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Neil Osheroff - One of the best experts on this subject based on the ideXlab platform.
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Bioflavonoids as poisons of human topoisomerase IIα and β
Cancer Research, 2007Co-Authors: Omari J. Bandele, Neil OsheroffAbstract:769 Type II topoisomerases are the primary targets of some of the most successful anticancer drugs used to treat human malignancies. Topoisomerase II removes knots and tangles from the genetic material by creating transient double-stranded breaks in the backbone of DNA. Agents that increase enzyme-mediated DNA cleavage are called topoisomerase II poisons due to their ability to convert topoisomerase II from an essential enzyme to a potent cellular toxin. Many anticancer drugs kill cells by acting as topoisomerase II poisons. Furthermore, naturally occurring topoisomerase II poisons such as Bioflavonoids are an integral component of the human diet. Studies suggest that the dietary intake of these compounds provides numerous health benefits to adults, including a reduction in several forms of cancer. Despite the therapeutic effects of Bioflavonoids, they also display clastogenic properties. Ingestion of Bioflavonoids by pregnant women has been linked to the initiation of specific types of infant leukemias. The mechanistic basis for the physiological actions of these compounds is not known, as they have a variety of effects on human cells. However, it has been suggested that at least some of the cellular effects of Bioflavonoids are mediated through their actions on topoisomerase II. While most poisons display activity against topoisomerase IIα and β, the relative contribution of the two isoforms to either the therapeutic or leukemogenic properties of these drugs are not known. Therefore, the present study more fully defines the activity and mechanism of action of Bioflavonoids against human topoisomerase IIα and β. Genistein and several other Bioflavonoids enhanced DNA cleavage mediated by both enzyme isoforms, however, topoisomerase IIβ was more sensitive to most of the compounds. Consistent with previous reports, Bioflavonoids required -OH groups at the 5,7, and 4’ positions for enhanced enzyme-induced DNA scission. Our studies indicate that the 5- and 4’-OH moieties of isoflavones are important because they mediate binding to topoisomerase II. The presence of additional -OH groups on the pendant phenyl ring appear to increase sensitivity of topoisomerase IIβ to these compounds. Protein mutagenesis identified one of the consensus ATP binding sites on topoisomerase IIα as a potential site of interaction of genistein. Although Bioflavonoids can undergo redox cycling, they do not alter the DNA cleavage activity of the enzyme through a quinone-based mechanism. Finally, Bioflavonoids increased DNA cleavage by topoisomerase IIα and β in cultured human CEM leukemia cells, however, genistein induced significantly less phosphorylation of histone H2AX than did etoposide. These results provide insight into the mechanism of action of Bioflavonoids against human type II topoisomerases. This work is supported by NIH grants GM33944 and CA09582.
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Bioflavonoids as Poisons of Human Topoisomerase IIα and IIβ
Biochemistry, 2007Co-Authors: Omari J. Bandele, Neil OsheroffAbstract:Bioflavonoids are human dietary components that have been linked to the prevention of cancer in adults and the generation of specific types of leukemia in infants. While these compounds have a broad range of cellular activities, many of their genotoxic effects have been attributed to their actions as topoisomerase II poisons. However, the activities of Bioflavonoids against the individual isoforms of human topoisomerase II have not been analyzed. Therefore, we characterized the activity and mechanism of action of three major classes of Bioflavonoids, flavones, flavonols, and isoflavones, against human topoisomerase IIα and IIβ. Genistein was the most active bioflavonoid tested and stimulated enzyme-mediated DNA cleavage ∼10-fold. Generally, compounds were more active against topoisomerase IIβ. DNA cleavage with both enzyme isoforms required a 5-OH and a 4‘-OH and was enhanced by the presence of additional hydroxyl groups on the pendant ring. Competition DNA cleavage and topoisomerase II binding studies in...
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Bioflavonoids as poisons of human topoisomerase II.
Cancer Research, 2006Co-Authors: Omari J. Bandele, Neil OsheroffAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 5536 Topoisomerase II is the primary target of some of the most successful anticancer drugs used in the treatment of human malignancies. These enzymes play essential roles in resolving knots and tangles in DNA by passing an intact helix through a double-stranded break that they generate in a separate segment of DNA. To maintain genomic stability during this process, topoisomerase II forms a covalent bond with the 5';-terminus of the cleaved DNA. This covalent enzyme-cleaved DNA complex is known as the cleavage complex . Agents that increase the concentration of enzyme-mediated DNA breaks are called topoisomerase II poisons due to their ability to convert topoisomerase II from an essential enzyme to a cellular toxin that fragments the genome. Although several poisons are widely used as anticancer drugs, they also have been linked to the initiation of specific types of leukemia. Naturally occurring topoisomerase II poisons such as genistein and other Bioflavonoids are believed to be chemopreventative in adults. However, consumption of these compounds during pregnancy increases the risk of infant AMLs. Thus, it is critical to understand how Bioflavonoids alter the catalytic function of human topoisomerase II. It has been suggested that human topoisomerase IIα and β play a role in mediating the cytotoxic effects of Bioflavonoids, but the question of which isoform is the more important target for these agents remains to be resolved. Therefore, the effects of genistein and other Bioflavonoids on the activity of human topoisomerase IIα and β were assessed. In vitro studies show that genistein, luteolin, apigenin, kaempferol, myricetin, and quercetin enhance DNA cleavage mediated by both isoforms, whereas many related compounds had little effect. Consistent with previous data, Bioflavonoids require -OH groups at the 5,7, and 4' positions and a double bond on the oxygenated ring for enhanced topoisomerase IIα-mediated DNA cleavage. The β isoform is more sensitive to most Bioflavonoids. Structure-activity studies suggest that the presence of additional -OH groups on the pendant phenyl ring are responsible for the increased sensitivity of topoisomerase IIβ to these agents. In vitro studies demonstrate that genistein increases the level of double-stranded DNA breaks mediated by both isoforms primarily by inhibiting the DNA religation reaction. In contrast, the other Bioflavonoids tested appear to act mainly by enhancing the forward rate of DNA cleavage. Studies using cultured human CEM leukemia cells demonstrate that genistein increases DNA cleavage by both isoforms. These results suggest that human topoisomerase IIα and β both play a role in producing the cytotoxic effects of Bioflavonoids. This work is supported by NIH grants GM33944 and CA09582.
Omari J. Bandele - One of the best experts on this subject based on the ideXlab platform.
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Bioflavonoids as poisons of human topoisomerase IIα and β
Cancer Research, 2007Co-Authors: Omari J. Bandele, Neil OsheroffAbstract:769 Type II topoisomerases are the primary targets of some of the most successful anticancer drugs used to treat human malignancies. Topoisomerase II removes knots and tangles from the genetic material by creating transient double-stranded breaks in the backbone of DNA. Agents that increase enzyme-mediated DNA cleavage are called topoisomerase II poisons due to their ability to convert topoisomerase II from an essential enzyme to a potent cellular toxin. Many anticancer drugs kill cells by acting as topoisomerase II poisons. Furthermore, naturally occurring topoisomerase II poisons such as Bioflavonoids are an integral component of the human diet. Studies suggest that the dietary intake of these compounds provides numerous health benefits to adults, including a reduction in several forms of cancer. Despite the therapeutic effects of Bioflavonoids, they also display clastogenic properties. Ingestion of Bioflavonoids by pregnant women has been linked to the initiation of specific types of infant leukemias. The mechanistic basis for the physiological actions of these compounds is not known, as they have a variety of effects on human cells. However, it has been suggested that at least some of the cellular effects of Bioflavonoids are mediated through their actions on topoisomerase II. While most poisons display activity against topoisomerase IIα and β, the relative contribution of the two isoforms to either the therapeutic or leukemogenic properties of these drugs are not known. Therefore, the present study more fully defines the activity and mechanism of action of Bioflavonoids against human topoisomerase IIα and β. Genistein and several other Bioflavonoids enhanced DNA cleavage mediated by both enzyme isoforms, however, topoisomerase IIβ was more sensitive to most of the compounds. Consistent with previous reports, Bioflavonoids required -OH groups at the 5,7, and 4’ positions for enhanced enzyme-induced DNA scission. Our studies indicate that the 5- and 4’-OH moieties of isoflavones are important because they mediate binding to topoisomerase II. The presence of additional -OH groups on the pendant phenyl ring appear to increase sensitivity of topoisomerase IIβ to these compounds. Protein mutagenesis identified one of the consensus ATP binding sites on topoisomerase IIα as a potential site of interaction of genistein. Although Bioflavonoids can undergo redox cycling, they do not alter the DNA cleavage activity of the enzyme through a quinone-based mechanism. Finally, Bioflavonoids increased DNA cleavage by topoisomerase IIα and β in cultured human CEM leukemia cells, however, genistein induced significantly less phosphorylation of histone H2AX than did etoposide. These results provide insight into the mechanism of action of Bioflavonoids against human type II topoisomerases. This work is supported by NIH grants GM33944 and CA09582.
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Bioflavonoids as Poisons of Human Topoisomerase IIα and IIβ
Biochemistry, 2007Co-Authors: Omari J. Bandele, Neil OsheroffAbstract:Bioflavonoids are human dietary components that have been linked to the prevention of cancer in adults and the generation of specific types of leukemia in infants. While these compounds have a broad range of cellular activities, many of their genotoxic effects have been attributed to their actions as topoisomerase II poisons. However, the activities of Bioflavonoids against the individual isoforms of human topoisomerase II have not been analyzed. Therefore, we characterized the activity and mechanism of action of three major classes of Bioflavonoids, flavones, flavonols, and isoflavones, against human topoisomerase IIα and IIβ. Genistein was the most active bioflavonoid tested and stimulated enzyme-mediated DNA cleavage ∼10-fold. Generally, compounds were more active against topoisomerase IIβ. DNA cleavage with both enzyme isoforms required a 5-OH and a 4‘-OH and was enhanced by the presence of additional hydroxyl groups on the pendant ring. Competition DNA cleavage and topoisomerase II binding studies in...
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Bioflavonoids as poisons of human topoisomerase II.
Cancer Research, 2006Co-Authors: Omari J. Bandele, Neil OsheroffAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 5536 Topoisomerase II is the primary target of some of the most successful anticancer drugs used in the treatment of human malignancies. These enzymes play essential roles in resolving knots and tangles in DNA by passing an intact helix through a double-stranded break that they generate in a separate segment of DNA. To maintain genomic stability during this process, topoisomerase II forms a covalent bond with the 5';-terminus of the cleaved DNA. This covalent enzyme-cleaved DNA complex is known as the cleavage complex . Agents that increase the concentration of enzyme-mediated DNA breaks are called topoisomerase II poisons due to their ability to convert topoisomerase II from an essential enzyme to a cellular toxin that fragments the genome. Although several poisons are widely used as anticancer drugs, they also have been linked to the initiation of specific types of leukemia. Naturally occurring topoisomerase II poisons such as genistein and other Bioflavonoids are believed to be chemopreventative in adults. However, consumption of these compounds during pregnancy increases the risk of infant AMLs. Thus, it is critical to understand how Bioflavonoids alter the catalytic function of human topoisomerase II. It has been suggested that human topoisomerase IIα and β play a role in mediating the cytotoxic effects of Bioflavonoids, but the question of which isoform is the more important target for these agents remains to be resolved. Therefore, the effects of genistein and other Bioflavonoids on the activity of human topoisomerase IIα and β were assessed. In vitro studies show that genistein, luteolin, apigenin, kaempferol, myricetin, and quercetin enhance DNA cleavage mediated by both isoforms, whereas many related compounds had little effect. Consistent with previous data, Bioflavonoids require -OH groups at the 5,7, and 4' positions and a double bond on the oxygenated ring for enhanced topoisomerase IIα-mediated DNA cleavage. The β isoform is more sensitive to most Bioflavonoids. Structure-activity studies suggest that the presence of additional -OH groups on the pendant phenyl ring are responsible for the increased sensitivity of topoisomerase IIβ to these agents. In vitro studies demonstrate that genistein increases the level of double-stranded DNA breaks mediated by both isoforms primarily by inhibiting the DNA religation reaction. In contrast, the other Bioflavonoids tested appear to act mainly by enhancing the forward rate of DNA cleavage. Studies using cultured human CEM leukemia cells demonstrate that genistein increases DNA cleavage by both isoforms. These results suggest that human topoisomerase IIα and β both play a role in producing the cytotoxic effects of Bioflavonoids. This work is supported by NIH grants GM33944 and CA09582.
Ramesh Srirangam - One of the best experts on this subject based on the ideXlab platform.
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potential of the Bioflavonoids in the prevention treatment of ocular disorders
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Soumyajit Majumdar, Ramesh SrirangamAbstract:Objectives Flavonoids are a common group of plant polyphenols that give colour and flavour to fruits and vegetables. In recent years, flavonoids have gained importance in the pharmaceutical field through their beneficial effects on human health and are widely available as nutritional supplements. Several pharmacological actions of the Bioflavonoids may be useful in the prevention or treatment of ocular diseases responsible for vision loss such as diabetic retinopathy, macular degeneration and cataract. This review aims to summarize the potential therapeutic applications of various Bioflavonoids in different ocular diseases and also discusses delivery of these agents to the ocular tissues. Key findings It is apparent that the flavonoids are capable of acting on various mechanisms or aetiological factors responsible for the development of different sight threatening ocular diseases. From a drug delivery perspective, ocular bioavailability depends on the physicochemical and biopharmaceutical characteristics of the selected flavonoids and very importantly the route of administration. Summary The potential therapeutic applications of various Bioflavonoids in ocular diseases is reviewed and the delivery of these agents to the ocular tissues is discussed. Whereas oral administration of Bioflavonoids may demonstrate some pharmacological activity in the outer sections of the posterior ocular segment, protection of the retinal ganglionic cells in vivo may be limited by this delivery route. Systemic or local administration of these agents may yield much higher and effective concentrations of the parent Bioflavonoids in the ocular tissues and at much lower doses.
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Potential of the Bioflavonoids in the prevention/treatment of ocular disorders
The Journal of pharmacy and pharmacology, 2010Co-Authors: Soumyajit Majumdar, Ramesh SrirangamAbstract:Objectives Flavonoids are a common group of plant polyphenols that give colour and flavour to fruits and vegetables. In recent years, flavonoids have gained importance in the pharmaceutical field through their beneficial effects on human health and are widely available as nutritional supplements. Several pharmacological actions of the Bioflavonoids may be useful in the prevention or treatment of ocular diseases responsible for vision loss such as diabetic retinopathy, macular degeneration and cataract. This review aims to summarize the potential therapeutic applications of various Bioflavonoids in different ocular diseases and also discusses delivery of these agents to the ocular tissues. Key findings It is apparent that the flavonoids are capable of acting on various mechanisms or aetiological factors responsible for the development of different sight threatening ocular diseases. From a drug delivery perspective, ocular bioavailability depends on the physicochemical and biopharmaceutical characteristics of the selected flavonoids and very importantly the route of administration. Summary The potential therapeutic applications of various Bioflavonoids in ocular diseases is reviewed and the delivery of these agents to the ocular tissues is discussed. Whereas oral administration of Bioflavonoids may demonstrate some pharmacological activity in the outer sections of the posterior ocular segment, protection of the retinal ganglionic cells in vivo may be limited by this delivery route. Systemic or local administration of these agents may yield much higher and effective concentrations of the parent Bioflavonoids in the ocular tissues and at much lower doses.
Wolfgang Tilgen - One of the best experts on this subject based on the ideXlab platform.
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treatment of progressive pigmented purpura with oral Bioflavonoids and ascorbic acid an open pilot study in 3 patients
Journal of The American Academy of Dermatology, 1999Co-Authors: Uwe Reinhold, S Seiter, Selma Ugurel, Wolfgang TilgenAbstract:Abstract Background: Bioflavonoids and ascorbic acid have been shown to increase capillary resistance and to mediate potent antioxidative radical scavenging activities. Objective: We evaluated the clinical effect of oral Bioflavonoids and ascorbic acid in patients with chronic progressive pigmented purpura (PPP). Methods: In an open pilot study, oral rutoside (50 mg twice a day) and ascorbic acid (500 mg twice a day) were administered to 3 patients with chronic PPP. Results: At the end of the 4-week treatment period, complete clearance of the skin lesions was achieved in all 3 patients. No adverse reactions were noted. All patients remained free of lesions at the end of 3 months after treatment. Conclusion: Our results suggest a beneficial effect of Bioflavonoids in combination with ascorbic acid on PPP. Because the disease is mostly resistant to other treatment modalities, placebo-controlled studies are necessary to determine the usefulness of this therapy in PPP. (J Am Acad Dermatol 1999;41:207-8.)
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Treatment of progressive pigmented purpura with oral Bioflavonoids and ascorbic acid: an open pilot study in 3 patients.
Journal of the American Academy of Dermatology, 1999Co-Authors: Uwe Reinhold, S Seiter, Selma Ugurel, Wolfgang TilgenAbstract:Bioflavonoids and ascorbic acid have been shown to increase capillary resistance and to mediate potent antioxidative radical scavenging activities. We evaluated the clinical effect of oral Bioflavonoids and ascorbic acid in patients with chronic progressive pigmented purpura (PPP). In an open pilot study, oral rutoside (50 mg twice a day) and ascorbic acid (500 mg twice a day) were administered to 3 patients with chronic PPP. At the end of the 4-week treatment period, complete clearance of the skin lesions was achieved in all 3 patients. No adverse reactions were noted. All patients remained free of lesions at the end of 3 months after treatment. Our results suggest a beneficial effect of Bioflavonoids in combination with ascorbic acid on PPP. Because the disease is mostly resistant to other treatment modalities, placebo-controlled studies are necessary to determine the usefulness of this therapy in PPP.
Soumyajit Majumdar - One of the best experts on this subject based on the ideXlab platform.
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potential of the Bioflavonoids in the prevention treatment of ocular disorders
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Soumyajit Majumdar, Ramesh SrirangamAbstract:Objectives Flavonoids are a common group of plant polyphenols that give colour and flavour to fruits and vegetables. In recent years, flavonoids have gained importance in the pharmaceutical field through their beneficial effects on human health and are widely available as nutritional supplements. Several pharmacological actions of the Bioflavonoids may be useful in the prevention or treatment of ocular diseases responsible for vision loss such as diabetic retinopathy, macular degeneration and cataract. This review aims to summarize the potential therapeutic applications of various Bioflavonoids in different ocular diseases and also discusses delivery of these agents to the ocular tissues. Key findings It is apparent that the flavonoids are capable of acting on various mechanisms or aetiological factors responsible for the development of different sight threatening ocular diseases. From a drug delivery perspective, ocular bioavailability depends on the physicochemical and biopharmaceutical characteristics of the selected flavonoids and very importantly the route of administration. Summary The potential therapeutic applications of various Bioflavonoids in ocular diseases is reviewed and the delivery of these agents to the ocular tissues is discussed. Whereas oral administration of Bioflavonoids may demonstrate some pharmacological activity in the outer sections of the posterior ocular segment, protection of the retinal ganglionic cells in vivo may be limited by this delivery route. Systemic or local administration of these agents may yield much higher and effective concentrations of the parent Bioflavonoids in the ocular tissues and at much lower doses.
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Potential of the Bioflavonoids in the prevention/treatment of ocular disorders
The Journal of pharmacy and pharmacology, 2010Co-Authors: Soumyajit Majumdar, Ramesh SrirangamAbstract:Objectives Flavonoids are a common group of plant polyphenols that give colour and flavour to fruits and vegetables. In recent years, flavonoids have gained importance in the pharmaceutical field through their beneficial effects on human health and are widely available as nutritional supplements. Several pharmacological actions of the Bioflavonoids may be useful in the prevention or treatment of ocular diseases responsible for vision loss such as diabetic retinopathy, macular degeneration and cataract. This review aims to summarize the potential therapeutic applications of various Bioflavonoids in different ocular diseases and also discusses delivery of these agents to the ocular tissues. Key findings It is apparent that the flavonoids are capable of acting on various mechanisms or aetiological factors responsible for the development of different sight threatening ocular diseases. From a drug delivery perspective, ocular bioavailability depends on the physicochemical and biopharmaceutical characteristics of the selected flavonoids and very importantly the route of administration. Summary The potential therapeutic applications of various Bioflavonoids in ocular diseases is reviewed and the delivery of these agents to the ocular tissues is discussed. Whereas oral administration of Bioflavonoids may demonstrate some pharmacological activity in the outer sections of the posterior ocular segment, protection of the retinal ganglionic cells in vivo may be limited by this delivery route. Systemic or local administration of these agents may yield much higher and effective concentrations of the parent Bioflavonoids in the ocular tissues and at much lower doses.