The Experts below are selected from a list of 1743 Experts worldwide ranked by ideXlab platform
Cundong Fan - One of the best experts on this subject based on the ideXlab platform.
-
natural borneol is a novel Chemosensitizer that enhances temozolomide induced anticancer efficiency against human glioma by triggering mitochondrial dysfunction and reactive oxide species mediated oxidative damage
OncoTargets and Therapy, 2018Co-Authors: Wenjian Liu, Yibo Yin, Jingyi Sun, Sai Feng, Yajun Hou, Mingfeng Yang, Baoliang Sun, Cundong FanAbstract:Background Temozolomide (TMZ)-based chemotherapy represents an effective way for treating human glioma. However, its clinical application is limited because of its side effects and resistance to standard chemotherapy. Hence, the search for novel Chemosensitizers to augment their anticancer efficiency has attracted much attention. Natural borneol (NB) has been identified as a potential Chemosensitizer in treating human cancers. However, the synergistic effect and mechanism of NB and TMZ in human glioma have not been investigated yet. Materials and methods U251 human glioma cells were cultured, and the cytotoxicity and apoptosis of NB and/or TMZ were examined by MTT assay, flow cytometric analysis and Western blot. Nude mice tumor model was also employed to evaluate the in vivo anticancer effect and mechanism. Results The results showed that the combined treatment of NB and TMZ more effectively inhibited human glioma growth via triggering mitochondria-mediated apoptosis in vitro, accompanied by the caspase activation. Combined treatment of NB and TMZ also caused mitochondrial dysfunction through disturbing Bcl-2 family expression. Further investigation revealed that NB enhanced TMZ-induced DNA damage through inducing reactive oxide species (ROS) overproduction. Moreover, glioma tumor xenograft growth in vivo was more effectively inhibited by the combined treatment with NB and TMZ through triggering apoptosis and anti-angiogenesis. Conclusion Taken together, our findings validated that the strategy of using NB and TMZ could be a highly efficient way to achieve anticancer synergism.
Guillaume M Wientjes - One of the best experts on this subject based on the ideXlab platform.
-
nontoxic suramin as a Chemosensitizer in patients dosing nomogram development
Pharmaceutical Research, 2006Co-Authors: Danny Chen, Guillaume M Wientjes, Sae Heum Song, Teng Kuang Yeh, Liang Zhao, Gregory A. Otterson, Rhonda Jensen, Michael Grever, Miguel A Villalonacalero, Anthony J. MurgoAbstract:Purpose We reported that suramin produced chemosensitization at nontoxic doses. This benefit was lost at the approximately 10-fold higher, maximally tolerated doses (MTD). The aim of the current study was to identify in patients the chemosensitizing suramin dose that delivers 10-50 microM plasma concentrations over 48 h. Methods Nonsmall cell lung cancer patients were given suramin, paclitaxel, and carboplatin, every 3 weeks. The starting chemosensitizing suramin dose was estimated based on previous results on MTD suramin in patients, and adjusted by using real-time pharmacokinetic monitoring. A dosing nomogram was developed by using population-based pharmacokinetic analysis of phase I results (15 patients, 85 treatment cycles), and evaluated in phase II patients (19 females, 28 males, 196 treatment cycles). Results The chemosensitizing suramin dose showed a terminal half-life of 202 h and a total body clearance of 0.029 L h(-1) m(-2) (higher than the 0.013 L h(-1) m(-2) value for MTD of suramin). The dosing nomogram, incorporating body surface area as the major covariate of intersubject variability and the time elapsed since the previous dose (to account for the residual concentrations due to the slow elimination), delivered the target concentrations in >95% of treatments. Conclusions The present study identified and validated a dosing nomogram and schedule to deliver low and nontoxic suramin concentrations that produce chemosensitization in preclinical models.
-
suramin as a Chemosensitizer oral pharmacokinetics in rats
Pharmaceutical Research, 2004Co-Authors: Adam Ogden, Guillaume M WientjesAbstract:Purpose. The purpose of this study was to determine if the 10-50 μM plasma concentrations of suramin required to produce chemosensitization could be achieved by oral administration.
-
population pharmacokinetics of low dose suramin as a Chemosensitizer in pet dogs with naturally occurring tumors
Cancer Research, 2004Co-Authors: Carrie E Koserek, Guillermo C Couto, Danny Chen, William C Kisseberth, Guillaume M WientjesAbstract:2003 Suramin is an inhibitor of multiple growth factors including fibroblast growth factors. Our preclinical in vitro and in vivo studies showed that suramin reversed FGF-induced chemoresistance in a narrow therapeutic range from ∼ 10-50 μM, with antagonism at higher concentrations. Suramin is currently under investigation in a Phase II trial as a Chemosensitizer in human non-small cell lung cancer patients treated with standard chemotherapy (paclitaxel plus carboplatin). A separate phase I/II trial evaluates the effectiveness of low dose suramin in pet dogs with naturally occurring tumors. The present study was to determine the pharmacokinetics of suramin in dogs, in order to identify the target suramin dose, in combination with chemotherapy. Eighteen dogs with late stage carcinoma, hemangiopericytoma, hemangiosarcoma or lymphoma were treated with suramin in combination with doxorubicin, receiving a total of 53 courses. Suramin was given at a fixed dose of 6.75 mg/kg as a 20-min infusion, and doxorubicin was given 3 hr later as 20-30 min infusion at a dose of 30 mg/m2 (or 1 mg/kg for body weight below 15 kg). The suramin pharmacokinetic data were analyzed using a nonlinear mixed-effect model (NONMEM) with a one-compartment model. The physiological parameters evaluated were age, body weight, body surface area (BSA), and gender. PBPK analysis of data obtained from 13 patients who received more than one treatment showed significant correlations between suramin clearance (CL) and BSA, CL and body weight, and volume of distribution (V) and BSA. Incorporation of the remaining covariates into the model did not significantly improve the model performance. These results led to a BSA-based suramin dose calculation method for individual patients, thereby eliminating the need of real-time pharmacokinetic monitoring for the use of low dose suramin as a Chemosensitizer. Supported by R01CA 91457 and R01CA78577, NCI, NIH.
Jean-michel Bolla - One of the best experts on this subject based on the ideXlab platform.
-
Multiparametric Profiling for Identification of Chemosensitizers against Gram-Negative Bacteria
Frontiers in Microbiology, 2018Co-Authors: Vincent Lôme, Jean-michel Brunel, Jean-marie Pagès, Jean-michel BollaAbstract:Antibiotic resistance is now a worldwide therapeutic problem. Since the beginning of anti-infectious treatment bacteria have rapidly shown an incredible ability to develop and transfer resistance mechanisms. In the last decades, the design variation of pioneer bioactive molecules has strongly improved their activity and the pharmaceutical companies partly won the race against the clock. Since the 1980s, the new classes of antibiotics that emerged were mainly directed to Gram-positive bacteria. Thus, we are now facing to multidrug-resistant Gram-negative bacteria, with no therapeutic options to deal with them. These bacteria are mainly resistant because of their double membrane that conjointly impairs antibiotic accumulation and extrudes these molecules when entered. The main challenge is to allow antibiotics to cross the impermeable envelope and reach their targets. One promising solution would be to associate, in a combination therapy, a usual antibiotic with a non-antibiotic Chemosensitizer. Nevertheless, for effective drug discovery, there is a prominent lack of tools required to understand the rules of permeation and accumulation into Gram-negative bacteria. By the use of a multidrug-resistant enterobacteria, we introduce a high-content screening procedure for Chemosensitizers discovery by quantitative assessment of drug accumulation, alteration of barriers, and deduction of their activity profile. We assembled and analyzed a control chemicals library to perform the proof of concept. The analysis was based on real-time monitoring of the efflux alteration and measure of the influx increase in the presence of studied compounds in an automatized bio-assay. Then, synergistic activity of compounds with an antibiotic was studied and kinetic data reduction was performed which led to the calculation of a score for each barrier to be altered.
-
Table_2.PDF
2018Co-Authors: Vincent Lôme, Jean-michel Brunel, Jean-marie Pagès, Jean-michel BollaAbstract:Antibiotic resistance is now a worldwide therapeutic problem. Since the beginning of anti-infectious treatment bacteria have rapidly shown an incredible ability to develop and transfer resistance mechanisms. In the last decades, the design variation of pioneer bioactive molecules has strongly improved their activity and the pharmaceutical companies partly won the race against the clock. Since the 1980s, the new classes of antibiotics that emerged were mainly directed to Gram-positive bacteria. Thus, we are now facing to multidrug-resistant Gram-negative bacteria, with no therapeutic options to deal with them. These bacteria are mainly resistant because of their double membrane that conjointly impairs antibiotic accumulation and extrudes these molecules when entered. The main challenge is to allow antibiotics to cross the impermeable envelope and reach their targets. One promising solution would be to associate, in a combination therapy, a usual antibiotic with a non-antibiotic Chemosensitizer. Nevertheless, for effective drug discovery, there is a prominent lack of tools required to understand the rules of permeation and accumulation into Gram-negative bacteria. By the use of a multidrug-resistant enterobacteria, we introduce a high-content screening procedure for Chemosensitizers discovery by quantitative assessment of drug accumulation, alteration of barriers, and deduction of their activity profile. We assembled and analyzed a control chemicals library to perform the proof of concept. The analysis was based on real-time monitoring of the efflux alteration and measure of the influx increase in the presence of studied compounds in an automatized bio-assay. Then, synergistic activity of compounds with an antibiotic was studied and kinetic data reduction was performed which led to the calculation of a score for each barrier to be altered.
Wenjian Liu - One of the best experts on this subject based on the ideXlab platform.
-
natural borneol is a novel Chemosensitizer that enhances temozolomide induced anticancer efficiency against human glioma by triggering mitochondrial dysfunction and reactive oxide species mediated oxidative damage
OncoTargets and Therapy, 2018Co-Authors: Wenjian Liu, Yibo Yin, Jingyi Sun, Sai Feng, Yajun Hou, Mingfeng Yang, Baoliang Sun, Cundong FanAbstract:Background Temozolomide (TMZ)-based chemotherapy represents an effective way for treating human glioma. However, its clinical application is limited because of its side effects and resistance to standard chemotherapy. Hence, the search for novel Chemosensitizers to augment their anticancer efficiency has attracted much attention. Natural borneol (NB) has been identified as a potential Chemosensitizer in treating human cancers. However, the synergistic effect and mechanism of NB and TMZ in human glioma have not been investigated yet. Materials and methods U251 human glioma cells were cultured, and the cytotoxicity and apoptosis of NB and/or TMZ were examined by MTT assay, flow cytometric analysis and Western blot. Nude mice tumor model was also employed to evaluate the in vivo anticancer effect and mechanism. Results The results showed that the combined treatment of NB and TMZ more effectively inhibited human glioma growth via triggering mitochondria-mediated apoptosis in vitro, accompanied by the caspase activation. Combined treatment of NB and TMZ also caused mitochondrial dysfunction through disturbing Bcl-2 family expression. Further investigation revealed that NB enhanced TMZ-induced DNA damage through inducing reactive oxide species (ROS) overproduction. Moreover, glioma tumor xenograft growth in vivo was more effectively inhibited by the combined treatment with NB and TMZ through triggering apoptosis and anti-angiogenesis. Conclusion Taken together, our findings validated that the strategy of using NB and TMZ could be a highly efficient way to achieve anticancer synergism.
Alexis Nzila - One of the best experts on this subject based on the ideXlab platform.
-
In Vitro Chemosensitization of Plasmodium falciparum to Antimalarials by Verapamil and Probenecid
Antimicrobial agents and chemotherapy, 2009Co-Authors: Victor Masseno, Steven Muriithi, Alexis NzilaAbstract:We tested the effect of probenecid and verapamil in chemosensitizing Plasmodium falciparum to 14 antimalarials using the multidrug-resistant strain V1S and the drug-sensitive 3D7. Verapamil chemosensitizes V1S to quinine and chloroquine. Interestingly, probenecid profoundly chemosensitizes V1S to piperaquine. Thus, probenecid could be used to increase piperaquine efficacy in vivo.
-
Chemosensitization of Plasmodium falciparum by Probenecid In Vitro
Antimicrobial agents and chemotherapy, 2003Co-Authors: Alexis Nzila, Gilbert Kokwaro, Eddy Mberu, Patrick G. Bray, Peter Winstanley, Kevin Marsh, Steve A. WardAbstract:Resistance to drugs can result from changes in drug transport, and this resistance can sometimes be overcome by a second drug that modifies the transport mechanisms of the cell. This strategy has been exploited to partly reverse resistance to chloroquine in Plasmodium falciparum. Studies with human tumor cells have shown that probenecid can reverse resistance to the antifolate methotrexate, but the potential for reversal of antifolate resistance has not been studied in P. falciparum. In the present study we tested the ability of probenecid to reverse antifolate resistance in P. falciparum in vitro. Probenecid, at concentrations that had no effect on parasite viability alone (50 μM), was shown to increase the sensitivity of a highly resistant parasite isolate to the antifolates pyrimethamine, sulfadoxine, chlorcycloguanil, and dapsone by seven-, five-, three-, and threefold, respectively. The equivalent effects against an antifolate-sensitive isolate were activity enhancements of approximately 3-, 6-, 1.2-, and 19-fold, respectively. Probenecid decreased the level of uptake of radiolabeled folic acid, suggesting a transport-based mechanism linked to folate salvage. When probenecid was tested with chloroquine, it chemosensitized the resistant isolate to chloroquine (i.e., enhanced the activity of chloroquine). This enhancement of activity was associated with increased levels of chloroquine accumulation. In conclusion, we have shown that probenecid can chemosensitize malaria parasites to antifolate compounds via a mechanism linked to reduced folate uptake. Notably, this effect is observed in both folate-sensitive and -resistant parasites. In contrast to the activities of antifolate compounds, the effect of probenecid on chloroquine sensitivity was selective for chloroquine-resistant parasites (patent P407595GB [W. P. Thompson & Co., Liverpool, United Kingdom] has been filed to protect this intellectual property).