The Experts below are selected from a list of 120 Experts worldwide ranked by ideXlab platform
Liang Shun Wang - One of the best experts on this subject based on the ideXlab platform.
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reversal of inflammation associated dihydrodiol dehydrogenases akr1c1 and akr1c2 overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin
International Journal of Cancer, 2007Co-Authors: Liang Shun Wang, Hao Wei Wang, Kuan-chih Chow, Jen-hwey ChiuAbstract:Dihydrodiol dehydrogenase (DDH) is a member of the aldo-keto reductases superfamily (AKR1C1–AKR1C4), which plays central roles in the metabolism of steroid hormone, prostaglandin and xenobiotics. We have previously detected overexpression of DDH as an indicator of poor prognosis and chemoresistance in human non-small lung cancer (NSCLC). We also found DDH expression to be closely related to chronic inflammatory conditions. The aim of this study was to investigate the links between inflammation, DDH expression and drug resistance in NSCLC cells. We showed that pro-inflammatory mediators including interleukin-6 (IL-6) could induce AKR1C1/1C2 expression in NSCLC cells and increase cellular resistance to cisplatin and adriamycin. This effect was nullified by Safingol, a protein kinase C inhibitor. Moreover, the expression of AKR1C1/1C2 was inversely correlated to NBS1 and apoptosis-inducing factor (AIF). We also showed that IL-6-induced AKR1C1/1C2 expression and drug resistance were inhibited by wogonin and chrysin, which are major flavonoids in Scutellaria baicalensis, a widely used traditional Chinese and Japanese medicine. In conclusion, this study demonstrated novel links of pro-inflammatory signals, AKR1C1/1C2 expression and drug resistance in NSCLC. The protein kinase C pathway may play an important role in this process. Overexpression of AKR1C1/1C2 may serve as a marker of chemoresistance. Further studies are warranted to evaluate wogonin and chrysin as a potential adjuvant therapy for drug-resistant NSCLC, especially for those with AKR1C1/1C2 overexpression. © 2007 Wiley-Liss, Inc.
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reversal of inflammation associated dihydrodiol dehydrogenases akr1c1 and akr1c2 overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin
International Journal of Cancer, 2007Co-Authors: Liang Shun Wang, Hao Wei Wang, Kuan-chih Chow, Jen-hwey Chiu, Chin Ping Lin, Kuang Tai Kuo, Chen Sung LinAbstract:Dihydrodiol dehydrogenase (DDH) is a member of the aldo-keto reductases superfamily (AKR1C1-AKR1C4), which plays central roles in the metabolism of steroid hormone, prostaglandin and xenobiotics. We have previously detected overexpression of DDH as an indicator of poor prognosis and chemoresistance in human non-small lung cancer (NSCLC). We also found DDH expression to be closely related to chronic inflammatory conditions. The aim of this study was to investigate the links between inflammation, DDH expression and drug resistance in NSCLC cells. We showed that pro-inflammatory mediators including interleukin-6 (IL-6) could induce AKR1C1/1C2 expression in NSCLC cells and increase cellular resistance to cisplatin and adriamycin. This effect was nullified by Safingol, a protein kinase C inhibitor. Moreover, the expression of AKR1C1/1C2 was inversely correlated to NBS1 and apoptosis-inducing factor (AIF). We also showed that IL-6-induced AKR1C1/1C2 expression and drug resistance were inhibited by wogonin and chrysin, which are major flavonoids in Scutellaria baicalensis, a widely used traditional Chinese and Japanese medicine. In conclusion, this study demonstrated novel links of pro-inflammatory signals, AKR1C1/1C2 expression and drug resistance in NSCLC. The protein kinase C pathway may play an important role in this process. Overexpression of AKR1C1/1C2 may serve as a marker of chemoresistance. Further studies are warranted to evaluate wogonin and chrysin as a potential adjuvant therapy for drug-resistant NSCLC, especially for those with AKR1C1/1C2 overexpression.
Patrick C Reynolds - One of the best experts on this subject based on the ideXlab platform.
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hydrophilic interaction liquid chromatography tandem mass spectrometric approach for simultaneous determination of Safingol and d erythro sphinganine in human plasma
Journal of Chromatography B, 2019Co-Authors: Barry J. Maurer, Patrick C Reynolds, Min H KangAbstract:Abstract A simple and specific hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed for the simultaneous determination of C18-L-threo-sphinganine (Safingol, an anti-neoplastic in phase I trials) and its diastereomer, C18-D-erythro-sphinganine (sphinganine), in human plasma. Sample pretreatment involved a protein precipitation with methanol using 25 μL aliquots of plasma. Chromatographic separation of the diastereomers and C17-D-erythro-sphinganine, an internal standard, was achieved on a Xbridge HILIC (3.5 μm, 100 × 2.1 mm) using isocratic elution with the mobile phase of 2 mM ammonium bicarbonate in water (pH 8.3) and acetonitrile at a flow rate of 0.3 mL/min. Electrospray ionization (ESI) mass spectrometry was operated in the positive ion mode with multiple reaction monitoring (MRM). The calibration curves obtained were linear over the concentration range of 0.2–100 ng/mL with a lower limit of quantification of 0.2 ng/mL. The relative standard deviation of intra-day and inter-day precision was below 8.27%, and the accuracy ranged from 92.23 to 110.06%. The extraction recoveries were found to be higher than 93.22% and IS-normalized matrix effect was higher than 90.92%. The analytes were stable for the durations of the stability studies. The validated method was successfully applied to the analyses of pharmacokinetic samples from patients treated with Safingol and all-trans-N-(4-hydroxyphenyl)retinamide; (fenretinide, 4-HPR) in a current phase I clinical trial (SPOC-2010-002, ClinicalTrials.gov Identifier: NCT01553071 ).
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hydrophilic interaction liquid chromatography tandem mass spectrometric approach for simultaneous determination of Safingol and d erythro sphinganine in human plasma
Journal of Chromatography B, 2019Co-Authors: Barry J. Maurer, Patrick C Reynolds, Min H KangAbstract:Abstract A simple and specific hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed for the simultaneous determination of C18-L-threo-sphinganine (Safingol, an anti-neoplastic in phase I trials) and its diastereomer, C18-D-erythro-sphinganine (sphinganine), in human plasma. Sample pretreatment involved a protein precipitation with methanol using 25 μL aliquots of plasma. Chromatographic separation of the diastereomers and C17-D-erythro-sphinganine, an internal standard, was achieved on a Xbridge HILIC (3.5 μm, 100 × 2.1 mm) using isocratic elution with the mobile phase of 2 mM ammonium bicarbonate in water (pH 8.3) and acetonitrile at a flow rate of 0.3 mL/min. Electrospray ionization (ESI) mass spectrometry was operated in the positive ion mode with multiple reaction monitoring (MRM). The calibration curves obtained were linear over the concentration range of 0.2–100 ng/mL with a lower limit of quantification of 0.2 ng/mL. The relative standard deviation of intra-day and inter-day precision was below 8.27%, and the accuracy ranged from 92.23 to 110.06%. The extraction recoveries were found to be higher than 93.22% and IS-normalized matrix effect was higher than 90.92%. The analytes were stable for the durations of the stability studies. The validated method was successfully applied to the analyses of pharmacokinetic samples from patients treated with Safingol and all-trans-N-(4-hydroxyphenyl)retinamide; (fenretinide, 4-HPR) in a current phase I clinical trial (SPOC-2010-002, ClinicalTrials.gov Identifier: NCT01553071 ).
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simultaneous determination of Safingol and d erythro sphinganine in human plasma by lc with fluorescence detection
Chromatographia, 2010Co-Authors: Hardeep Singh, Patrick C Reynolds, Barry J. Maurer, Min H KangAbstract:l-threo-Sphinganine (Safingol) is a putative synthetic sphingosine kinase inhibitor currently being tested in clinical trials as an anticancer agent. To enable defining the pharmacokinetic properties of Safingol in humans, we developed a sensitive analytical method to simultaneously quantitate Safingol and its naturally-occurring diastereomer, d-erythro-sphinganine in human plasma. Of the two different fluorogenic derivatization agents (NDA and OPA) and several pH conditions compared for the derivatization, we found that NDA derivatization achieved more than 20 times greater sensitivity compared with OPA derivatization, and pH 9.0 showed the highest sensitivity for both compounds. An analytical method for liquid chromatography (LC) with a fluorescence detector (FLD) was developed and validated with calibration curve ranges of 20–1,000 ng mL−1 for Safingol and d-erythro-sphinganine. Our LC-FLD method using NDA-derivatization enabled simultaneous quantification of Safingol and its naturally-occurring diastereomer, d-erythro-sphinganine with satisfactory sensitivity in human plasma.
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a fluorescence microplate cytotoxicity assay with a 4 log dynamic range that identifies synergistic drug combinations
Molecular Cancer Therapeutics, 2007Co-Authors: Tomas Frgala, Ondrej Kalous, Robert T Proffitt, Patrick C ReynoldsAbstract:Purpose: Cytotoxicity assays in 96-well tissue culture plates allow rapid sample handling for multicondition experiments but have a limited dynamic range. Using DIMSCAN, a fluorescence digital image system for quantifying relative cell numbers in tissue culture plates, we have developed a 96-well cytotoxicity assay with a >4-log dynamic range. Methods: To overcome background fluorescence that limits detection of viable cells with fluorescein diacetate, we used 2′4′5′6′-tetrabromofluorescein (eosin Y) to quench background fluorescence in the medium and in nonviable cells to enhance the reduction of background fluorescence achieved with digital image thresholding. The sensitivity and linearity of the new assay were tested with serial dilutions of neuroblastoma and leukemia cell lines. DIMSCAN was compared with other in vitro cytotoxicity assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, and trypan blue dye exclusion. Results: Without background fluorescence reduction, scans produced a nearly flat curve across various cell concentrations from 100 to 106 cells per well. Either digital image thresholding or eosin Y dramatically reduced background fluorescence, and combining them achieved a linear correlation ( r > 0.9) of relative fluorescence to viable cell number over >4 logs of dynamic range, even in the presence of 4 × 104 nonviable cells per well. Cytotoxicity of deferoxamine for neuroblastoma cell lines measured by the DIMSCAN assay achieved dose-response curves similar to data obtained by manual trypan blue counts or colony formation in soft agar but with a wider dynamic range. Long-term cultures documented the clonogenic ability of viable cells detected by DIMSCAN over the entire dynamic range. The cytotoxicity of two drug combinations (buthionine sulfoximine + melphalan or fenretinide + Safingol) was tested using both DIMSCAN and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the wider dynamic range of DIMSCAN facilitated detection of synergistic interactions. Conclusion: DIMSCAN offers the ability to rapidly and efficiently conduct cytotoxicity assays in 96-well plates with a dynamic range of >4 logs. This assay enables rapid testing of anticancer drug combinations in microplates. [Mol Cancer Ther 2007;6(3):886–97]
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synergistic cytotoxicity in solid tumor cell lines between n 4 hydroxyphenyl retinamide and modulators of ceramide metabolism
Journal of the National Cancer Institute, 2000Co-Authors: Barry J. Maurer, Lisa Melton, Carolyn Billups, Myles C Cabot, Patrick C ReynoldsAbstract:BACKGROUND: We previously reported that N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) treatment caused large increases of ceramide levels in neuroblastoma cell lines and induced cell death by a combination of apoptosis and necrosis through p53 (also known as TP53)-independent and caspase-independent pathways. Our goal was to determine if several molecules that inhibit enzymes involved in ceramide metabolism-L-threo-dihydrosphingosine (Safingol), d, l-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP), and tamoxifen-enhanced 4-HPR-mediated cytotoxicity and/or affected ceramide levels. METHODS: Cellular lipids were quantified by radiolabeling and thin-layer chromatography. Cytotoxicity and cytotoxic synergy (expressed as combination index, where combination index 1 indicates antagonism) were measured in cultured cancer cell lines with the use of a fluorescence-based assay of cell viability employing digital imaging microscopy. Statistical tests were two-sided. RESULTS: 4-HPR increased ceramide levels by de novo synthesis. Safingol (1-4 microM) was incorporated into a stereochemical variant of ceramide and synergized with a 3:1 molar ratio of 4-HPR (3-12 microM), to produce a 100-fold to 10 000-fold (2 to 4 logs) increase in cytotoxicity relative to 4-HPR alone in neuroblastoma (combination index <0.1), lung (combination index <0.1-0.2), melanoma (combination index <0.1-0.2), prostate (combination index <0.1-1.0), colon (combination index 0.1-0.3), breast (combination index = 0.1-0.5), and pancreas (combination index = 0.2) cell lines, including p53 mutant and alkylator-resistant cell lines. The 4-HPR and Safingol combination was cytotoxic in low-oxygen conditions and was minimally toxic to normal fibroblasts and bone marrow myeloid progenitor cells. Addition of agents that retard ceramide glucosylation and/or acylation, such as PPMP or tamoxifen, to 4-HPR or to the combination of 4-HPR and Safingol further increased cytotoxicity to tumor cells. CONCLUSIONS: Combinations of 4-HPR and modulators of ceramide metabolism may form the basis for a novel chemotherapy that is functional under hypoxic conditions (e.g., such as those within tumors) and is p53 independent and caspase independent.
Barry J. Maurer - One of the best experts on this subject based on the ideXlab platform.
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hydrophilic interaction liquid chromatography tandem mass spectrometric approach for simultaneous determination of Safingol and d erythro sphinganine in human plasma
Journal of Chromatography B, 2019Co-Authors: Barry J. Maurer, Patrick C Reynolds, Min H KangAbstract:Abstract A simple and specific hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed for the simultaneous determination of C18-L-threo-sphinganine (Safingol, an anti-neoplastic in phase I trials) and its diastereomer, C18-D-erythro-sphinganine (sphinganine), in human plasma. Sample pretreatment involved a protein precipitation with methanol using 25 μL aliquots of plasma. Chromatographic separation of the diastereomers and C17-D-erythro-sphinganine, an internal standard, was achieved on a Xbridge HILIC (3.5 μm, 100 × 2.1 mm) using isocratic elution with the mobile phase of 2 mM ammonium bicarbonate in water (pH 8.3) and acetonitrile at a flow rate of 0.3 mL/min. Electrospray ionization (ESI) mass spectrometry was operated in the positive ion mode with multiple reaction monitoring (MRM). The calibration curves obtained were linear over the concentration range of 0.2–100 ng/mL with a lower limit of quantification of 0.2 ng/mL. The relative standard deviation of intra-day and inter-day precision was below 8.27%, and the accuracy ranged from 92.23 to 110.06%. The extraction recoveries were found to be higher than 93.22% and IS-normalized matrix effect was higher than 90.92%. The analytes were stable for the durations of the stability studies. The validated method was successfully applied to the analyses of pharmacokinetic samples from patients treated with Safingol and all-trans-N-(4-hydroxyphenyl)retinamide; (fenretinide, 4-HPR) in a current phase I clinical trial (SPOC-2010-002, ClinicalTrials.gov Identifier: NCT01553071 ).
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hydrophilic interaction liquid chromatography tandem mass spectrometric approach for simultaneous determination of Safingol and d erythro sphinganine in human plasma
Journal of Chromatography B, 2019Co-Authors: Barry J. Maurer, Patrick C Reynolds, Min H KangAbstract:Abstract A simple and specific hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed for the simultaneous determination of C18-L-threo-sphinganine (Safingol, an anti-neoplastic in phase I trials) and its diastereomer, C18-D-erythro-sphinganine (sphinganine), in human plasma. Sample pretreatment involved a protein precipitation with methanol using 25 μL aliquots of plasma. Chromatographic separation of the diastereomers and C17-D-erythro-sphinganine, an internal standard, was achieved on a Xbridge HILIC (3.5 μm, 100 × 2.1 mm) using isocratic elution with the mobile phase of 2 mM ammonium bicarbonate in water (pH 8.3) and acetonitrile at a flow rate of 0.3 mL/min. Electrospray ionization (ESI) mass spectrometry was operated in the positive ion mode with multiple reaction monitoring (MRM). The calibration curves obtained were linear over the concentration range of 0.2–100 ng/mL with a lower limit of quantification of 0.2 ng/mL. The relative standard deviation of intra-day and inter-day precision was below 8.27%, and the accuracy ranged from 92.23 to 110.06%. The extraction recoveries were found to be higher than 93.22% and IS-normalized matrix effect was higher than 90.92%. The analytes were stable for the durations of the stability studies. The validated method was successfully applied to the analyses of pharmacokinetic samples from patients treated with Safingol and all-trans-N-(4-hydroxyphenyl)retinamide; (fenretinide, 4-HPR) in a current phase I clinical trial (SPOC-2010-002, ClinicalTrials.gov Identifier: NCT01553071 ).
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simultaneous determination of Safingol and d erythro sphinganine in human plasma by lc with fluorescence detection
Chromatographia, 2010Co-Authors: Hardeep Singh, Patrick C Reynolds, Barry J. Maurer, Min H KangAbstract:l-threo-Sphinganine (Safingol) is a putative synthetic sphingosine kinase inhibitor currently being tested in clinical trials as an anticancer agent. To enable defining the pharmacokinetic properties of Safingol in humans, we developed a sensitive analytical method to simultaneously quantitate Safingol and its naturally-occurring diastereomer, d-erythro-sphinganine in human plasma. Of the two different fluorogenic derivatization agents (NDA and OPA) and several pH conditions compared for the derivatization, we found that NDA derivatization achieved more than 20 times greater sensitivity compared with OPA derivatization, and pH 9.0 showed the highest sensitivity for both compounds. An analytical method for liquid chromatography (LC) with a fluorescence detector (FLD) was developed and validated with calibration curve ranges of 20–1,000 ng mL−1 for Safingol and d-erythro-sphinganine. Our LC-FLD method using NDA-derivatization enabled simultaneous quantification of Safingol and its naturally-occurring diastereomer, d-erythro-sphinganine with satisfactory sensitivity in human plasma.
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synergistic cytotoxicity in solid tumor cell lines between n 4 hydroxyphenyl retinamide and modulators of ceramide metabolism
Journal of the National Cancer Institute, 2000Co-Authors: Barry J. Maurer, Lisa Melton, Carolyn Billups, Myles C Cabot, Patrick C ReynoldsAbstract:BACKGROUND: We previously reported that N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) treatment caused large increases of ceramide levels in neuroblastoma cell lines and induced cell death by a combination of apoptosis and necrosis through p53 (also known as TP53)-independent and caspase-independent pathways. Our goal was to determine if several molecules that inhibit enzymes involved in ceramide metabolism-L-threo-dihydrosphingosine (Safingol), d, l-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP), and tamoxifen-enhanced 4-HPR-mediated cytotoxicity and/or affected ceramide levels. METHODS: Cellular lipids were quantified by radiolabeling and thin-layer chromatography. Cytotoxicity and cytotoxic synergy (expressed as combination index, where combination index 1 indicates antagonism) were measured in cultured cancer cell lines with the use of a fluorescence-based assay of cell viability employing digital imaging microscopy. Statistical tests were two-sided. RESULTS: 4-HPR increased ceramide levels by de novo synthesis. Safingol (1-4 microM) was incorporated into a stereochemical variant of ceramide and synergized with a 3:1 molar ratio of 4-HPR (3-12 microM), to produce a 100-fold to 10 000-fold (2 to 4 logs) increase in cytotoxicity relative to 4-HPR alone in neuroblastoma (combination index <0.1), lung (combination index <0.1-0.2), melanoma (combination index <0.1-0.2), prostate (combination index <0.1-1.0), colon (combination index 0.1-0.3), breast (combination index = 0.1-0.5), and pancreas (combination index = 0.2) cell lines, including p53 mutant and alkylator-resistant cell lines. The 4-HPR and Safingol combination was cytotoxic in low-oxygen conditions and was minimally toxic to normal fibroblasts and bone marrow myeloid progenitor cells. Addition of agents that retard ceramide glucosylation and/or acylation, such as PPMP or tamoxifen, to 4-HPR or to the combination of 4-HPR and Safingol further increased cytotoxicity to tumor cells. CONCLUSIONS: Combinations of 4-HPR and modulators of ceramide metabolism may form the basis for a novel chemotherapy that is functional under hypoxic conditions (e.g., such as those within tumors) and is p53 independent and caspase independent.
Min H Kang - One of the best experts on this subject based on the ideXlab platform.
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hydrophilic interaction liquid chromatography tandem mass spectrometric approach for simultaneous determination of Safingol and d erythro sphinganine in human plasma
Journal of Chromatography B, 2019Co-Authors: Barry J. Maurer, Patrick C Reynolds, Min H KangAbstract:Abstract A simple and specific hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed for the simultaneous determination of C18-L-threo-sphinganine (Safingol, an anti-neoplastic in phase I trials) and its diastereomer, C18-D-erythro-sphinganine (sphinganine), in human plasma. Sample pretreatment involved a protein precipitation with methanol using 25 μL aliquots of plasma. Chromatographic separation of the diastereomers and C17-D-erythro-sphinganine, an internal standard, was achieved on a Xbridge HILIC (3.5 μm, 100 × 2.1 mm) using isocratic elution with the mobile phase of 2 mM ammonium bicarbonate in water (pH 8.3) and acetonitrile at a flow rate of 0.3 mL/min. Electrospray ionization (ESI) mass spectrometry was operated in the positive ion mode with multiple reaction monitoring (MRM). The calibration curves obtained were linear over the concentration range of 0.2–100 ng/mL with a lower limit of quantification of 0.2 ng/mL. The relative standard deviation of intra-day and inter-day precision was below 8.27%, and the accuracy ranged from 92.23 to 110.06%. The extraction recoveries were found to be higher than 93.22% and IS-normalized matrix effect was higher than 90.92%. The analytes were stable for the durations of the stability studies. The validated method was successfully applied to the analyses of pharmacokinetic samples from patients treated with Safingol and all-trans-N-(4-hydroxyphenyl)retinamide; (fenretinide, 4-HPR) in a current phase I clinical trial (SPOC-2010-002, ClinicalTrials.gov Identifier: NCT01553071 ).
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hydrophilic interaction liquid chromatography tandem mass spectrometric approach for simultaneous determination of Safingol and d erythro sphinganine in human plasma
Journal of Chromatography B, 2019Co-Authors: Barry J. Maurer, Patrick C Reynolds, Min H KangAbstract:Abstract A simple and specific hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed for the simultaneous determination of C18-L-threo-sphinganine (Safingol, an anti-neoplastic in phase I trials) and its diastereomer, C18-D-erythro-sphinganine (sphinganine), in human plasma. Sample pretreatment involved a protein precipitation with methanol using 25 μL aliquots of plasma. Chromatographic separation of the diastereomers and C17-D-erythro-sphinganine, an internal standard, was achieved on a Xbridge HILIC (3.5 μm, 100 × 2.1 mm) using isocratic elution with the mobile phase of 2 mM ammonium bicarbonate in water (pH 8.3) and acetonitrile at a flow rate of 0.3 mL/min. Electrospray ionization (ESI) mass spectrometry was operated in the positive ion mode with multiple reaction monitoring (MRM). The calibration curves obtained were linear over the concentration range of 0.2–100 ng/mL with a lower limit of quantification of 0.2 ng/mL. The relative standard deviation of intra-day and inter-day precision was below 8.27%, and the accuracy ranged from 92.23 to 110.06%. The extraction recoveries were found to be higher than 93.22% and IS-normalized matrix effect was higher than 90.92%. The analytes were stable for the durations of the stability studies. The validated method was successfully applied to the analyses of pharmacokinetic samples from patients treated with Safingol and all-trans-N-(4-hydroxyphenyl)retinamide; (fenretinide, 4-HPR) in a current phase I clinical trial (SPOC-2010-002, ClinicalTrials.gov Identifier: NCT01553071 ).
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simultaneous determination of Safingol and d erythro sphinganine in human plasma by lc with fluorescence detection
Chromatographia, 2010Co-Authors: Hardeep Singh, Patrick C Reynolds, Barry J. Maurer, Min H KangAbstract:l-threo-Sphinganine (Safingol) is a putative synthetic sphingosine kinase inhibitor currently being tested in clinical trials as an anticancer agent. To enable defining the pharmacokinetic properties of Safingol in humans, we developed a sensitive analytical method to simultaneously quantitate Safingol and its naturally-occurring diastereomer, d-erythro-sphinganine in human plasma. Of the two different fluorogenic derivatization agents (NDA and OPA) and several pH conditions compared for the derivatization, we found that NDA derivatization achieved more than 20 times greater sensitivity compared with OPA derivatization, and pH 9.0 showed the highest sensitivity for both compounds. An analytical method for liquid chromatography (LC) with a fluorescence detector (FLD) was developed and validated with calibration curve ranges of 20–1,000 ng mL−1 for Safingol and d-erythro-sphinganine. Our LC-FLD method using NDA-derivatization enabled simultaneous quantification of Safingol and its naturally-occurring diastereomer, d-erythro-sphinganine with satisfactory sensitivity in human plasma.
Hao Wei Wang - One of the best experts on this subject based on the ideXlab platform.
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reversal of inflammation associated dihydrodiol dehydrogenases akr1c1 and akr1c2 overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin
International Journal of Cancer, 2007Co-Authors: Liang Shun Wang, Hao Wei Wang, Kuan-chih Chow, Jen-hwey ChiuAbstract:Dihydrodiol dehydrogenase (DDH) is a member of the aldo-keto reductases superfamily (AKR1C1–AKR1C4), which plays central roles in the metabolism of steroid hormone, prostaglandin and xenobiotics. We have previously detected overexpression of DDH as an indicator of poor prognosis and chemoresistance in human non-small lung cancer (NSCLC). We also found DDH expression to be closely related to chronic inflammatory conditions. The aim of this study was to investigate the links between inflammation, DDH expression and drug resistance in NSCLC cells. We showed that pro-inflammatory mediators including interleukin-6 (IL-6) could induce AKR1C1/1C2 expression in NSCLC cells and increase cellular resistance to cisplatin and adriamycin. This effect was nullified by Safingol, a protein kinase C inhibitor. Moreover, the expression of AKR1C1/1C2 was inversely correlated to NBS1 and apoptosis-inducing factor (AIF). We also showed that IL-6-induced AKR1C1/1C2 expression and drug resistance were inhibited by wogonin and chrysin, which are major flavonoids in Scutellaria baicalensis, a widely used traditional Chinese and Japanese medicine. In conclusion, this study demonstrated novel links of pro-inflammatory signals, AKR1C1/1C2 expression and drug resistance in NSCLC. The protein kinase C pathway may play an important role in this process. Overexpression of AKR1C1/1C2 may serve as a marker of chemoresistance. Further studies are warranted to evaluate wogonin and chrysin as a potential adjuvant therapy for drug-resistant NSCLC, especially for those with AKR1C1/1C2 overexpression. © 2007 Wiley-Liss, Inc.
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reversal of inflammation associated dihydrodiol dehydrogenases akr1c1 and akr1c2 overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin
International Journal of Cancer, 2007Co-Authors: Liang Shun Wang, Hao Wei Wang, Kuan-chih Chow, Jen-hwey Chiu, Chin Ping Lin, Kuang Tai Kuo, Chen Sung LinAbstract:Dihydrodiol dehydrogenase (DDH) is a member of the aldo-keto reductases superfamily (AKR1C1-AKR1C4), which plays central roles in the metabolism of steroid hormone, prostaglandin and xenobiotics. We have previously detected overexpression of DDH as an indicator of poor prognosis and chemoresistance in human non-small lung cancer (NSCLC). We also found DDH expression to be closely related to chronic inflammatory conditions. The aim of this study was to investigate the links between inflammation, DDH expression and drug resistance in NSCLC cells. We showed that pro-inflammatory mediators including interleukin-6 (IL-6) could induce AKR1C1/1C2 expression in NSCLC cells and increase cellular resistance to cisplatin and adriamycin. This effect was nullified by Safingol, a protein kinase C inhibitor. Moreover, the expression of AKR1C1/1C2 was inversely correlated to NBS1 and apoptosis-inducing factor (AIF). We also showed that IL-6-induced AKR1C1/1C2 expression and drug resistance were inhibited by wogonin and chrysin, which are major flavonoids in Scutellaria baicalensis, a widely used traditional Chinese and Japanese medicine. In conclusion, this study demonstrated novel links of pro-inflammatory signals, AKR1C1/1C2 expression and drug resistance in NSCLC. The protein kinase C pathway may play an important role in this process. Overexpression of AKR1C1/1C2 may serve as a marker of chemoresistance. Further studies are warranted to evaluate wogonin and chrysin as a potential adjuvant therapy for drug-resistant NSCLC, especially for those with AKR1C1/1C2 overexpression.
