Michael Losiewicz - Academia.edu (original) (raw)
Papers by Michael Losiewicz
Environmental Toxicology, Mar 14, 2020
Microcystin‐leucine arginine (MC‐LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacter... more Microcystin‐leucine arginine (MC‐LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA‐122 (miR‐122) is specifically expressed in the liver. This study focuses on the role of miR‐122 in MC‐LR‐induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 μg/kg·BW MC‐LR, 25 μg/kg·BW MC‐LR, Negative control agomir and 25 μg/kg·BW MC‐LR + miR‐122 agomir). The results show that MC‐LR decreases the expressions of miR‐122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR‐122 agomir pretreatment improves MC‐LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR‐122 agomir can prevent the accumulation of hepatic iron induced by MC‐LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL‐6/STAT signaling pathways.
Biochemical and Biophysical Research Communications, Jun 1, 1994
L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benz... more L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benzopyran-4-one] directly inhibits immunoprecipitated Cdc2 kinase activity from G2/M synchronized MDA-MB-468 breast carcinoma cells and is at least 250-fold more potent than either quercetin or genistein. Purified sea-star Cdc2 kinase (IC50 = 0.5 microM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC50 = 0.4 microM). This inhibition was competitive with respect to ATP (KiATP = 0.041 microM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH2, KiCDK1S1 = 0.14 microM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.
International Journal of Oncology, Dec 1, 1996
Flavopiridol is a new synthetic flavone, structurally related to a natural alkaloid, originally p... more Flavopiridol is a new synthetic flavone, structurally related to a natural alkaloid, originally purified from Dysoxylum binectariferum, a plant indigenous to India and used in Indian folk medicine. Flavopiridol was detected by a tandem screening system consisting in inhibition of the EGF-receptor Tyrosine Phosphokinase and cytotoxicity. As a cytostatic mechanism, however, Flavopiridol strongly inhibits the cyclin-dependent kinases (cdkl, cdk2, cdk4, cdk7), with the potential to cause inhibition of cell cycle progression in G, and G 2 by multiple mechanisms relatable to cdk inhibition. In certain cell types, Flavopiridol induces apoptosis. The antitumor activity of that compound on human xenograft tumors is similar to standard cytostatic drugs and superior to them at least in prostate carcinoma. The dose limiting toxicity is diarrhea. Compared with other flavonoids or other kinase inhibitors Flavopiridol can be regarded as unique as no other compound is yet known that as specifically and potently inhibits nearly all the main cyclin dependent kinases and by that mechanisms can arrest cell cycle progression in G, as well as in G 2 and no other specific kinase inhibitor is known, which after i.v. or oral application reduces the growth of subcutaneous or subrenal xenografts of human tumors of different types. Initial results of a phase I study at the National Cancer Institute (NCI), USA, (Investigational New Drug Application no. 46211) provided some clinical and laboratory evidence for antineoplastic effect at nontoxic doses (no grade IV toxicities encountered). Thus, Flavopiridol is clearly in need of further clinical evaluation of its tumor therapeutic potential. In this review the chemical profile, tumorpharmacology (in vitro activity,
Ecotoxicology and Environmental Safety
Blood, 1998
Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cycl... more Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4:120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (I...
Environmental Toxicology, 2019
Microcystin‐LR (MC‐LR), a potent endotoxin, can induce reproductive toxicity. In order to investi... more Microcystin‐LR (MC‐LR), a potent endotoxin, can induce reproductive toxicity. In order to investigate the role and mechanisms of apoptosis (p53‐dependent and mitochondrial pathways) of germ cells induced by MC‐LR, the co‐cultured primary Sertoli‐germ cells from Sprague‐Dawley rats were used for the experiments. Expression levels of proteins, genes, and mitochondrial membrane potential (MMP) were obtained after exposing co‐cultured Sertoli‐germ cells to MC‐LR with or without the addition of the p53 inhibitor, pifithrin‐α (PFT‐α), and MMP inhibitor, cyclosporin A (CsA). Results indicated that MC‐LR could activate p53‐dependent pathway‐associated proteins in Sertoli‐germ cells, leading to a decrease in MMP (indicating the opening of mitochondrial permeability transition pore [mPTP] and the release of Cytochrome‐c [Cyt‐c]) from the mitochondria into the cytoplasm and eventually the induction of apoptosis. PFT‐α inhibited the expression ofp53, ameliorated the MMP of the co‐cultured Sertoli‐germ cells, and prevented the release of Cyt‐c from the mitochondria into the cytoplasm, which reduces the occurrence of apoptosis. Similarly, the decreased release of Cyt‐c from the mitochondria into the cytoplasm and the declined level of apoptosis in Sertoli‐germ cells induced by MC‐LR were observed after the addition of CsA. These results indicated that the apoptosis of the co‐cultured Sertoli‐germ cells induced by MC‐LR was mediated by the p53‐dependent pathway, with the involvement of the opening of mPTP.
Oncotarget, Jan 15, 2016
MYCN amplification is the most common genetic alteration in neuroblastoma and plays a critical ro... more MYCN amplification is the most common genetic alteration in neuroblastoma and plays a critical role in neuroblastoma tumorigenesis. MYCN regulates neuroblastoma cell differentiation, which is one of the mechanisms underlying its oncogenic function. We recently identified a group of differentiation-inducing microRNAs. Given the demonstrated inter-regulation between MYCN and microRNAs, we speculated that MYCN and the differentiation-inducing microRNAs might form an interaction network to control the differentiation of neuroblastoma cells. In this study, we found that eight of the thirteen differentiation-inducing microRNAs, miR-506-3p, miR-124-3p, miR-449a, miR-34a-5p, miR-449b-5p, miR-103a-3p, miR-2110 and miR-34b-5p, inhibit N-Myc expression by either directly targeting the MYCN 3'UTR or through indirect regulations. Further investigation showed that both MYCN-dependent and MYCN-independent pathways play roles in mediating the differentiation-inducing function of miR-506-3p and ...
Biochemical Pharmacology, 1999
AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210 bcr-abl ... more AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210 bcr-abl phosphorylation with concurrent inhibition of p210 bcr-abl -expressing K562 cell growth (Kaur G and Sausville EA, Anticancer Drugs 7: 815824, 1996). To assess the specificity ...
Biochemical and Biophysical Research Communications, 1994
L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benz... more L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benzopyran-4-one] directly inhibits immunoprecipitated Cdc2 kinase activity from G2/M synchronized MDA-MB-468 breast carcinoma cells and is at least 250-fold more potent than either quercetin or genistein. Purified sea-star Cdc2 kinase (IC50 = 0.5 microM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC50 = 0.4 microM). This inhibition was competitive with respect to ATP (KiATP = 0.041 microM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH2, KiCDK1S1 = 0.14 microM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.
Toxins
The widespread distribution of cyanobacteria in the aquatic environment is increasing the risk of... more The widespread distribution of cyanobacteria in the aquatic environment is increasing the risk of water pollution caused by cyanotoxins, which poses a serious threat to human health. However, the structural characterization, distribution and identification techniques of cyanotoxins have not been comprehensively reviewed in previous studies. This paper aims to elaborate the existing information systematically on the diversity of cyanotoxins to identify valuable research avenues. According to the chemical structure, cyanotoxins are mainly classified into cyclic peptides, alkaloids, lipopeptides, nonprotein amino acids and lipoglycans. In terms of global distribution, the amount of cyanotoxins are unbalanced in different areas. The diversity of cyanotoxins is more obviously found in many developed countries than that in undeveloped countries. Moreover, the threat of cyanotoxins has promoted the development of identification and detection technology. Many emerging methods have been deve...
2345 The antiproliferative effects of platinum drugs are usually ascribed to Pt-DNA adducts. Howe... more 2345 The antiproliferative effects of platinum drugs are usually ascribed to Pt-DNA adducts. However, protein-Pt adducts, which are an order of magnitude more numerous than DNA-Pt adducts, might be an additional factor that contributes to apoptosis by distorting protein redox homeostasis. The redox status of cellular proteins is mainly controlled by the antiapoptotic thioredoxin (Trx) and its regenerating enzyme thioredoxin reductase (TrxR). The Trx system was implicated in the sensitivity/resistance to cisplatin. Our previous studies with the third generation platinum drug oxaliplatin suggested that this drug in particular may exert effects on targets other than DNA. For example, oxaliplatin needs to form only half of DNA-Pt adducts formed by cisplatin for equitoxic effects. The objective of this study was to examine the potential of oxaliplatin to target the Trx system. The results demonstrate that oxaliplatin inhibits the activity of purified human Trx with the IC 50 of ∼20 μM af...
Ecotoxicology and Environmental Safety
ACS Symposium Series, 1993
Blood, Jan 15, 1998
Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cycl... more Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4: 120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (...
Biochemical Pharmacology, 1999
AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210 bcr-abl ... more AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210 bcr-abl phosphorylation with concurrent inhibition of p210 bcr-abl -expressing K562 cell growth (Kaur G and Sausville EA, Anticancer Drugs 7: 815824, 1996). To assess the specificity ...
Biochemical and Biophysical Research Communications, 1994
L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benz... more L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benzopyran-4-one] directly inhibits immunoprecipitated Cdc2 kinase activity from G2/M synchronized MDA-MB-468 breast carcinoma cells and is at least 250-fold more potent than either quercetin or genistein. Purified sea-star Cdc2 kinase (IC50 = 0.5 microM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC50 = 0.4 microM). This inhibition was competitive with respect to ATP (KiATP = 0.041 microM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH2, KiCDK1S1 = 0.14 microM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.
Environmental Toxicology, Mar 14, 2020
Microcystin‐leucine arginine (MC‐LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacter... more Microcystin‐leucine arginine (MC‐LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA‐122 (miR‐122) is specifically expressed in the liver. This study focuses on the role of miR‐122 in MC‐LR‐induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 μg/kg·BW MC‐LR, 25 μg/kg·BW MC‐LR, Negative control agomir and 25 μg/kg·BW MC‐LR + miR‐122 agomir). The results show that MC‐LR decreases the expressions of miR‐122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR‐122 agomir pretreatment improves MC‐LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR‐122 agomir can prevent the accumulation of hepatic iron induced by MC‐LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL‐6/STAT signaling pathways.
Biochemical and Biophysical Research Communications, Jun 1, 1994
L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benz... more L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benzopyran-4-one] directly inhibits immunoprecipitated Cdc2 kinase activity from G2/M synchronized MDA-MB-468 breast carcinoma cells and is at least 250-fold more potent than either quercetin or genistein. Purified sea-star Cdc2 kinase (IC50 = 0.5 microM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC50 = 0.4 microM). This inhibition was competitive with respect to ATP (KiATP = 0.041 microM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH2, KiCDK1S1 = 0.14 microM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.
International Journal of Oncology, Dec 1, 1996
Flavopiridol is a new synthetic flavone, structurally related to a natural alkaloid, originally p... more Flavopiridol is a new synthetic flavone, structurally related to a natural alkaloid, originally purified from Dysoxylum binectariferum, a plant indigenous to India and used in Indian folk medicine. Flavopiridol was detected by a tandem screening system consisting in inhibition of the EGF-receptor Tyrosine Phosphokinase and cytotoxicity. As a cytostatic mechanism, however, Flavopiridol strongly inhibits the cyclin-dependent kinases (cdkl, cdk2, cdk4, cdk7), with the potential to cause inhibition of cell cycle progression in G, and G 2 by multiple mechanisms relatable to cdk inhibition. In certain cell types, Flavopiridol induces apoptosis. The antitumor activity of that compound on human xenograft tumors is similar to standard cytostatic drugs and superior to them at least in prostate carcinoma. The dose limiting toxicity is diarrhea. Compared with other flavonoids or other kinase inhibitors Flavopiridol can be regarded as unique as no other compound is yet known that as specifically and potently inhibits nearly all the main cyclin dependent kinases and by that mechanisms can arrest cell cycle progression in G, as well as in G 2 and no other specific kinase inhibitor is known, which after i.v. or oral application reduces the growth of subcutaneous or subrenal xenografts of human tumors of different types. Initial results of a phase I study at the National Cancer Institute (NCI), USA, (Investigational New Drug Application no. 46211) provided some clinical and laboratory evidence for antineoplastic effect at nontoxic doses (no grade IV toxicities encountered). Thus, Flavopiridol is clearly in need of further clinical evaluation of its tumor therapeutic potential. In this review the chemical profile, tumorpharmacology (in vitro activity,
Ecotoxicology and Environmental Safety
Blood, 1998
Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cycl... more Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4:120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (I...
Environmental Toxicology, 2019
Microcystin‐LR (MC‐LR), a potent endotoxin, can induce reproductive toxicity. In order to investi... more Microcystin‐LR (MC‐LR), a potent endotoxin, can induce reproductive toxicity. In order to investigate the role and mechanisms of apoptosis (p53‐dependent and mitochondrial pathways) of germ cells induced by MC‐LR, the co‐cultured primary Sertoli‐germ cells from Sprague‐Dawley rats were used for the experiments. Expression levels of proteins, genes, and mitochondrial membrane potential (MMP) were obtained after exposing co‐cultured Sertoli‐germ cells to MC‐LR with or without the addition of the p53 inhibitor, pifithrin‐α (PFT‐α), and MMP inhibitor, cyclosporin A (CsA). Results indicated that MC‐LR could activate p53‐dependent pathway‐associated proteins in Sertoli‐germ cells, leading to a decrease in MMP (indicating the opening of mitochondrial permeability transition pore [mPTP] and the release of Cytochrome‐c [Cyt‐c]) from the mitochondria into the cytoplasm and eventually the induction of apoptosis. PFT‐α inhibited the expression ofp53, ameliorated the MMP of the co‐cultured Sertoli‐germ cells, and prevented the release of Cyt‐c from the mitochondria into the cytoplasm, which reduces the occurrence of apoptosis. Similarly, the decreased release of Cyt‐c from the mitochondria into the cytoplasm and the declined level of apoptosis in Sertoli‐germ cells induced by MC‐LR were observed after the addition of CsA. These results indicated that the apoptosis of the co‐cultured Sertoli‐germ cells induced by MC‐LR was mediated by the p53‐dependent pathway, with the involvement of the opening of mPTP.
Oncotarget, Jan 15, 2016
MYCN amplification is the most common genetic alteration in neuroblastoma and plays a critical ro... more MYCN amplification is the most common genetic alteration in neuroblastoma and plays a critical role in neuroblastoma tumorigenesis. MYCN regulates neuroblastoma cell differentiation, which is one of the mechanisms underlying its oncogenic function. We recently identified a group of differentiation-inducing microRNAs. Given the demonstrated inter-regulation between MYCN and microRNAs, we speculated that MYCN and the differentiation-inducing microRNAs might form an interaction network to control the differentiation of neuroblastoma cells. In this study, we found that eight of the thirteen differentiation-inducing microRNAs, miR-506-3p, miR-124-3p, miR-449a, miR-34a-5p, miR-449b-5p, miR-103a-3p, miR-2110 and miR-34b-5p, inhibit N-Myc expression by either directly targeting the MYCN 3'UTR or through indirect regulations. Further investigation showed that both MYCN-dependent and MYCN-independent pathways play roles in mediating the differentiation-inducing function of miR-506-3p and ...
Biochemical Pharmacology, 1999
AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210 bcr-abl ... more AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210 bcr-abl phosphorylation with concurrent inhibition of p210 bcr-abl -expressing K562 cell growth (Kaur G and Sausville EA, Anticancer Drugs 7: 815824, 1996). To assess the specificity ...
Biochemical and Biophysical Research Communications, 1994
L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benz... more L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benzopyran-4-one] directly inhibits immunoprecipitated Cdc2 kinase activity from G2/M synchronized MDA-MB-468 breast carcinoma cells and is at least 250-fold more potent than either quercetin or genistein. Purified sea-star Cdc2 kinase (IC50 = 0.5 microM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC50 = 0.4 microM). This inhibition was competitive with respect to ATP (KiATP = 0.041 microM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH2, KiCDK1S1 = 0.14 microM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.
Toxins
The widespread distribution of cyanobacteria in the aquatic environment is increasing the risk of... more The widespread distribution of cyanobacteria in the aquatic environment is increasing the risk of water pollution caused by cyanotoxins, which poses a serious threat to human health. However, the structural characterization, distribution and identification techniques of cyanotoxins have not been comprehensively reviewed in previous studies. This paper aims to elaborate the existing information systematically on the diversity of cyanotoxins to identify valuable research avenues. According to the chemical structure, cyanotoxins are mainly classified into cyclic peptides, alkaloids, lipopeptides, nonprotein amino acids and lipoglycans. In terms of global distribution, the amount of cyanotoxins are unbalanced in different areas. The diversity of cyanotoxins is more obviously found in many developed countries than that in undeveloped countries. Moreover, the threat of cyanotoxins has promoted the development of identification and detection technology. Many emerging methods have been deve...
2345 The antiproliferative effects of platinum drugs are usually ascribed to Pt-DNA adducts. Howe... more 2345 The antiproliferative effects of platinum drugs are usually ascribed to Pt-DNA adducts. However, protein-Pt adducts, which are an order of magnitude more numerous than DNA-Pt adducts, might be an additional factor that contributes to apoptosis by distorting protein redox homeostasis. The redox status of cellular proteins is mainly controlled by the antiapoptotic thioredoxin (Trx) and its regenerating enzyme thioredoxin reductase (TrxR). The Trx system was implicated in the sensitivity/resistance to cisplatin. Our previous studies with the third generation platinum drug oxaliplatin suggested that this drug in particular may exert effects on targets other than DNA. For example, oxaliplatin needs to form only half of DNA-Pt adducts formed by cisplatin for equitoxic effects. The objective of this study was to examine the potential of oxaliplatin to target the Trx system. The results demonstrate that oxaliplatin inhibits the activity of purified human Trx with the IC 50 of ∼20 μM af...
Ecotoxicology and Environmental Safety
ACS Symposium Series, 1993
Blood, Jan 15, 1998
Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cycl... more Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4: 120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (...
Biochemical Pharmacology, 1999
AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210 bcr-abl ... more AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210 bcr-abl phosphorylation with concurrent inhibition of p210 bcr-abl -expressing K562 cell growth (Kaur G and Sausville EA, Anticancer Drugs 7: 815824, 1996). To assess the specificity ...
Biochemical and Biophysical Research Communications, 1994
L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benz... more L86-8275 [(-) cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1- methyl)-piperidinyl]-4H-benzopyran-4-one] directly inhibits immunoprecipitated Cdc2 kinase activity from G2/M synchronized MDA-MB-468 breast carcinoma cells and is at least 250-fold more potent than either quercetin or genistein. Purified sea-star Cdc2 kinase (IC50 = 0.5 microM) was inhibited with a similar potency to immunoprecipitated Cdc2 kinase from MDA-MB-468 cells (IC50 = 0.4 microM). This inhibition was competitive with respect to ATP (KiATP = 0.041 microM) and noncompetitive with respect to a synthetic peptide substrate, CDK1S1 (AAKAKKTPKKAKK-CONH2, KiCDK1S1 = 0.14 microM). These data suggest L86-8275 as a lead structure for the development of inhibitors of the cyclin-dependent kinases.