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1
Besse, Andrej, Lenka Besse, Sara C. Stolze, Amin Sobh, Esther A. Zaal, Alwin J. van der Ham, Mario Ruiz, et al. "Nelfinavir Overcomes Proteasome Inhibitor Resistance in Multiple Myeloma By Modulating Membrane Lipid Bilayer Composition and Fluidity." Blood 136, Supplement 1 (November 5, 2020): 11. http://dx.doi.org/10.1182/blood-2020-136253.
Повний текст джерелаАнотація:
INTRODUCTION Nelfinavir is a highly lipophilic, first generation HIV-protease inhibitor (HIV-PI) approved for HIV treatment. It has largely been replaced by next-generation HIV-PI with increased specificity and efficacy for HIV therapy, partly reflecting the significant rate of the off-target activity of nelfinavir. Increasing preclinical and clinical evidence shows that nelfinavir has broad anti-cancer activity as a single agent and in combination, potentially related to its off-target activity in mammalian cells. Nelfinavir is particularly effective in the treatment of proteasome inhibitor-refractory multiple myeloma (MM), where the combination of nelfinavir+bortezomib+dexamethasone yielded an overall response rate (ORR, PR or better) > 65% in a Phase II clinical trial. The targets and molecular mechanism of action of nelfinavir in MM are unknown. This hampers both, a rational clinical repositioning and development of nelfinavir as antineoplastic drug, as well as the design, synthesis and testing of next generation nelfinavir-like compounds with optimized antineoplastic activity and improved specificity or pharmacologic properties. We therefore aimed to take an unbiased target-identification approach to identify molecular targets of nelfinavir in human malignant cells and link them to cell biological processes and mechanisms that mediate sensitivity or resistance to nelfinavir treatment. METHODS Proteome-wide affinity-purification of targets binding the nelfinavir active site was combined with genome-wide CRISPR/Cas9-based screening to identify protein partners interacting with nelfinavir and candidate genetic contributors affecting nelfinavir cytotoxicity. Multiple intracellular reporter systems including RUSH system, ATP/ADP constructs; FRAP microscopy, Seahorse measurements, flow cytometry, qPCR, metabolic labelling, lipidomics and viability assays were used to dissect functional alterations in pathways related to nelfinavir targets. RESULTS We identified a common set of proteins interacting specifically with the active site of nelfinavir. These proteins are embedded in intracellular, lipid-rich membranes of mitochondria (VDAC1,2,3, ANT2), endoplasmic reticulum (BCAP31, CANX, SRPRB) and nuclear envelope (PGRMC2) and are consistent across multiple cancer cell types. ADIPOR2, a key regulator gene of membrane lipid fluidity, was identified as a key nelfinavir resistance gene, while genes involved in fatty acids (FAs) and cholesterol metabolism, vesicular trafficking and mitochondria biogenesis are candidate sensitivity genes. We further show that via binding to proteins in lipid-rich membranes nelfinavir affects membrane composition and reduces membrane fluidity, leading to induction of FAs synthesis and the unfolded protein response (UPR). Via its structural interference with membrane fluidity, nelfinavir impairs the function and mobility of a diverse set of membrane-associated proteins and processes, such as glucose flux and processing, mitochondria respiration, energy supply, transmembrane vesicular transport and ABCB1-mediated drug efflux, as we show in different reporter systems in live MM cells. These functional effects are prevented by addition of metabolically inert lipids to be incorporated in membranes, supporting a direct structural activity of nelfinavir. The adaptive biology of proteasome inhibitor (PI)-resistant myeloma relies on metabolic reprogramming and changes in lipid composition, drug export and down-modulation of the UPR. Modulation of membrane fluidity and depletion of FAs/cholesterol is synergistic with proteasome inhibitors in PI-resistant MM. Thus, the mechanism of action of nelfinavir perfectly matches with the biology of PI-resistant MM, serving as a molecular rational for its significant clinical activity. CONCLUSION We here demonstrate in vitro that the activity of nelfinavir against MM cells is triggered through changes in lipid metabolism and the fluidity of lipid-rich membranes. Pharmacologic targeting of membrane fluidity is a novel, potent mechanism to achieve anti-cancer activity, in particular against PI-refractory MM. This mechanism explains the clinical activity of nelfinavir in MM treatment as well as the key side effects of nelfinavir during antiretroviral therapy. Disclosures No relevant conflicts of interest to declare.
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Fassmannová, Dominika, František Sedlák, Jindřich Sedláček, Ivan Špička, and Klára Grantz Šašková. "Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma." Cancers 12, no. 5 (April 25, 2020): 1065. http://dx.doi.org/10.3390/cancers12051065.
Повний текст джерелаАнотація:
Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir’s effectiveness in the treatment of multiple myeloma.
3
Patick, A. K., M. Duran, Y. Cao, D. Shugarts, M. R. Keller, E. Mazabel, M. Knowles, S. Chapman, D. R. Kuritzkes, and M. Markowitz. "Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from Patients Treated with the Protease Inhibitor Nelfinavir." Antimicrobial Agents and Chemotherapy 42, no. 10 (October 1, 1998): 2637–44. http://dx.doi.org/10.1128/aac.42.10.2637.
Повний текст джерелаАнотація:
ABSTRACT Nelfinavir mesylate (formerly AG1343) is a potent and selective inhibitor of human immunodeficiency virus (HIV) protease approved for the treatment of individuals infected with HIV. Nucleotide sequence analysis of protease genes from plasma HIV type 1 (HIV-1) RNA revealed a unique aspartic acid (D)-to-asparagine (N) substitution at residue 30 (D30N) in 25 of 55 patients treated with nelfinavir for a median of 13 weeks. Although the appearance of D30N was occasionally associated with concurrent or sequential emergence of other changes (e.g., at residues 35, 36, 46, 71, 77, and 88), genotypic changes associated with phenotypic resistance to other protease inhibitors were not observed (e.g., at residues 48, 50, 82, and 84) or were only rarely observed (e.g., at residue 90). In phenotypic assays, viral isolates with high-level resistance to nelfinavir remained susceptible to indinavir, saquinavir, ritonavir, and amprenavir (formerly VX-478/141W94). Similar results were observed in phenotypic assays utilizing HIV-1 NL4-3, which contained the D30N substitution alone or in combination with substitutions at other residues (e.g., residues 46, 71, and 88). These data indicate that the initial pathway of resistance to nelfinavir is unique and suggest that individuals failing short courses of nelfinavir-containing regimens may respond to regimens containing other protease inhibitors.
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Yerly, Sabine, Martin Rickenbach, Matei Popescu, Patrick Taffe, Charles Craig, Luc Perrin, M. Battegay, et al. "Drug Resistance Mutations in HIV-1-Infected Subjects during Protease Inhibitor-Containing Highly Active Antiretroviral Therapy with Nelfinavir or Indinavir." Antiviral Therapy 6, no. 3 (April 1, 2000): 185–89. http://dx.doi.org/10.1177/135965350100600304.
Повний текст джерелаАнотація:
Objectives The aim of this retrospective study was to evaluate treatment outcome and characterize the pattern of genotype mutations in subjects with treatment failure on highly active antiretroviral therapy (HAART) containing nelfinavir or indinavir. Study design and methods The database of the Swiss HIV Cohort Study was screened for all subjects naive to protease inhibitor (PI) treatment who started HAART with nelfinavir or indinavir, responded initially (HIV-RNA <400 copies/ml) and received >24 weeks of treatment. Responders with subsequent treatment failure (HIV-RNA >1000 copies/ml, bordered by HIV-RNA >400 copies/ml) were selected for genotypic analysis. Results Initial treatment response, maintenance of response and subsequent virological failure were observed at a comparable frequency in 1143 nelfinavir and 1555 indinavir subjects. Of the treatment-naive patients, 13% who took nelfinavir and 16% who took indinavir had HIV-RNA >1000 copies/ml at least once. These values increased to 24 and 27%, respectively, for reverse transcriptase inhibitor-experienced subjects. Genotypic analysis in a subset of subjects with virological failure identified 30N as the only primary mutation in the nelfinavir subjects (8 out of 21, 38%) whereas isolated or combined 82A/T and 46I/L mutations were detected in the indinavir subjects (9 out of 20, 45%). Conclusions In this population of previously PI-naive subjects, the rate of virological failure and the frequency of resistance mutations at the time of virological failure were comparable in subjects receiving nelfinavir- or indinavir-containing HAART. In nelfinavir subjects, 30N was the only primary mutation whereas isolated or combined 82A/T and 46I/L mutations were detected in indinavir subjects.
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Kachko, Ilana, Adva Maissel, Livnat Mazor, Ronit Ben-Romano, Robert T. Watson, June C. Hou, Jeffrey E. Pessin, Nava Bashan, and Assaf Rudich. "Postreceptoral Adipocyte Insulin Resistance Induced by Nelfinavir Is Caused by Insensitivity of PKB/Akt to Phosphatidylinositol-3,4,5-Trisphosphate." Endocrinology 150, no. 6 (January 29, 2009): 2618–26. http://dx.doi.org/10.1210/en.2008-1205.
Повний текст джерелаАнотація:
Adipocyte insulin resistance can be caused by proximal insulin signaling defects but also from postreceptor mechanisms, which in large are poorly characterized. Adipocytes exposed for 18 h to the HIV protease inhibitor nelfinavir manifest insulin resistance characterized by normal insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate proteins, preserved in vitro phosphatidylinositol 3-kinase (PI 3-kinase) assay activity but impaired activation of PKB/Akt and stimulation of glucose uptake. Here we aimed to assess whether impaired PKB/Akt activation is indeed rate limiting for insulin signaling propagation in response to nelfinavir and the mechanism for defective PKB/Akt activation. Nelfinavir treatment of 3T3-L1 adipocytes impaired the insulin-stimulated translocation and membrane fusion of myc-glucose transporter (GLUT)-4-green fluorescent protein (GFP) reporter. Phosphorylation of PKB/Akt substrates including glycogen synthase kinase-3 and AS160 decreased in response to nelfinavir, and this remained true, even in cells with forced generation of phosphatidylinositol-3,4,5-trisphohphate (PIP3) by a membrane-targeted active PI 3-kinase, confirming that impaired PKB/Akt activation was rate limiting for insulin signal propagation. Cells expressing a GFP-tagged pleckstrin homology domain of general receptors for phosphoinositides 1, which binds PIP3, revealed intact PIP3-mediated plasma membrane translocation of this reporter in nelfinavir-treated cells. However, expression of a membrane-targeted catalytic subunit of PI 3-kinase failed to induce myc-GLUT4-GFP translocation in the absence of insulin, as it did in control cells. Conversely, a membrane-targeted and constitutively active PKB/Akt mutant was normally phosphorylated on S473 and T308, confirming intact PKB/Akt kinases activity, and induced myc-GLUT4-GFP translocation. Collectively, nelfinavir uncovers a postreceptor mechanism for insulin resistance, caused by interference with the sensing of PIP3 by PKB/Akt, leading to impaired GLUT4 translocation and membrane fusion.
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&NA;. "Nelfinavir + saquinavir resistance testing in HIV management." Inpharma Weekly &NA;, no. 1325 (February 2002): 20. http://dx.doi.org/10.2165/00128413-200213250-00052.
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Petrich, Adam M., Violetta V. Leshchenko, Pei-Yu Kuo, B. Hilda Ye, Joseph A. Sparano, and Samir Parekh. "Genomic and Pathway Connectivity Analyses Identify Novel Strategies to Overcome mTOR Inhibitor Resistance In DLBCL." Blood 116, no. 21 (November 19, 2010): 436. http://dx.doi.org/10.1182/blood.v116.21.436.436.
Повний текст джерелаАнотація:
Abstract Abstract 436 mTOR inhibitors have been used with clinical success in solid tumors and non-Hodgkin lymphoma (NHL), and are attractive therapeutic options for DLBCL (diffuse large B-cell lymphoma, which has been shown to have constitutively active mTOR signaling). However, resistance to this class of agents remains problematic, and mechanisms of resistance are poorly understood. We performed candidate drug discovery using connectivity mapping and global gene expression profiling (GEP) to understand the pathways and genes responsible for resistance to the mTOR inhibitor Rapamycin (Sirolimus), which is the active metabolite of several clinically available mTOR inhibitors (eg, Temsirolimus, Everolimus). Treatment of DLBCL cell lines by Rapamycin at varying doses permitted stratification of cell lines into 2 groups of 3 cell lines each: sensitive (SU-DHL6, WSU-NHL, and Karpas-422) and resistant (SU-DHL4, OCI-Ly19, and Farage). Using the Affymetrix Human Gene 1.0 ST Array, we generated a profile of 1164 differentially-expressed genes (P<0.01) in the resistant cell lines. Pathway analysis of this particular gene expression signature enriched most strongly for the networks “EIF2 signaling” and “Regulation of eIF4 and p70S6K,” both of which are known to be involved in the PI3K and mTOR/AKT pathway. The genes thus identified present novel opportunities to understand and overcome resistance to mTOR inhibitors in DLBCL and other cancers. The Connectivity Map (CMAP) database contains a reference collection of more than 7,000 expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We next analyzed the differentially-expressed genes associated with mTOR inhibitor resistance with the CMAP database in order to identify compounds likely to reverse the profile associated with resistance. From over 6,000 agents, the top 2% (by connectivity score) contained two PI3K inhibitors (Wortmannin and LY-294002), the protease inhibitor Saquinavir, and multiple HDAC inhibitors (including both Vorinostat and Trichostatin-A in the top 40 drugs). Among protease inhibitors, Nelfinavir (and to a lesser extent Saquinavir), has been shown to have potent cytotoxicity in a variety of solid tumors, by inhibition of the AKT signaling pathway. To validate the hypothesis that modulation of AKT might help overcome mTOR inhibitor resistance, we targeted AKT with two agents: Nelfinavir and MK-2206. We found that Nelfinavir demonstrated significant cytotoxicity at clinically achievable levels in all DLBCL cell lines tested (including those resistant to Rapamycin), and inhibited phosphorylation of AKT and downstream proteins (including p70S6 kinase; S6 ribosomal protein; 4-EBP-1) in a dose-dependent fashion. Baseline total AKT and phosphorylated AKT levels correlated with degree of sensitivity to Nelfinavir. Inhibition of downstream mTOR signaling by Rapamycin synergized with Nelfinavir in cell kill and inhibition of cell cycle progression. MK-2206, an AKT inhibitor which has shown success in early-phase clinical trials, was evaluated in the same panel of cell lines and likewise demonstrated synergism with Rapamycin in cytotoxicity and cell cycle inhibition. The degree of synergism between Rapamycin and either Nelfinavir and MK-2206, as calculated using the Chou-Talalay equation, was comparable. We have also demonstrated synergy between Nelfinavir and doxorubicin, a key component in commonly utilized regimens for AIDS lymphoma patients such as CHOP (Cytoxan, Adriamycin, Oncovin and Prednisone). We are now validating these in vitro results in a mouse xenograft model of DLBCL. In conclusion, our study demonstrates that AKT inhibition by Nelfinavir results in potent cytotoxicity in DLBCL cell lines at clinically relevant doses. Our results may have implications for combination therapy beyond NHL in non-hematologic malignancies where mTOR inhibitors and MK-2206 are being used independently with clinical success. Furthermore, the synergistic combination of either Nelfinavir or MK-2206, along with Rapamycin, may permit use of lower doses of each drug to therapeutically inhibit mTOR/AKT signaling while potentially reducing toxicity from off-target effects from the individual drugs. Finally, the use of Nelfinavir has particular relevance in AIDS patients with DLBCL, where the drug has both anti-viral and anti-lymphoma potential. Disclosures: No relevant conflicts of interest to declare.
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Chow, W. A., S. Guo, and F. Valdes-Albini. "HIV protease inhibitor (PI) therapy for liposarcoma." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9564. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9564.
Повний текст джерелаАнотація:
9564 Background: Liposarcomas are the second most common soft-tissue sarcoma. Highly-active anti-retroviral therapy (HAART) with HIV PIs results in “HIV-1 protease inhibitor associated lipodystrophy syndrome,” characterized by peripheral fat wasting, central fat accumulation, insulin resistance, and hyperlipidemia. Based upon this syndrome, we hypothesized that HIV PIs might represent a novel liposarcoma therapy. Methods: SW872, LiSa-2, and FU-DDLS-1 liposarcoma, and control 293 embryonic kidney and HT1080 fibrosarcoma cell lines were treated with HIV PIs and subjected to cellular and molecular assays. Results: Clonogenic assays with SW872 cells using HIV PIs (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) were performed. Nelfinavir demonstrated the most potent clonogenic inhibition without affecting 293 and HT1080 clonogenicity, and was studied further. Nelfinavir inhibited SW872 and LiSa-2 proliferation dose-dependently, and HT1080 proliferation at the highest concentration, without affecting FU-DDLS-1 nor 293 proliferation. Nelfinavir induced a G1 cell cycle arrest in SW872 and HT1080, but not in 293 cells. It also induced dose-dependent apoptosis in SW872, but not in 293 nor HT1080 cells. Western analyses for sterol regulatory element binding protein-1 (SREBP-1) expression, a key transcriptional regulator of fatty acid and cholesterol synthesis, were performed. Nelfinavir induced expression of SREBP-1 in nelfinavir-sensitive SW872 and LiSa-2 cells, and modestly in HT1080 cells, but not in insensitive FU-DDLS-1 nor 293 cells. Additionally, nelfinavir reduced protein expression of proliferating cell nuclear antigen (PCNA) in sensitive SW872 and LiSa-2 cells, and induced expression of the anti-proliferative protein, p21, as well as pro-apoptotic proteins, Bax and Fas, in a dose-dependent manner. Finally, forced expression of SREBP-1 with a Tet-On inducible SW872 cell line, in the absence of nelfinavir, induced expression of p21, Bax, Fas, reduced expression of PCNA, and inhibited cell proliferation. Conclusions: These studies demonstrate that nelfinavir inhibits cellular proliferation, and induces apoptosis in sensitive-liposarcoma cells through upregulation of SREBP-1. These studies validate nelfinavir as a potential, novel targeted therapy for liposarcoma. No significant financial relationships to disclose.
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Schmidt, Barbara, Klaus Korn, Brigitte Moschik, Christiane Paatz, Klaus Überla, and Hauke Walter. "Low Level of Cross-Resistance to Amprenavir (141W94) in Samples from Patients Pretreated with Other Protease Inhibitors." Antimicrobial Agents and Chemotherapy 44, no. 11 (November 1, 2000): 3213–16. http://dx.doi.org/10.1128/aac.44.11.3213-3216.2000.
Повний текст джерелаАнотація:
ABSTRACT The therapeutic success of an antiretroviral salvage regimen containing protease inhibitors (PI) is limited by PI-resistant viral strains exhibiting various degrees of resistance and cross-resistance. To evaluate the extent of cross-resistance to the new PI amprenavir, 155 samples from 132 human immunodeficiency virus type 1-infected patients were analyzed for viral genotype by direct sequencing of the protease gene. Concomitantly, drug sensitivity to indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir was analyzed by a recombinant virus assay. A total of 111 patients had been pretreated with 1-4 PI, but all were naive to amprenavir. A total of 105 samples (67.7%) were sensitive to amprenavir; 25 samples (16.1%) were intermediately resistant, and another 25 samples were highly resistant (4- to 8-fold- and >8-fold-reduced sensitivity, respectively). The mutations 46I/L, 54L/V, 84V, and 90M showed the strongest association with amprenavir resistance (P < 0.0001). The scoring system using 84V and/or any two of a number of mutations (10I/R/V/F, 46I/L, 54L/V, and 90M) predicted amprenavir resistance with a sensitivity of 86.0% and a specificity of 81.0% within the analyzed group of samples. Of 62 samples with resistance against 4 PI, 23 (37.1%) were still sensitive to amprenavir. In comparison, only 2 of 23 samples (8.7%) from nelfinavir-naive patients with resistance against indinavir, saquinavir, and ritonavir were still sensitive to nelfinavir. Amprenavir thus appears to be an interesting alternative for PI salvage therapy.
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Kolli, M., A. Ozen, N. Kurt-Yilmaz, and C. A. Schiffer. "HIV-1 Protease-Substrate Coevolution in Nelfinavir Resistance." Journal of Virology 88, no. 13 (April 9, 2014): 7145–54. http://dx.doi.org/10.1128/jvi.00266-14.
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Ford, Jennifer, David Cornforth, Patrick G. Hoggard, Zoe Cuthbertson, E. Rhiannon Meaden, Ian Williams, Margaret Johnson, et al. "Intracellular and Plasma Pharmacokinetics of Nelfinavir and M8 in HIV-Infected Patients: Relationship with P-Glycoprotein Expression." Antiviral Therapy 9, no. 1 (January 2004): 77–84. http://dx.doi.org/10.1177/135965350400900101.
Повний текст джерелаАнотація:
One of the targets of antiretroviral therapy is within cells infected with HIV. In order to improve therapeutic efficacy, it is therefore important that the intracellular pharmacokinetics of drugs, such as nelfinavir mesylate and its active metabolite M8, are studied in addition to plasma pharmacokinetics. Previously, the intracellular accumulation of protease inhibitors has been reported in vivo, displaying the following hierarchy: nelfinavir > saquinavir > ritonavir > indinavir. Multidrug resistance transporters, such as P-glycoprotein (P-gp), may result in a lower intracellular concentration of drug via an efflux mechanism, thus contributing to sanctuary site formation. The objective of this study was to determine concentrations of nelfinavir and M8 in plasma and peripheral blood mononuclear cells from HIV-infected patients, and to ascertain the relationship between intracellular accumulation and lymphocyte P-gp expression. Venous blood samples from 12 HIV-infected patients (viral load <50 copies/ml) receiving nelfinavir (1250 mg twice daily) and dual nucleoside reverse transcriptase inhibitor therapy were collected over a full dosage interval (0, 2, 4, 8 and 12 h). Plasma and intracellular (cell-associated) drug concentrations were measured by HPLC-MS/MS. Drug exposure in plasma and cells was expressed as the area under the concentration–time curve (AUC0-12h), derived from non-compartmental modelling. The ratio of intracellular AUC0-12h/total plasma AUC0-12h was calculated to determine cellular drug accumulation. P-gp expression on lymphocytes was determined by flow cytometry. The median (range) AUC0-12h of nelfinavir in plasma and cellular compartments was 21.8 mg.h.l-1 (5.64–50.8) and 104.6 mg.h.l-1 (23.1–265.7), respectively. Corresponding values for M8 in plasma and cells were 6.60 mg.h.l–1 (2.16–17.3) and 19.6 mg.h.l–1 (5.14–60.8). A ratio of plasma M8/plasma nelfinavir (AUC0–12h) and intracellular M8/intracellular nelfinavir (AUC0–12h) gave median values of 0.32 and 0.17, respectively. The cellular accumulations [median; (range)] of nelfinavir and M8 were 5.30 (2.28–16.2) and 2.32 (1.01–10.7), respectively. A significant correlation between plasma and intracellular nelfinavir minimum concentration (Cmin) (r2=0.34; P=0.049), but not between plasma and intracellular M8 Cmin was observed. C0h concentrations were higher than C12h for both nelfinavir and M8. No relationship was observed between nelfinavir or M8 accumulation and lymphocyte cell surface expression of P-gp. This study illustrates that intracellular concentrations were higher than plasma concentrations for both nelfinavir and M8, suggesting lymphocyte accumulation. The mechanism of differential intracellular accumulation of nelfinavir and M8 remains to be elucidated. It may be that affinities for influx transporters or fundamental drug characteristics play a major role in the greater accumulation of nelfinavir than M8.
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Hammer, Scott M., Roland Bassett, Kathleen E. Squires, Margaret A. Fischl, Lisa M. Demeter, Judith S. Currier, John W. Mellors, et al. "A Randomized Trial of Nelfinavir and Abacavir in Combination with Efavirenz and Adefovir Dipivoxil in HIV-1-Infected Persons with Virological Failure Receiving Indinavir." Antiviral Therapy 8, no. 6 (August 1, 2002): 507–18. http://dx.doi.org/10.1177/135965350300800615.
Повний текст джерелаАнотація:
Objectives (1) To determine the efficacy and safety of nelfinavir versus placebo and abacavir versus other approved nucleoside reverse transcriptase inhibitors (NRTIs), in combination with efavirenz and adefovir dipovoxil, in subjects experiencing virological failure on an indinavir-containing regimen. (2) To determine the relationship of baseline viral drug resistance genotype and phenotype to virological outcome. Design and methods A prospective, randomized, controlled, multicentre study in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive subjects conducted by the Adult AIDS Clinical Trials Group (ACTG 372B) and an open-label, single-arm, multicentre study in NNRTI-experienced subjects (ACTG 372D). Ninety-four subjects were randomized in ACTG 372B, which used a factorial design. All subjects received efavirenz and adefovir dipivoxil, and were randomly assigned to nelfinavir versus nelfinavir placebo and abacavir versus previously FDA-approved NRTIs. Twenty subjects received abacavir, efavirenz, adefovir dipivoxil and nelfinavir in ACTG 372D. Primary analysis time-point was at 16 weeks with follow-up through 48 weeks. Measures of efficacy were plasma HIV-1 RNA levels and CD4 cell counts. Adverse events were recorded according to ACTG criteria. Baseline reverse transcriptase and protease genotype, and drug susceptibility phenotype were determined. Resistance analyses were combined for ACTG 372B and D. Results At 16 weeks in ACTG 372B, 67% of subjects reached a primary study treatment failure end-point. In factorial analyses, nelfinavir was superior to nelfinavir placebo in rate of this failure end-point (56 vs 78%, P=0.02), but abacavir was not different from other NRTIs. No differences by nelfinavir or abacavir factor were noted at week 48. The failure end-point rate was significantly lower in those with baseline RNA levels ≤15000 copies/ml versus those with >15000 copies/ml (42 vs 79%, P<0.001). Higher genotypic and phenotypic sensitivity scores were significantly correlated with better virological responses ( P=0.003 and 0.030, respectively). Conclusions: (1) Treatment responses were low in this trial of nelfinavir, abacavir, efavirenz and adefovir dipivoxil for subjects experiencing virological failure on an indinavir-containing regimen. (2) Subjects with plasma HIV-1 RNA levels ≤15000 copies/ml had a significantly better virological response than those with >15000 copies/ml at baseline. Switching at lower, rather than higher, viral load levels improved response rates in treatment-experienced subjects. (3) Summary measures of regimen sensitivity (such as, genotypic and phenotypic sensitivity scores) are useful in the evaluation of multidrug combination regimens.
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Ferrarelli, Leslie K. "Repurposing an HIV drug for melanoma." Science Signaling 9, no. 423 (April 12, 2016): ec85-ec85. http://dx.doi.org/10.1126/scisignal.aaf8440.
Повний текст джерелаАнотація:
Inhibitors of the kinases BRAF or MEK (BRAF/MEK) can reduce tumor growth in some patients with melanoma, but resistance often develops. Microphthalmia-associated transcription factor (MITF) is implicated in promoting melanoma development. Smith et al. found that long-term treatment of cell cultures and mice bearing xenografts with BRAF/MEK inhibitors increased the abundance of MITF and its transcription factor PAX3 and that silencing MITF sensitized drug-resistant melanoma cells to the inhibitors. In a screen for small molecules that could reduce the abundance of MITF or PAX3, the most effective drug was nelfinavir mesylate, a protease inhibitor currently used to treat human immunodeficiency virus (HIV) infection. Nelfinavir sensitized melanoma cells to BRAF/MEK inhibitors but not in the context of ectopic overexpression of PAX3 or MITF. PAX3 abundance is suppressed by the transcriptional repressor SKI, which functions in complex with the transforming growth factor–β (TGF-β) effectors SMAD2 and SMAD4. BRAF/MEK inhibitors decreased the amount of SKI at the PAX3 promoter. Nelfinavir increased the amount of total as well as nuclear, phosphorylated (activated) SMAD2, the amount of SMAD2/SMAD4/SKI complexes, and the amount of SKI bound to the PAX3 promoter and consequently reduced the abundance of PAX3 and MITF. Nelfinavir could not reduce MITF abundance in the absence of SMAD4. The findings indicate that by counteracting the effects of BRAF/MEK inhibitors on SMAD2/SMAD4/SKI transrepression of PAX3, nelfinavir may be able to prevent drug resistance in melanoma; however, it is not yet clear through which proteases nelfinavir mediates these effects on SMAD2 and SKI. Furthermore, because MITF suppression is conversely associated with metastatic disease, the immediate clinical application of nelfinavir for melanoma patients is cautioned against (see Kim and Ronai). With further investigation, the findings of Smith et al. suggest that patients might be selected for nelfinavir-based therapy based on early-stage disease and tumor cell markers, such as the abundances of SMAD2, SMAD4, and SKI.M. P. Smith, H. Brunton, E. J. Rowling, J. Ferguson, I. Arozarena, Z. Miskolczi, J. L. Lee, M. R. Girotti, R. Marais, M. P. Levesque, R. Dummer, D. T. Frederick, K. T. Flaherty, Z. A. Cooper, J. A. Wargo, C. Wellbrock, Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29, 270–284 (2016). [PubMed] H. Kim, Z. A. Ronai, HIV drug to aid melanoma therapies? Cancer Cell 29, 245–246 (2016). [PubMed]
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Schütt, M., J. Zhou, M. Meier, and H. H. Klein. "Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells." Journal of Endocrinology 183, no. 3 (December 2004): 445–54. http://dx.doi.org/10.1677/joe.1.05620.
Повний текст джерелаАнотація:
The mechanism by which chronic treatment with HIV (human immunodeficiency virus)-1 protease inhibitors leads to a deterioration of glucose metabolism appears to involve insulin resistance, and may also involve impaired insulin secretion. Here we investigated the long-term effects of HIV-1 protease inhibitors on glucose-stimulated insulin secretion from beta cells and explored whether altered insulin secretion might be related to altered insulin signaling. INS-1 cells were incubated for 48 h with different concentrations of amprenavir, indinavir, nelfinavir, ritonavir or saquinavir, stimulated with 20 mM d-glucose, and insulin determined in the supernatant. To evaluate insulin signaling, cells were stimulated with 100 nM insulin for 2 min, and insulin-receptor substrate (IRS)-1, -2 and Akt phosphorylation determined. Incubation for 48 h with ritonavir, nelfinavir and saquinavir resulted in impaired glucose-induced insulin secretion at 2.5, 5 and 5 μM respectively, whereas amprenavir or indinavir had no effects even at 20 and 100 μM respectively. The impaired insulin secretion by ritonavir, nelfinavir and saquinavir was associated with decreased insulin-stimulated IRS-2 phosphorylation, and, for nelfinavir and saquinavir, with decreased insulin-stimulated IRS-1 and Thr308-Akt phosphorylation. No such effects on signaling were observed with amprenavir or indinavir. In conclusion, certain HIV-1 protease inhibitors, such as ritonavir, nelfinavir and saquinavir, not only induce peripheral insulin resistance, but also impair glucose-stimulated insulin secretion from beta cells. With respect to the long-term effect on beta-cell function there appear to be differences between the protease inhibitors that may be clinically relevant. Finally, these effects on insulin secretion after a 48 h incubation with protease inhibitor were associated with a reduction of the insulin-stimulated phosphorylation of insulin signaling parameters, particularly IRS-2, suggesting that protease inhibitor-induced alterations in the insulin signaling pathway may contribute to the impaired beta-cell function.
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Perrin, Virginie, and Fabrizio Mammano. "Parameters Driving the Selection of Nelfinavir-Resistant Human Immunodeficiency Virus Type 1 Variants." Journal of Virology 77, no. 18 (September 15, 2003): 10172–75. http://dx.doi.org/10.1128/jvi.77.18.10172-10175.2003.
Повний текст джерелаАнотація:
ABSTRACT We investigated the parameters driving nelfinavir resistance, along the D30N and L90M evolutionary pathways. The advantage of the D30N mutant was mostly due to its resistance level, while the L90M mutation allowed preservation of infectivity coupled with minimal resistance. Emergence of secondary mutations further increased the selective advantage of viruses harboring D30N.
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Mo, Hongmei, Neil Parkin, Kent D. Stewart, Liangjun Lu, Tatyana Dekhtyar, Dale J. Kempf, and Akhteruzzaman Molla. "Identification and Structural Characterization of I84C and I84A Mutations That Are Associated with High-Level Resistance to Human Immunodeficiency Virus Protease Inhibitors and Impair Viral Replication." Antimicrobial Agents and Chemotherapy 51, no. 2 (November 13, 2006): 732–35. http://dx.doi.org/10.1128/aac.00690-06.
Повний текст джерелаАнотація:
ABSTRACT Two novel human immunodeficiency virus protease mutations, I84C and I84A, were identified in patient isolates. The mutants with I84C displayed high-level resistance (median, at least 56-fold) to nelfinavir and saquinavir, but the majority remained susceptible to lopinavir. In contrast, isolates with the I84A mutation exhibited ≥33-fold median increased levels of resistance to nelfinavir, indinavir, amprenavir, ritonavir, lopinavir, saquinavir, and atazanavir. Isolates with the I84A or I84C mutation tended to be more resistant than the isolates with the I84V mutation. Modeling of the structure of the mutant proteases indicated that the I84V, I84C, and I84A mutations all create unoccupied volume in the active site, with I84A introducing the greatest change in the accessible surface area from that of the wild-type structure.
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Subeha, Mahbuba R., and Carlos M. Telleria. "The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir." Cancers 12, no. 11 (November 19, 2020): 3437. http://dx.doi.org/10.3390/cancers12113437.
Повний текст джерелаАнотація:
Traditional cancer treatments may lose efficacy following the emergence of novel mutations or the development of chemoradiotherapy resistance. Late diagnosis, high-cost of treatment, and the requirement of highly efficient infrastructure to dispense cancer therapies hinder the availability of adequate treatment in low-income and resource-limited settings. Repositioning approved drugs as cancer therapeutics may reduce the cost and timeline for novel drug development and expedite the availability of newer, efficacious options for patients in need. Nelfinavir is a human immunodeficiency virus (HIV) protease inhibitor that has been approved and is extensively used as an anti-infective agent to treat acquired immunodeficiency syndrome (AIDS). Yet nelfinavir has also shown anti-cancer effects in in vitro and in vivo studies. The anti-cancer mechanism of nelfinavir includes modulation of different cellular conditions, such as unfolded protein response, cell cycle, apoptosis, autophagy, the proteasome pathway, oxidative stress, the tumor microenvironment, and multidrug efflux pumps. Multiple clinical trials indicated tolerable and reversible toxicities during nelfinavir treatment in cancer patients, either as a monotherapy or in combination with chemo- or radiotherapy. Since orally available nelfinavir has been a safe drug of choice for both adult and pediatric HIV-infected patients for over two decades, exploiting its anti-cancer off-target effects will enable fast-tracking this newer option into the existing repertoire of cancer chemotherapeutics.
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Solas, Caroline, Alain Lafeuillade, Philippe Halfon, Stéphane Chadapaud, Gilles Hittinger, and Bruno Lacarelle. "Discrepancies between Protease Inhibitor Concentrations and Viral Load in Reservoirs and Sanctuary Sites in Human Immunodeficiency Virus-Infected Patients." Antimicrobial Agents and Chemotherapy 47, no. 1 (January 2003): 238–43. http://dx.doi.org/10.1128/aac.47.1.238-243.2003.
Повний текст джерелаАнотація:
ABSTRACT The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.
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Gonzalez, Luis M. F., Renato S. Aguiar, Adriana Afonso, Patricia A. Brindeiro, Mônica B. Arruda, Marcelo A. Soares, Rodrigo M. Brindeiro, and Amílcar Tanuri. "Biological characterization of human immunodeficiency virus type 1 subtype C protease carrying indinavir drug-resistance mutations." Journal of General Virology 87, no. 5 (May 1, 2006): 1303–9. http://dx.doi.org/10.1099/vir.0.81517-0.
Повний текст джерелаАнотація:
Human immunodeficiency virus type 1 subtype C isolates belong to one of the most prevalent strains circulating worldwide and are responsible for the majority of new infections in the sub-Saharan region and other highly populated areas of the globe. In this work, the impact of drug-resistance mutations in the protease gene of subtype C viruses was analysed and compared with that of subtype B counterparts. A series of recombinant subtype C and B viruses was constructed carrying indinavir (IDV)-resistance mutations (M46V, I54V, V82A and L90M) and their susceptibility to six FDA-approved protease inhibitor compounds (amprenavir, indinavir, lopinavir, ritonavir, saquinavir and nelfinavir) was determined. A different impact of these mutations was found when nelfinavir and lopinavir were tested. The IDV drug-resistance mutations in the subtype C protease backbone were retained for a long period in culture without selective pressure when compared with those in subtype B counterparts in washout experiments.
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Johnston, Elizabeth, Mark A. Winters, Soo-Yon Rhee, Thomas C. Merigan, Celia A. Schiffer, and Robert W. Shafer. "Association of a Novel Human Immunodeficiency Virus Type 1 Protease Substrate Cleft Mutation, L23I, with Protease Inhibitor Therapy and In Vitro Drug Resistance." Antimicrobial Agents and Chemotherapy 48, no. 12 (December 2004): 4864–68. http://dx.doi.org/10.1128/aac.48.12.4864-4868.2004.
Повний текст джерелаАнотація:
ABSTRACT We observed a previously uncharacterized mutation in the protease substrate cleft, L23I, in 31 of 4,303 persons undergoing human immunodeficiency virus type 1 genotypic resistance testing. In combination with V82I, L23I was associated with a sevenfold reduction in nelfinavir susceptibility and a decrease in replication capacity. In combination with other drug resistance mutations, L23I was associated with multidrug resistance and a compensatory increase in replication capacity.
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Grossman, Zehava, Ellen E. Paxinos, Diana Averbuch, Shlomo Maayan, Neil T. Parkin, Dan Engelhard, Margalit Lorber, et al. "Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir." Antimicrobial Agents and Chemotherapy 48, no. 6 (June 2004): 2159–65. http://dx.doi.org/10.1128/aac.48.6.2159-2165.2004.
Повний текст джерелаАнотація:
ABSTRACT Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as “subtype-C-infected patients”) versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC50) change in susceptibility to nelfinavir only. Other mutations increased IC50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ± 22% to 22% ± 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.
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Gong, Yi-Fei, Brett S. Robinson, Ronald E. Rose, Carol Deminie, Timothy P. Spicer, David Stock, Richard J. Colonno, and Pin-fang Lin. "In Vitro Resistance Profile of the Human Immunodeficiency Virus Type 1 Protease Inhibitor BMS-232632." Antimicrobial Agents and Chemotherapy 44, no. 9 (September 1, 2000): 2319–26. http://dx.doi.org/10.1128/aac.44.9.2319-2326.2000.
Повний текст джерелаАнотація:
ABSTRACT BMS-232632 is an azapeptide human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor that displays potent anti-HIV-1 activity (50% effective concentration [EC50], 2.6 to 5.3 nM; EC90, 9 to 15 nM). In vitro passage of HIV-1 RF in the presence of inhibitors showed that BMS-232632 selected for resistant variants more slowly than nelfinavir or ritonavir did. Genotypic and phenotypic analysis of three different HIV strains resistant to BMS-232632 indicated that an N88S substitution in the viral protease appeared first during the selection process in two of the three strains. An I84V change appeared to be an important substitution in the third strain used. Mutations were also observed at the protease cleavage sites following drug selection. The evolution to resistance seemed distinct for each of the three strains used, suggesting multiple pathways to resistance and the importance of the viral genetic background. A cross-resistance study involving five other protease inhibitors indicated that BMS-232632-resistant virus remained sensitive to saquinavir, while it showed various levels (0.1- to 71-fold decrease in sensitivity)-of cross-resistance to nelfinavir, indinavir, ritonavir, and amprenavir. In reciprocal experiments, the BMS-232632 susceptibility of HIV-1 variants selected in the presence of each of the other HIV-1 protease inhibitors showed that the nelfinavir-, saquinavir-, and amprenavir-resistant strains of HIV-1 remained sensitive to BMS-232632, while indinavir- and ritonavir-resistant viruses displayed six- to ninefold changes in BMS-232632 sensitivity. Taken together, our data suggest that BMS-232632 may be a valuable protease inhibitor for use in combination therapy.
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Sugiura, Wataru, Zene Matsuda, Yoshiyuki Yokomaku, Kurt Hertogs, Brendan Larder, Tsuyoshi Oishi, Aiko Okano, et al. "Interference between D30N and L90M in Selection and Development of Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1." Antimicrobial Agents and Chemotherapy 46, no. 3 (March 2002): 708–15. http://dx.doi.org/10.1128/aac.46.3.708-715.2002.
Повний текст джерелаАнотація:
ABSTRACT We studied the evolutionary relationships between the two protease inhibitor (PI) resistance mutations, D30N and L90M, of human immunodeficiency virus type 1 (HIV-1). The former is highly specific for nelfinavir resistance, while the latter is associated with resistance to several PIs, including nelfinavir. Among patients with nelfinavir treatment failure, we found that D30N acquisition was strongly suppressed when L90M preexisted. Thus, D30N/L90M double mutations not only were detected in a very limited number of patients but also accounted for a minor fraction within each patient. In the disease course, the D30N and L90M clones readily evolved independently of each other, and later the D30N/L90M double mutants emerged. The double mutants appeared to originate from the D30N lineage but not from the L90M lineage, or were strongly associated with the former. However, their evolutionary pathways appeared to be highly complex and to still have something in common, as they always contained several additional polymorphisms, including L63P and N88D, as common signatures. These results suggest that D30N and L90M are mutually exclusive during the evolutionary process. Supporting this notion, the D30N/L90M mutation was also quite rare in a large clinical database. Recombinant viruses with the relevant mutations were generated and compared for the ability to process p55 gag and p160 pol precursor proteins as well as for their infectivity. L90M caused little impairment of the cleavage activities, but D30N was detrimental, although significant residual activity was observed. In contrast, D30N/L90M demonstrated severe impairment. Thus, the concept of mutual antagonism of the two mutations was substantiated biochemically and functionally.
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Gupta, Vinay, Christian G. Samuleson, Susan Su, and Thomas C. Chen. "Nelfinavir potentiation of imatinib cytotoxicity in meningioma cells via survivin inhibition." Neurosurgical Focus 23, no. 4 (October 2007): E9. http://dx.doi.org/10.3171/foc-07/10/e9.
Повний текст джерелаАнотація:
✓ Although most meningiomas are treated surgically, it may not be possible to completely remove atypical, malignant, and surgically inaccessible meningiomas; in the majority of these cases there is tumor recurrence. The authors have already reported initial preclinical results on the efficacy of imatinib in the treatment of meningiomas; however, a recent Phase II trial of imatinib in patients with recurrent meningiomas did not demonstrate significant antitumor activity. To enhance the activity of imatinib, the authors investigated the use of a combination therapy with nelfinavir on primary meningioma cells and meningioma cell lines IOMM-Lee and CH157. Cytotoxicity was measured using methylthiotetrazole and colony formation assays. In low-dose combination therapy with imatinib, nelfinavir potentiated the antiproliferative and anti–colony formation effects of imatinib. Primary meningioma cells responded better to combination therapy than to imatinib alone. Treatment induced a dose-dependent antiproliferative effect, decreased cell survival, and inhibited colony formation. Western blotting demonstrated decreased levels of survivin protein on combination therapy. Because meningiomas have very high levels of survivin protein, survivin inhibition by nelfinavir may represent a potential mechanism for the additive effect observed with imatinib. Moreover, an increase in the proapoptotic Bax/Bcl-2 protein ratio was demonstrated with the combination of imatinib and nelfinavir. The authors propose that nelfinavir not only potentiates imatinib efficacy, it also abrogates resistance to imatinib by decreasing survivin protein levels in meningiomas. In an in vivo assay, this combination therapy was found to be more effective than imatinib alone. More preclinical work with in vivo models is needed to determine if this new combination therapy will translate into a viable future therapy for meningiomas.
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Winters, Mark A., Jonathan M. Schapiro, Jody Lawrence, and Thomas C. Merigan. "Human Immunodeficiency Virus Type 1 Protease Genotypes and In Vitro Protease Inhibitor Susceptibilities of Isolates from Individuals Who Were Switched to Other Protease Inhibitors after Long-Term Saquinavir Treatment." Journal of Virology 72, no. 6 (June 1, 1998): 5303–6. http://dx.doi.org/10.1128/jvi.72.6.5303-5306.1998.
Повний текст джерелаАнотація:
ABSTRACT An understanding of the mechanisms of virologic cross-resistance between human immunodeficiency virus type 1 protease inhibitors is important for the establishment of effective treatment strategies for patients who no longer respond to their initial protease inhibitor. Protease gene sequencing results from patients treated with saquinavir showed significant increases in the frequency of the G48V protease mutation in patients receiving higher doses of the drug. In addition, all six patients who developed the G48V mutation during saquinavir therapy developed the V82A mutation either on continued saquinavir or after a switch to nelfinavir or indinavir. In vitro susceptibility assays showed that all 13 isolates with reduced susceptibilities to two or more protease inhibitors had either the G48V or L90M mutation, along with an average of six other protease mutations. Reduced susceptibility to nelfinavir was found in 14 isolates, but only 1 possessed the D30N mutation. These results suggest that mutations selected in vivo by initial saquinavir therapy may provide more cross-resistance to the other protease inhibitors than has been previously reported.
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Kirk, Ole, Jens D. Lundgren, Court Pedersen, Lars R. Mathiesen, Henrik Nielsen, Terese L. Katzenstein, Niels Obel, and Jan Gerstoft. "A Randomized Trial Comparing Initial Haart Regimens of Nelfinavir/Nevirapine and Ritonavir/Saquinavir in Combination with Two Nucleoside Reverse Transcriptase Inhibitors." Antiviral Therapy 8, no. 6 (August 1, 2002): 595–602. http://dx.doi.org/10.1177/135965350300800611.
Повний текст джерелаАнотація:
Background A triple-class HAART regimen may be associated with a better virological effect than conventional regimens, but may also lead to toxicity and more profound resistance. Methods Randomized, controlled, open-label trial of 233 protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-naive HIV-infected patients allocated to a regimen of nelfinavir and nevirapine (1250/200 mg twice daily; n=118) or ritonavir and saquinavir (400/400 mg twice daily; n=115), both in combination with two nucleoside reverse transcriptase inhibitors. The primary end-point was HIV RNA ≤20 copies/ml after 48 weeks (missing value=failure). Patients remained under follow-up also in case of switch from the randomized therapy. Results At baseline, the median CD4 cell counts were 126 (range: 0–942) (nelfinavir/nevirapine) and 150 (0–642) (ritonavir/saquinavir) cells/mm3, and HIV RNA measurements 5.0 copies/ml (1.3–6.4) in both groups. A total of 102 (86%) and 101 (88%) were antiretroviral-naive. Within 48 weeks, 35 and 44% discontinued randomized therapy; P=0.13. Of these, 80 and 73% switched therapy due to adverse events; P=0.99. At week 48, 69 and 56%, respectively, had a HIV RNA ≤20 copies/ml; P=0.037. Conclusion A regimen of nelfinavir/nevirapine had a favourable virological effect and tolerability over a 48-week period compared with ritonavir/saquinavir, when administered in combination with two nucleoside reverse transcriptase inhibitors. However, more extensive follow-up is required to determine the long-term consequences of triple class HAART regimens, including the development of broad drug resistance.
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Sugiura, Wataru, Tsuyoshi Oishi, Aiko Okano, Masakazu Matsuda, Hanae Abumi, Kaneo Yamada, Mitsuru Koike, et al. "Two Possible Pathways for Acquisition of Mutations Related to Nelfinavir Resistance." Japanese Journal of Infectious Diseases 52, no. 4 (October 30, 1999): 175–76. http://dx.doi.org/10.7883/yoken.52.175.
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Liu, Wei, Qiang Meng, Yaoting Sun, Changyuan Wang, Xiaokui Huo, Zhihao Liu, Pengyuan Sun, Huijun Sun, Xiaodong Ma, and Kexin Liu. "Targeting P-Glycoprotein: Nelfinavir Reverses Adriamycin Resistance in K562/ADR Cells." Cellular Physiology and Biochemistry 51, no. 4 (2018): 1616–31. http://dx.doi.org/10.1159/000495650.
Повний текст джерелаАнотація:
Background/Aims: The emergence of multidrug resistance (MDR) caused by P-glycoprotein (P-gp) overexpression is a serious obstacle to the treatment of chronic myelocytic leukemia. In recent years, some clinical trials have shown that nelfinavir (NFV), a traditional anti-HIV drug, has anti-cancer effects. Some researchers have also shown NFV might be a potential P-gp inhibitor. This study is aimed at investigating whether nelfinavir can act as an MDR-reversal drug and to clarify its molecular mechanism as well. Methods: K562 and K562/ADR cell lines were applied in the study. Cytotoxicity was detected by CCK-8 reagents. Cell apoptosis was detected by flow cytometry and inverted fluorescence microscopy to detect the binding of apoptotic dyes to cells. Western blot was used to detect the expression of proteins. Drug-protein molecular docking simulation by using Sybyl-x 2.0 software. Results: Non-toxic concentrations of NFV (1.25–5 μM) could reverse Adriamycin (ADR), colchicine, paclitaxel, and imatinib resistance of K562/ADR cells, with reversal indexes of up to 10.8, 7.4, 57, and 9.3, respectively. NFV inhibited P-gp efflux function, as evidenced by the significant increase in the intracellular accumulation of ADR and Rho-123, without affecting P-gp protein and mRNA expression levels. Further ATP content detection and molecular docking simulations showed that NFV could decrease intracellular ATP content and has a high affinity with the active functional regions of P-gp, respectively. When co-administered with ADR, NFV increased intracellular reactive oxygen species as well as blocked the ERK/Akt signaling pathway, leading to cell apoptosis. Conclusion: NFV inhibited P-gp function, decreased intracellular ATP content, and promoted cell apoptosis in K562/ADR cells, thereby reversing MDR. These findings encourage further animal and clinical MDR studies with a combination therapy consisting of NFV and chemotherapeutic drugs.
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Doualla-Bell, Florence, Ava Avalos, Tendani Gaolathe, Madisa Mine, Simani Gaseitsiwe, Ndwapi Ndwapi, Vladimir A. Novitsky, et al. "Impact of Human Immunodeficiency Virus Type 1 Subtype C on Drug Resistance Mutations in Patients from Botswana Failing a Nelfinavir-Containing Regimen." Antimicrobial Agents and Chemotherapy 50, no. 6 (June 2006): 2210–13. http://dx.doi.org/10.1128/aac.01447-05.
Повний текст джерелаАнотація:
ABSTRACT Among 16 human immunodeficiency virus-infected (subtype C) Batswana patients who failed nelfinavir (NFV)-containing regimens, the most prevalent mutation observed was D30N (54%), followed by L90M (31%). L89I, K20T/I, and E35D polymorphic changes were also identified. These findings suggest that subtype C viruses in Botswana may develop resistance to NFV via subtype-specific pathways.
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Atkinson, B., J. Isaacson, M. Knowles, E. Mazabel, and A. K. Patick. "Correlation between Human Immunodeficiency Virus Genotypic Resistance and Virologic Response in Patients Receiving Nelfinavir Monotherapy or Nelfinavir with Lamivudine and Zidovudine." Journal of Infectious Diseases 182, no. 2 (August 2000): 420–27. http://dx.doi.org/10.1086/315726.
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Ziermann, Rainer, Kay Limoli, Kalyan Das, Edward Arnold, Christos J. Petropoulos, and Neil T. Parkin. "A Mutation in Human Immunodeficiency Virus Type 1 Protease, N88S, That Causes In Vitro Hypersensitivity to Amprenavir." Journal of Virology 74, no. 9 (May 1, 2000): 4414–19. http://dx.doi.org/10.1128/jvi.74.9.4414-4419.2000.
Повний текст джерелаАнотація:
ABSTRACT Amprenavir (Agenerase, 141-W94, VX-478) is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PRI) recently approved for the treatment of HIV-1 infection in the United States. A major cause of treatment failure is the development of resistance to PRIs. One potential use for amprenavir is as salvage therapy for patients for whom treatment that includes one (or more) of the other four currently approved PRIs—saquinavir, indinavir, ritonavir, and nelfinavir—has failed. We evaluated the cross-resistance to amprenavir of viruses that evolved during treatment with the two most commonly prescribed PRIs, nelfinavir and indinavir. Unexpectedly, a dramatic increase in susceptibility (2.5- to 12.5-fold) was observed with 20 of 312 (6.4%) patient viruses analyzed. The most pronounced increases in susceptibility were strongly associated with an N88S mutation in protease. All viruses that carried the N88S mutation were hypersensitive to amprenavir. Site-directed mutagenesis studies confirmed the causal role of N88S in determining amprenavir hypersensitivity. The presence of the N88S mutation and associated amprenavir hypersensitivity may be useful in predicting an improved clinical response to amprenavir salvage therapy.
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Walter, Hauke, Barbara Schmidt, Astrid Rascu, Martin Helm, Brigitte Moschik, Christiane Paatz, Michael Kurowski, Klaus Korn, Klaus Überla, and Thomas Harrer. "Phenotypic HIV-1 Resistance Correlates with Treatment Outcome of Nelfinavir Salvage Therapy." Antiviral Therapy 5, no. 4 (May 1, 1999): 249–56. http://dx.doi.org/10.1177/135965350000500403.
Повний текст джерелаАнотація:
In order to analyse whether drug sensitivity testing would be beneficial for clinical decision-making in heavily pretreated patients, we retrospectively studied viral genotype and phenotypic drug resistance in 12 HIV-1-infected patients, each of them with a history of failing at least one therapeutic regimen including one or two protease inhibitors (PIs). The salvage therapy included nelfinavir as new PI in all cases. Four patients showed a sustained and five patients a transient viral load decrease. Three patients failed to show a significant decline of plasma HIV-1 RNA. In the baseline samples of these cases, resistance against all components of their combination therapy could be detected, whereas at least one antiretroviral drug was still active in the cases with transient treatment response. All patients with sustained therapy response harboured viruses that were either fully sensitive or resistant to only one of the drugs administered. In our study, phenotypic drug resistance was predictive for the success of antiretroviral salvage regimens.
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Bakker, Andreas. "Predictive Value of Genotypic and Phenotypic Resistance in 2 Nelfinavir‐Experienced Patients." Journal of Infectious Diseases 181, no. 5 (May 2000): 1862–63. http://dx.doi.org/10.1086/315480.
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Rufo, Paul A., Patricia W. Lin, Adriana Andrade, Lianwei Jiang, Lucia Rameh, Charles Flexner, Seth L. Alper, and Wayne I. Lencer. "Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling." American Journal of Physiology-Cell Physiology 286, no. 5 (May 2004): C998—C1008. http://dx.doi.org/10.1152/ajpcell.00357.2003.
Повний текст джерелаАнотація:
Aspartyl protease inhibitors (APIs) effectively extend the length and quality of life in human immunodeficiency virus (HIV)-infected patients, but dose-limiting side effects such as lipodystrophy, insulin resistance, and diarrhea have limited their clinical utility. Here, we show that the API nelfinavir induces a secretory form of diarrhea in HIV-infected patients. In vitro studies demonstrate that nelfinavir potentiates muscarinic stimulation of Cl- secretion by T84 human intestinal cell monolayers through amplification and prolongation of an apical membrane Ca2+-dependent Cl- conductance. This stimulated ion secretion is associated with increased magnitude and duration of muscarinically induced intracellular Ca2+ transients via activation of a long-lived, store-operated Ca2+ entry pathway. The enhanced intracellular Ca2+ signal is associated with uncoupling of the Cl- conductance from downregulatory intracellular mediators generated normally by muscarinic activation. These data show that APIs modulate Ca2+ signaling in secretory epithelial cells and identify a novel target for treatment of clinically important API side effects.
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Gonzalez, Luis M. F., Rodrigo M. Brindeiro, Renato S. Aguiar, Helena S. Pereira, Celina M. Abreu, Marcelo A. Soares, and Amilcar Tanuri. "Impact of Nelfinavir Resistance Mutations on In Vitro Phenotype, Fitness, and Replication Capacity of Human Immunodeficiency Virus Type 1 with Subtype B and C Proteases." Antimicrobial Agents and Chemotherapy 48, no. 9 (September 2004): 3552–55. http://dx.doi.org/10.1128/aac.48.9.3552-3555.2004.
Повний текст джерелаАнотація:
ABSTRACT Human immunodeficiency virus type 1 subtype B and C proteases were manipulated to contain 90M, 88D, or 89L, and their in vitro biological properties were studied. We showed that D30N has significantly more impact in subtype C than in subtype B counterparts, accounting for the reported low prevalence of this mutation in patients failing nelfinavir-based regimens.
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Pellegrin, Isabelle, Dominique Breilh, François Montestruc, Anne Caumont, Isabelle Garrigue, Philippe Morlat, Cécile Le Camus, Marie-Claude Saux, Hervé J. A. Fleury, and Jean-Luc Pellegrin. "Virologic response to nelfinavir-based regimens: pharmacokinetics and drug resistance mutations (VIRAPHAR study)." AIDS 16, no. 10 (July 2002): 1331–40. http://dx.doi.org/10.1097/00002030-200207050-00004.
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Antunes, Dinler A., Maurício M. Rigo, Marialva Sinigaglia, Rúbia M. de Medeiros, Dennis M. Junqueira, Sabrina E. M. Almeida, and Gustavo F. Vieira. "New Insights into the In Silico Prediction of HIV Protease Resistance to Nelfinavir." PLoS ONE 9, no. 1 (January 31, 2014): e87520. http://dx.doi.org/10.1371/journal.pone.0087520.
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Quiros-Roldan, E., F. Moretti, C. Torti, V. Tirelli, S. Casari, and G. Carosi. "HIV-1 genotype resistance pattern and evolution in patients failing nelfinavir-containing regimens." Journal of Clinical Laboratory Analysis 19, no. 1 (2005): 26–29. http://dx.doi.org/10.1002/jcla.20051.
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Gonsalves, Wilson I., Shaji Kumar, Gabriela Perez, Stephanie Saathoff, Diana M. Wilson, Anna Young, and Sikander Ailawadhi. "Trial in Progress: Phase I Open-Label Study of Metformin and Nelfinavir in Combination with Bortezomib in Patients with Relapsed and/or Refractory Multiple Myeloma." Blood 138, Supplement 1 (November 5, 2021): 2735. http://dx.doi.org/10.1182/blood-2021-149437.
Повний текст джерелаАнотація:
Abstract Background: GLUT4 inhibition is an attractive therapeutic option in multiple myeloma (MM) given the dependence of MM cells on glucose transport. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor in MM cells to counter the possibility of therapeutic resistance to GLUT4 inhibition has demonstrated synergistic promise (Dalva-Aydemir et al, Clin Can Res 2015). Using a GLUT4 inhibitor such as the HIV protease inhibitor nelfinavir is an attractive choice since it not only inhibits the transport function of GLUT4, but it also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (Driessen et al, Blood 2018). Thus, in summary the FDA-approved oral HIV-PI nelfinavir, long used for the treatment of HIV disease, can bind to glucose transporters (GLUT4) on MM cells and reversibly inhibit glucose uptake, thus disrupting the Warburg effect. Nelfinavir can also enhance the activity of PIs such as bortezomib overcome its resistance in MM cells. Metformin, an oral FDA-approved drug for the treatment of Type II Diabetes has the ability to disrupt the electron transport chain of defective mitochondria within MM cells, thus blocking the ability of such mitochondria to generate energy and anabolic substrates as compensatory mechanisms required for proliferation in the setting of GLUT4 inhibition. Thus, this study will look at the safety and tolerability of repurposing the existing FDA-approved drugs for Type II diabetes and HIV in combination with bortezomib for the treatment of relapsed and/or refractory myeloma. Methods: This study is a phase 1 clinical trial of metformin and nelfinavir in combination with bortezomib for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design with 3 dose levels planned. Part B is a dose expansion cohort at the Maximal Tolerated Dose (MTD) determined in Part A. Up to a maximum of 36 patients will be enrolled and treated for a maximum of six 21-day cycles. Bortezomib is administered in its usual weekly subcutaneous dosing schedule of days 1, 8 and 15 of a 21-day cycle at a dose level of 1.3 mg/m2. Metformin will be administered for 14 days of a 21-day cycle and started at a dose level of 500 mg twice daily and will be investigated to a maximum dose of 1000 mg twice daily. Nelfinavir will also be administered for 14 days of a 21-day cycle and started at a dose level of 1250 mg twice daily and will be investigated to a maximum dose of 2500 mg twice daily. Key inclusion criteria include having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, adequate hematologic reserve, kidney function and liver function. This trial especially allows patients with non-secretory disease yet measurable by bone marrow assessments or cross-sectional imaging of plasmacytomas to be enrolled which constitutes an unmet need in the real-world MM population. Finally, this allows patients to be treated with a dexamethasone-free regimen. The primary objective of this trial is to determine the MTD of metformin and nelfinavir in combination with bortezomib. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated with this combination. Potential predictive biomarkers as well as resistance mechanisms using genomic RNA, immunohistochemistry and metabolomics-based assessment platforms will be evaluated in this study. Recruitment is ongoing with no safety concerns. This trial is registered on clinicaltrials.gov: NCT03829020. This investigator-initiated trial was funded by the generous gift of the Helen Diller Family Foundation. Disclosures Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Novartis: Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.
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Chandler, Becky, Maria Detsika, Andrew Owen, Sorcha Evans, Ruben C. Hartkoorn, Patricia A. Cane, David J. Back, and Saye H. Khoo. "Effect of Transporter Modulation on the Emergence of Nelfinavir Resistance In Vitro." Antiviral Therapy 12, no. 5 (July 2007): 831–34. http://dx.doi.org/10.1177/135965350701200515.
Повний текст джерелаАнотація:
Background HIV drug resistance is of increasing concern and could result from inadequate drug potency, poor therapy adherence and the existence of pharmacological sanctuary sites for viral replication. One contributing factor to the generation of such sites could be drug efflux transporters, which have been shown capable of effluxing HIV protease inhibitors from cells. Methods In this ‘proof-of-concept’ study, the ability of the efflux transport inhibitor verapamil to modulate the intracellular accumulation of radiolabeled nelfinavir (NFV) and the antiviral effect of NFV was assessed in MT4 cells. Wild-type virus was then serially passaged with increasing concentrations of NFV with and without verapamil and resistance mutations monitored by sequencing of the viral protease gene. Results The cellular accumulation ratio of 3H-NFV was 116.8 ±9.7 in controls and was significantly increased to 149.8 ±24.5 following incubation with verapamil (P<0.05, n=4). The EC50 of NFV was decreased in MT4 cells in the presence of verapamil from 8.5 ±1.3 nM to 4.4 ±0.8 nM ( P<0.001, n=6). Of the 24 isolates passaged without verapamil, 21 carried the D30N mutation at detectable levels. Of the 23 passaged with verapamil, 14 carried the mutation (odds ratio=4.5; P<0.05). Conclusions These results suggest that ‘intracellular boosting’ of PIs is achievable through inhibition of drug efflux proteins in vitro and that such boosting has the ability to enhance suppression of viral replication, slowing the emergence of resistance mutations.
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Kumar, Pranav, Robert Lodge, Frédéric Raymond, Jean-François Ritt, Pascal Jalaguier, Jacques Corbeil, Marc Ouellette, and Michel J. Tremblay. "Gene expression modulation and the molecular mechanisms involved in Nelfinavir resistance inLeishmania donovaniaxenic amastigotes." Molecular Microbiology 89, no. 3 (July 5, 2013): 565–82. http://dx.doi.org/10.1111/mmi.12298.
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Svedhem, Veronica, A. Lindkvist, T. Bergroth, Lidman Knut, and A. Sönnerborg. "Diverse pattern of protease inhibitor resistance mutations in HIV-1 infected patients failing nelfinavir." Journal of Medical Virology 76, no. 4 (2005): 447–51. http://dx.doi.org/10.1002/jmv.20381.
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Chandra, Surabhi, Subramanyam N. Murthy, Debasis Mondal, and Krishna C. Agrawal. "Therapeutic effects of Nigella sativa on chronic HAART-induced hyperinsulinemia in ratsThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue)." Canadian Journal of Physiology and Pharmacology 87, no. 4 (April 2009): 300–309. http://dx.doi.org/10.1139/y09-014.
Повний текст джерелаАнотація:
Prolonged use of highly active antiretroviral therapy (HAART) is associated with insulin resistance in HIV-1-positive patients. Small animal models that recapitulate the long-term effects of HAART may facilitate the identification of therapeutic agents to suppress these side effects. We investigated the protective effects of black seed oil (BSO) from Nigella sativa in Sprague–Dawley rats treated with a daily HAART regimen for 7 months. The antiretroviral drugs, consisting of nelfinavir (200 mg/kg), zidovudine (50 mg/kg), and efavirenz (20 mg/kg), were mixed with diet with or without BSO (400 µL/kg) supplementation. Significant increases in insulin and C-peptide levels were observed in HAART-treated groups, and concomitant BSO treatment reduced this hyperinsulinemia. Interestingly, HAART-treated rats showed reduced size of pancreatic islets that was not seen in BSO-exposed rats. In vitro studies showed that nelfinavir, alone and in combination with HAART, induced oxidative stress and decreased glucose-induced insulin production in INS-1 cells. Suppressed insulin production was restored in cells coexposed to either BSO or thymoquinone. Our findings demonstrated that chronic HAART may increase serum insulin levels by dysregulating both insulin production by β cells and insulin action at the periphery. These deleterious effects may be prevented by dietary supplementation with BSO.
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Driessen, Christoph, Jürgen Bader, Marianne Kraus, Markus Jörger, Hilde Rosing, Gregoire Berthod, Felicitas Hitz, et al. "SAKK 65/08: A Phase I Dose Escalation Study of Bortezomib in Combination with Nelfinavir in Patients with Advanced Hematologic Malignancies." Blood 124, no. 21 (December 6, 2014): 4747. http://dx.doi.org/10.1182/blood.v124.21.4747.4747.
Повний текст джерелаАнотація:
Abstract Rationale: Overcoming proteasome inhibitor (PI) resistance is a challenge in multiple myeloma (MM) therapy since most MM patients ultimately develop PI resistance. Induction of excessive activation of the unfolded protein response (UPR) is the major mechanism of PI-induced cytotoxicity in MM. The UPR is a complex transcriptional response that balances biosynthesis, folding and proteasomal destruction of cellular protein. UPR inactivation results in PI resistance in vitro, and MM cells with low UPR activation accumulate and drive the relapse in PI-resistant MM patients. Pharmacologic activation of the UPR overcomes PI-resistance in preclinical models of MM and provides an option for clinical testing. The HIV protease inhibitor nelfinavir (NFV) has UPR-inducing activity via an unknown mechanism that may involve interference with regulatory proteases in the UPR and/or proteasome activity. NFV has single agent activity in MM and sensitizes MM and AML cells for PI treatment in vitro and in vivo. Methods: We performed a multicenter phase I dose escalation study to assess safety and recommended dose for phase II of NFV in combination with bortezomib (BTZ) in patients with advanced hematologic malignancies, and to detect signals for activity. NFV was given d 1-14 twice daily p.o. at the dose levels 1250 mg (DL0), 1875 mg (DL1) and 2500 mg (DL2), BTZ was dosed 1.3 mg/m2 d 1, 4, 8, 11 i.v. in 21 day cycles. The first treatment cycle was preceded by one week of NFV monotherapy for assessment of pharmacokinetic/pharmacodynamic parameters (NFV plasma concentrations, proteasome activity and expression of UPR-related proteins in peripheral blood mononuclear cells (PBMC)). Patients were treated for 3 cycles per protocol with the option to receive up to a total of 7 cycles. Results: 12 patients were treated in the dose escalation cohort (median age 58 years; 8 patients with MM, 1 each with ALL, AML, DLBCL, MCL) for an average of 2.6 cycles. All MM patients had received prior BTZ. DLT was determined in cycle 1 in which 93 % of planned dose was delivered. One DLT was observed (G4 ALT elevation at DL2 that spontaneously resolved). Toxicity was mostly mild, could be handled symptomatically, and did not lead to study drug discontinuation except for one case of thrombocytopenia. Diarrhoea G1-2 was the most frequent toxicity observed. Ten patients were evaluable for best response while on trial therapy after having received at least one full cycle. Of these, three patients achieved a PR (1 MCL, 2 MM), 4 remained in SD for at least 2 cycles (2 MM, 1 AML, 1 ALL), while 3 progressed (2 MM, 1 DLBCL). Peak NFV plasma concentrations during monotherapy were in the dose range putatively required for UPR activation, tended to be higher in patients treated at DL1, compared to DL2 (means 13.3 vs. 8.9 mM, p=0.08) and were significantly higher during NFV monotherapy than during combination therapy with BTZ (means 9.24 vs. 6.60 mM, p=0.04), suggesting induction of NFV clearance either by autoinduction, concomitant BTZ application, or both. Pharmacodynamic analysis revealed upregulation of proteins related to UPR-induced apoptosis by NFV monotherapy in PBMC (CHOP +56%, p=0.008; PARP +57%, p=0.04, n=10). Activity of the BTZ-insensitive proteasome b2 subunit in PBMC decreased (-16%, p=0.01) during NFV monotherapy, compared to baseline, as did the BTZ-sensitive b1/b5 subunit (-17%, p=0.001). To detect additional signals for activity, an extension cohort of 6 heavily pretreated MM patients that had shown BTZ-resistance during the past 12 months and were in addition lenalidomide-resistant was treated at the recommended dose (DL2). Three of these patients achieved a PR and 2 a MR, while 1 showed PD with a mean of 4.3 cycles administered. Overall, 12 MM patients could be evaluated for best response while on therapy with BTZ + NFV in this study, of which 5 achieved a paraprotein reduction of > 50% compared to baseline (figure 1). Conclusion: Nelfinavir 2500 mg p.o. twice daily induces UPR activation and proteasome inhibition. It can safely be combined with bortezomib (1.3 mg/m2 d 1, 4, 8, 11) to potentially increase bortezomib sensitivity of hematologic malignancies. The combination yields promising clinical activity signals in patients with bortezomib-resistant myeloma. Figure 1: Best paraprotein response, relative to baseline, of evaluable patients with relapsed-refractory myeloma treated with bortezomib + nelfinavir at any dose level for at least one full cycle. Figure 1:. Best paraprotein response, relative to baseline, of evaluable patients with relapsed-refractory myeloma treated with bortezomib + nelfinavir at any dose level for at least one full cycle. Disclosures Off Label Use: the presentation will include off label use of nelfinavir as investigational medicinal product (IMP). Hitz:Celgene: Research Funding.
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Snoeck, Joke, Rami Kantor, Robert W. Shafer, Kristel Van Laethem, Koen Deforche, Ana Patricia Carvalho, Brian Wynhoven, et al. "Discordances between Interpretation Algorithms for Genotypic Resistance to Protease and Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Are Subtype Dependent." Antimicrobial Agents and Chemotherapy 50, no. 2 (February 2006): 694–701. http://dx.doi.org/10.1128/aac.50.2.694-701.2006.
Повний текст джерелаАнотація:
ABSTRACT The major limitation of drug resistance genotyping for human immunodeficiency virus remains the interpretation of the results. We evaluated the concordance in predicting therapy response between four different interpretation algorithms (Rega 6.3, HIVDB-08/04, ANRS [07/04], and VGI 8.0). Sequences were gathered through a worldwide effort to establish a database of non-B subtype sequences, and demographic and clinical information about the patients was gathered. The most concordant results were found for nonnucleoside reverse transcriptase (RT) inhibitors (93%), followed by protease inhibitors (84%) and nucleoside RT inhibitor (NRTIs) (76%). For therapy-naive patients, for nelfinavir, especially for subtypes C and G, the discordances were driven mainly by the protease (PRO) mutational pattern 82I/V + 63P + 36I/V for subtype C and 82I + 63P + 36I + 20I for subtype G. Subtype F displayed more discordances for ritonavir in untreated patients due to the combined presence of PRO 20R and 10I/V. In therapy-experienced patients, subtype G displayed a lot of discordances for saquinavir and indinavir due to mutational patterns involving PRO 90 M and 82I. Subtype F had more discordance for nelfinavir attributable to the presence of PRO 88S and 82A + 54V. For the NRTIs lamivudine and emtricitabine, CRF01_AE had more discordances than subtype B due to the presence of RT mutational patterns 65R + 115 M and 118I + 215Y, respectively. Overall, the different algorithms agreed well on the level of resistance scored, but some of the discordances could be attributed to specific (subtype-dependent) combinations of mutations. It is not yet known whether therapy response is subtype dependent, but the advice given to clinicians based on a genotypic interpretation algorithm differs according to the subtype.
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Casado, Jose L., Santiago Moreno, Kurt Hertogs, Fernando Dronda, Antonio Antela, Pascale Dehertogh, María J. Perez-Elías, and Ana Moreno. "Plasma drug levels, genotypic resistance, and virological response to a nelfinavir plus saquinavir-containing regimen." AIDS 16, no. 1 (January 2002): 47–52. http://dx.doi.org/10.1097/00002030-200201040-00007.
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Kakehasi, Fabiana M., Unaí Tupinambás, Silvia Cleto, Agdemir Aleixo, Elisa Lin, Victor H. Melo, Regina A. L. P. Aguiar, and Jorge A. Pinto. "Persistence of Genotypic Resistance to Nelfinavir among Women Exposed to Prophylactic Antiretroviral Therapy during Pregnancy." AIDS Research and Human Retroviruses 23, no. 12 (December 2007): 1515–20. http://dx.doi.org/10.1089/aid.2007.0025.
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Kraus, M., J. Bader, H. Overkleeft, and C. Driessen. "Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance." Blood Cancer Journal 3, no. 3 (March 2013): e103-e103. http://dx.doi.org/10.1038/bcj.2013.2.
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Lagathu, Claire, Brenda Eustace, Matthieu Prot, Dan Frantz, Yong Gu, Jean-Philippe Bastard, Mustapha Maachi, et al. "Some HIV Antiretrovirals Increase Oxidative Stress and Alter Chemokine, Cytokine or Adiponectin Production in Human Adipocytes and Macrophages." Antiviral Therapy 12, no. 4 (May 2007): 489–500. http://dx.doi.org/10.1177/135965350701200407.
Повний текст джерелаАнотація:
Objectives Adipose tissue from patients with HIV-related lipodystrophy presents a state of chronic inflammation. Altered expression of cytokines/adipokines and macrophage infiltration could be involved in patients’ insulin resistance and lipoatrophy. We tested whether antiretrovirals affected adipokine release by human subcutaneous adipocytes and cytokine/chemokine production by human macrophages and examined whether reactive oxygen species (ROS) hyperproduction was related to the effect of antiretrovirals. Methods Differentiated human adipocytes and PMA-THP-1 macrophages were treated with protease inhibitors (PIs: indinavir, nelfinavir, amprenavir, lopinavir, ritonavir and atazanavir) or nucleoside reverse transcriptase inhibitors (NRTIs: stavudine, zidovudine and abacavir) for 24–48 h without or with diphenylene iodonium (DPI), an inhibitor of oxidative stress. Lipid content was assessed by Oil Red O staining and ROS production by nitroblue tetrazolium (NBT) reduction. Cytokine/chemokines, adiponectin and leptin release was evaluated by ELISA or multiplex assays. Results In human adipocytes, PIs and NRTIs (except amprenavir, atazanavir and abacavir) reduced lipid content, adiponectin and leptin release and increased in parallel ROS production and monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 release. The effects of PIs, but not of NRTIs, were prevented by the addition of DPI. In PMA-THP-1 macrophages, all PIs, but no NRTI, increased macrophage inflammatory protein-1α and MCP-1 release. Lopinavir, nelfinavir, zidovudine and stavudine markedly increased ROS production and release of IL-1β and tumour necrosis factor-α. Conclusions Some PIs altered adipokine secretion and lipid content through ROS production in human subcutaneous adipocytes. Thymidine analogues altered adipocyte functions but their effect on adipokine secretion was not reverted by ROS production inhibition. Increased chemokine/cytokine production by adipocytes and macrophages could be involved in macrophage recruitment and participate in lipoatrophy and insulin resistance.
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Kim, Sanggu, Yun-Cheol Kim, Hangfei Qi, Kunkai Su, Sherie L. Morrison, and Samson A. Chow. "Efficient Identification of Human Immunodeficiency Virus Type 1 Mutants Resistant to a Protease Inhibitor by Using a Random Mutant Library." Antimicrobial Agents and Chemotherapy 55, no. 11 (August 29, 2011): 5090–98. http://dx.doi.org/10.1128/aac.00687-11.
Повний текст джерелаАнотація:
ABSTRACTEmergence of drug-resistant mutant viruses during the course of antiretroviral therapy is a major hurdle that limits the success of chemotherapeutic treatment to suppress human immunodeficiency virus type 1 (HIV-1) replication and AIDS progression. Development of new drugs and careful patient management based on resistance genotyping data are important for enhancing therapeutic efficacy. However, identifying changes leading to drug resistance can take years of clinical studies, and conventionalin vitroassays are limited in generating reliable drug resistance data. Here we present an efficientin vitroscreening assay for selecting drug-resistant variants from a library of randomly mutated HIV-1 strains generated by transposon-directed base-exchange mutagenesis. As a test of principle, we screened a library of mutant HIV-1 strains containing random mutations in the protease gene by using a reporter T-cell line in the presence of the protease inhibitor (PI) nelfinavir (NFV). Analysis of replicating viruses from a single round of infection identified 50 amino acid substitutions at 35 HIV-1 protease residue positions. The selected mutant viruses showed specific resistance to NFV and included most of the known NFV resistance mutations. Therefore, the new assay is efficient for identifying changes leading to drug resistance. The data also provide insights into the molecular mechanisms underlying the development of drug resistance.