz. The study was aimed to investigate the effects of rifampicin, CYP2B6 and ABCB1 polymorphisms on efavirenz exposure in Chinese PLWH co-infected with TB. METHOD: PLWH were screened according to inclusion and exclusion criteria and divided into HIV group and HIV/TB group. Efavirenz plasma concentration (C0) was determined, dose-adjusted concentration (C0/D) was calculated, and genotypes of CYP2B6 516G>T, 785A>G, and ABCB1 2677G>T, 3435C>T were analyzed. RESULTS: 252 PLWH were enrolled, including 75 co-infected with TB and concomitant with rifampicin. Efavirenz C0 and C0/D were both higher in HIV group (1.94 µg/mL, 0.2007 (µg/ml)/(mg/kg/d)) compared with HIV/TB group (1.52 µg/mL, 0.1557 (µg/ml)/(mg/kg/d)) (p = .001). Efavirenz C0/D was significantly higher in patients with variant genotypes of CYP2B6 516G>T and 785A>G (p<.001), and was significantly lower in HIV/TB group compared with HIV group among patients with CYP2B6 516 GG, TT, and 785 AA, AG genotypes (p < .05). CONCLUSION: Efavirenz exposure is reduced by co-administration with rifampicin, and related to genetic polymorphisms of CYP2B6.
Subject(s)
Anti-HIV Agents , HIV Infections , Tuberculosis , Humans , Rifampin/therapeutic use , Cytochrome P-450 CYP2B6/genetics , HIV , East Asian People , Anti-HIV Agents/therapeutic use , HIV Infections/complications , HIV Infections/drug therapy , Tuberculosis/complications , Tuberculosis/drug therapy , Benzoxazines/therapeutic use , Polymorphism, Genetic , Genotype , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/therapeutic useABSTRACT
Multi drug resistance (MDR) in tumor might be caused leading to the overexpression of transporters, such as ATP-binding cassette sub-family B member 1 (ABCB1). A combination of non-toxic and potent ABC inhibitors along with conventional anti-cancer drugs is needed to reverse MDR in tumors. A variety of phytochemicals have been previously shown to reverse MDR. Annonaceous acetogenins (AAs) with C35/C37 long-chain fatty acids were reported for their anti-tumor activity, however, their effect on reversing MDR is not yet investigated. We aimed to investigate some selective AAs against the B1 subtype of ABC transporter using computational studies. Various modules of Maestro software were utilized for our in-silico analysis. Few well-characterized AAs were screened for their drug-likeness properties and tested for binding affinity at ATP and drug binding sites of ABCB1 through molecular docking. The stability of the ligand-protein complex (lowest docking score) was then determined by a molecular dynamic (MD) simulation study. Out of 24 AAs, Annonacin A (-8.10 kcal/mol) and Annohexocin (-10.49 kcal/mol) docked with a greater binding affinity at the ATP binding site than the first-generation inhibitor of ABCB1 (Verapamil: -3.86 kcal/mol). MD simulation of Annonacin A: ABCB1 complex for 100 ns also indicated that Annonacin A would stably bind to the ATP binding site. We report that Annonacin A binds at a greater affinity with ABCB1 and might act as a potential drug lead to reverse MDR in tumor cells. Communicated by Ramaswamy H. Sarma.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Acetogenins/pharmacology , Molecular Dynamics Simulation , Molecular Docking Simulation , Drug Resistance, Neoplasm , Drug Resistance, Multiple , Neoplasms/drug therapy , Adenosine Triphosphate , Nucleotides/metabolism , Cell Line, Tumor , Antineoplastic Agents/pharmacology , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B/pharmacology , ATP Binding Cassette Transporter, Subfamily B/therapeutic useABSTRACT
BACKGROUND: This study aimed to analyze associations between genetic variants and plasma concentrations along with clinical outcomes in dabigatran in patients with non-valvular atrial fibrillation (NVAF). METHODS: We conducted a prospective study and enrolled NVAF patients treated with dabigatran in the real world. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration. All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up. RESULTS: Eighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. There was a significant association between the CES1 SNP rs8192935 and trough plasma concentrations of dabigatran (P = 0.013). Our results showed that the CES1 SNP rs8192935 significantly influenced dabigatran trough concentrations in the Chinese population, and carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 SNP c.2482-2236G > A (rs4148738) was associated with major bleeding events in the addictive model (P = 0.046, OR = 3.29) and dominant model (P = 0.040, OR = 8.17). Additionally, the ABCB1 SNP c.3435 C > T (rs1045642) was associated with the incidence of major bleeding events in the addictive model (P = 0.043, OR = 3.34) and dominant model (P = 0.046, OR = 7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events. CONCLUSION: Our results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events for the first time in a Chinese population.
Subject(s)
Atrial Fibrillation , Dabigatran , Humans , Atrial Fibrillation/diagnosis , Atrial Fibrillation/drug therapy , Atrial Fibrillation/genetics , Antithrombins , Prospective Studies , Hemorrhage/epidemiology , Polymorphism, Single Nucleotide , Anticoagulants/therapeutic use , Carboxylic Ester Hydrolases/genetics , Carboxylic Ester Hydrolases/metabolism , Carboxylic Ester Hydrolases/therapeutic use , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/therapeutic useABSTRACT
Cancer patients have an increased risk of developing venous thromboembolic events. Anticoagulation management includes prophylactic or therapeutic doses of low molecular weight heparins (LMWHs) or direct oral anticoagulants (DOACs). However, the management of thrombosis in patients with cancer is complex due to various individual and disease-related factors, including drug-drug interactions (DDIs). Furthermore, DDIs may impact both, cancer and venous thrombosis, treatment effectiveness and safety; their relevance is highlighted by the advances in cancer therapeutics. Given that these new oncology drugs are extensively used, more attention should be given to monitoring potential DDIs to minimize risks. Recognition of DDIs is of utmost importance in an era of rapid developments in cancer treatments and introduction of novel treatments and protocols. When managing cancer-associated thrombosis (CAT), the concomitant use of a DOAC and a moderate or strong modulator (inhibitor or inducer) of CYP3A4 or a P-glycoprotein (P-gp) is most likely to be associated with significant DDIs. Therefore, LMWHs remain the first-line option for the long-term management of CAT under these circumstances and physicians must consider utilizing LMWHs as first line. This review describes the risk of DDIs and their potential impact and outcomes in patients with cancer associated thrombosis (CAT) receiving anticoagulation.
Subject(s)
Neoplasms , Thrombosis , Venous Thromboembolism , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Administration, Oral , Anticoagulants/adverse effects , Cytochrome P-450 CYP3A , Drug Interactions , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Neoplasms/complications , Neoplasms/drug therapy , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control , Venous Thromboembolism/drug therapyABSTRACT
Catechin is a bioflavonoid known for its anti-cancer properties. In the present study, we combined theoretical and experimental approaches to reveal the potential of catechin application in the electroporation (EP) or electrochemotherapy (ECT) of pancreatic cancer cells. The molecular dynamics simulations were implemented to examine the interactions of catechin with a model of a membrane, its influence on the membrane's thickness, and the impact of the catechin-membrane interaction on the pore formation. The data were confronted with experimental measurement of the threshold electric field required for permeabilization of pancreatic cancer cells to a fluorescent dye YO-PRO-1. Further, we examined the influence of catechin on cell viability following electroporation with cisplatin or calcium ions. Finally, we investigated the catechin impact on four proteins associated with multidrug resistance: P-glycoprotein, MRP1, BCRP, and LRP. We demonstrated that catechin may boost the effects of electroporation through various mechanisms: i) increasing the cell permeability prior to electroporation ii) increasing the electroporation threshold iii) sensitization of cells to chemotherapeutic compounds. We showed that catechin incubation influences mRNA levels and mitigates the immunoreactivity of Pgp, MRP1, BCRP, and LRP but these changes did not translate to the efficacy of electrochemotherapy.
Subject(s)
Catechin , Electrochemotherapy , Pancreatic Neoplasms , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Catechin/pharmacology , Catechin/therapeutic use , Cell Line, Tumor , Electroporation , Humans , Neoplasm Proteins , Pancreatic Neoplasms/drug therapy , Pancreatic NeoplasmsABSTRACT
A cell-based drug delivery system based on yeast-cell wall loaded with sitagliptin, a drug with an anti-inflammatory effect, was developed to control neuroinflammation associated with Alzheimer's disease. The optimized nanoparticles had a spherical shape with a negative surface charge, and were shown to be less toxic than the carrier and sitagliptin. Moreover, the nanoparticles caused anti-inflammatory effects against tumor necrosis factor-alpha in mice model of neuroinflammation. The pharmacokinetics study showed the brain concentration of drug in the nanoparticles group was much higher than in the control group. To evaluate the effect of P-glycoprotein on brain entry of sitagliptin, the experiment was repeated with verapamil, as a P-glycoprotein inhibitor. Brain concentration of the nanoparticles group remained approximately unchanged, proving the "Trojan Horse" effect of the developed nanocarriers. The results are promising for using yeast-cell wall as a carrier for targeted delivery to immune cells for the management of inflammation.
Subject(s)
Alzheimer Disease , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Anti-Inflammatory Agents/therapeutic use , Cell Wall/metabolism , Mice , Neuroinflammatory Diseases , Saccharomyces cerevisiae , Sitagliptin Phosphate/pharmacology , Sitagliptin Phosphate/therapeutic useABSTRACT
The blood-brain barrier (BBB) presents a major hurdle in the development of central nervous system (CNS) active therapeutics, and expression of the P-glycoprotein (P-gp) efflux transporter at the blood-brain interface further impedes BBB penetrance of most small molecules. Designing efflux liabilities out of compounds can be laborious, and there is currently no generalizable approach to directly transform periphery-limited agents to ones active in the CNS. Here, we describe a target-agnostic, prospective assessment of P-gp efflux using diverse compounds. Our results demonstrate that reducing the molecular size or appending a carboxylic acid in many cases enables evasion of P-gp efflux in cell-based experiments and in mice. These strategies were then applied to transform a periphery-limited V600EBRAF inhibitor, dabrafenib, into versions that possess potent and selective anti-cancer activity but now also evade P-gp-mediated efflux. When compared to dabrafenib, the compound developed herein (everafenib) has superior BBB penetrance and superior efficacy in an intracranial mouse model of metastatic melanoma, suggesting it as a lead candidate for the treatment of melanoma metastases to the brain and gliomas with BRAF mutation. More generally, the results described herein suggest the actionability of the trends observed in these target-agnostic efflux studies and provide guidance for the conversion of non-BBB-penetrant drugs into versions that are BBB-penetrant and efficacious.
Subject(s)
Melanoma , Proto-Oncogene Proteins B-raf , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Animals , Blood-Brain Barrier/metabolism , Melanoma/metabolism , Mice , Prospective Studies , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
BACKGROUND: According to retrospective osteosarcoma series, ABCB1/P-glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk-adapted treatment strategy using mifamurtide in Pgp+ patients was performed. METHODS: This was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high-grade osteosarcoma stratified according to Pgp expression. All patients received high-dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis ≥ 90%; good responders [GRs]) or with high-dose ifosfamide (HDIFO) at 3 g/m2 /d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp- patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m2 (from 5 to 10 courses). The primary end point was event-free survival (EFS). A postamendment analysis was performed. RESULTS: In all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp-, and 124 (64%) were Pgp+. The median follow-up was 51 months. For Pgp+ patients, 5-year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%-76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp- patients, the 5-year EFS rate was 66.4% (90% CI, 55.6%-75.1%). CONCLUSIONS: This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.
Subject(s)
Bone Neoplasms , Osteosarcoma , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Bone Neoplasms/surgery , Child , Disease-Free Survival , Extremities/pathology , Humans , Ifosfamide , Italy , Methotrexate , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Osteosarcoma/surgery , Prospective Studies , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
ABCB1 is an important gene that closely related to analgesic tolerance to opioids, and plays an important role in their postoperative treatment. Recent studies have demonstrated that ABCB1 genotype is significantly associated with the chemico-resistance and chemical sensitivity in breast cancer patients. So, it is become very important to investigate the important role of ABCB1 for predicting drug response in breast cancer patients. In this study, by conducting the Cox proportional hazards regression analysis in breast cancer patients, significant differences were found in prognosis between the ABCB1 high- and low-expression subtypes. Meanwhile, by using immune infiltration profiles as well as transcriptomics datasets, the ABCB1 high subtype was found to be significantly enriched in many immune-related KEGG pathways and biological processes, and was characterized by the high infiltration levels of immune cell types. Furthermore, bioinformatics inference revealed that the ABCB1 subtypes were associated with the therapeutic effect of immunotherapy, which would be important for patient prognosis. In conclusion, these findings may provide useful help for recognizing the diversity between ABCB1 subtypes in tumor immune microenvironment, and may unravel prognosis outcomes and immunotherapy utility for ABCB1 in breast cancer.
Subject(s)
Biological Phenomena , Breast Neoplasms , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Prognosis , Tumor Microenvironment/geneticsABSTRACT
Despite the approval of a considerable number of last generation antiepileptic drugs (AEDs) (only in the last decade, six drugs have gained Food and Drug Administration approval), the global figures of seizure control have seemingly not improved, and available AED can still be regarded as symptomatic treatments. Fresh thinking in AEDs drug discovery, including the development of drugs with novel mechanisms of action, is required to achieve truly innovative antiepileptic medications. The transporter hypothesis proposes that inadequate penetration of AEDs across the blood-brain barrier, caused by increased expression of efflux transporters such as P-glycoprotein (P-gp), contributes to drug-resistant epilepsy. Neuroinflammation due to high levels of glutamate has been identified as one of the causes of P-gp upregulation, and several studies in animal models of epilepsy suggest that antiinflammatory drugs might prevent P-gp overexpression and, thus, avoid the development of refractory epilepsy. We have applied ligand-based in silico screening to select compounds that exert dual anticonvulsant and antiinflammatory effects. Five of the hits were tested in animal models of seizure, with protective effects. Later, two of them (sebacic acid (SA) and gamma-decanolactone) were submitted to the recently described MP23 model of drug-resistant seizures. All in all, SA displayed the best profile, showing activity in the maximal electroshock seizure (MES) and pentylenetetrazol (PTZ) seizure models, and reversing resistance to phenytoin (PHT) and decreasing the P-gp upregulation in the MP23 model. Furthermore, pretreatment with SA in the pilocarpine status epilepticus (SE) model resulted in decreased histamine release in comparison with nontreated animals. This is the first report of the use of the MP23 model to screen for novel anticonvulsant compounds that may avoid the development of P-gp-related drug resistance.
Subject(s)
Anticonvulsants , Pharmaceutical Preparations , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , Animals , Anticonvulsants/therapeutic use , Disease Models, Animal , Mice , Seizures/drug therapyABSTRACT
Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP-binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P-glycoprotein (P-gp/ABCB1) has been most well-established. The clinical co-administration of P-gp drug efflux inhibitors, in combination with anticancer drugs which are P-gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P-gp-mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P-gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure-activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P-gp inhibitors in the past 5 years. The development of P-gp inhibitors will increase our knowledge of the mechanisms and functions of P-gp-mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P-gp transporter overexpression has been implicated in MDR.
Subject(s)
Antineoplastic Agents , Neoplasms , ATP Binding Cassette Transporter, Subfamily B/pharmacology , ATP Binding Cassette Transporter, Subfamily B/therapeutic use , ATP Binding Cassette Transporter, Subfamily B, Member 1/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , Neoplasms/drug therapyABSTRACT
BACKGROUND: MDR1 is a highly polymorphic gene that encodes P-glycoprotein (P-gp). This protein anchor to the cell membrane and transports toxins, xenobiotic, chemicals, and drugs from the intracellular to extracellular and thus protect cells. Polymorphism of the MDR1 gene seems to be effective in gene expression and response to treatment. Since one of the main mechanisms of drug resistance is the removal of the drug from the cell by ATP-dependent efflux proteins, thus MDR1, single nucleotide polymorphism (SNP) C3435T can be used as a predictor for treatment outcomes. METHODS: The peripheral blood-EDTA samples were collected from 71 patients with chronic hepatitis C. The total genomic DNA extraction was carried out. The PCR was performed for detection of the MDR1 gene in HCV patients and MDR1 gene polymorphism was genotyped by the PCR-RFLP method. RESULTS: Out of 71 patients 52 (73.3%) were male, 19 (26.7%) female with mean age-min-max; 41.17 ± 8.3-(26-59). The distribution of MDR1 genotype in 48(67.6%) responders were CC 13 (27%), CT 34 (71%) and TT 1(2%), while MDR1 genotypes in 8 (11.3%) non responders were CC 2(25%), CT 1(12.5%) TT 5(62.5%) and in 15(21.1%) recurrence were 5 (33%) CC, 6 (40%) CT and 4 (27%) TT genotype. The patients with heterozygous CT (C3435T) genotype 34/48(71%) were found better response than non-responders with TT 5/8(62.5%) genotype (p < 0.05). CONCLUSION: Our result reveals that 71% of the responders were CT genotypes (C3435T) and 62.5% of non-responders were TT genotype (T3435T). With aforementioned results, determination of different forms of SNPs in MDR1 gene should be considered as a predictor in the treatment of all chronic HCV patients. The homozygous TT genotype and high prevalence of T allele may be related to low antiviral response during combined therapy in treatment of chronic HCV patients.