The Experts below are selected from a list of 3936 Experts worldwide ranked by ideXlab platform
Robert A Casero - One of the best experts on this subject based on the ideXlab platform.
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Polyamine Metabolism and cancer treatments challenges and opportunities
Nature Reviews Cancer, 2018Co-Authors: Robert A Casero, Tracy Murray Stewart, Anthony E PeggAbstract:Advances in our understanding of the Metabolism and molecular functions of Polyamines and their alterations in cancer have led to resurgence in the interest of targeting Polyamine Metabolism as an anticancer strategy. Increasing knowledge of the interplay between Polyamine Metabolism and other cancer-driving pathways, including the PTEN–PI3K–mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting Polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated Polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, Polyamine blocking therapy, a strategy that combines the inhibition of Polyamine biosynthesis with the simultaneous blockade of Polyamine transport, can be more effective than therapies based on Polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant Polyamine Metabolism for anticancer therapy. This Review discusses new insights into molecular mechanisms that link the dysregulation of Polyamine Metabolism with carcinogenesis and strategies for targeting this pathway for cancer therapy.
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coupling of the Polyamine and iron Metabolism pathways in the regulation of proliferation mechanistic links to alterations in key Polyamine biosynthetic and catabolic enzymes
Biochimica et Biophysica Acta, 2018Co-Authors: Darius J R Lane, Robert A Casero, Donghun Bae, Aritee R Siafakas, Yohan Suryo Rahmanto, Lina Alakra, Patric J Jansson, Des R RichardsonAbstract:Many biological processes result from the coupling of metabolic pathways. Considering this, proliferation depends on adequate iron and Polyamines, and although iron-depletion impairs proliferation, the metabolic link between iron and Polyamine Metabolism has never been thoroughly investigated. This is important to decipher, as many disease states demonstrate co-dysregulation of iron and Polyamine Metabolism. Herein, for the first time, we demonstrate that cellular iron levels robustly regulate 13 Polyamine pathway proteins. Seven of these were regulated in a conserved manner by iron-depletion across different cell-types, with four proteins being down-regulated (i.e., acireductone dioxygenase 1 [ADI1], methionine adenosyltransferase 2α [MAT2α], Antizyme and Polyamine oxidase [PAOX]) and three proteins being up-regulated (i.e., S-adenosyl methionine decarboxylase [AMD1], Antizyme inhibitor 1 [AZIN1] and spermidine/spermine-N1-acetyltransferase 1 [SAT1]). Depletion of iron also markedly decreased Polyamine pools (i.e., spermidine and/or spermine, but not putrescine). Accordingly, iron-depletion also decreased S-adenosylmethionine that is essential for spermidine/spermine biosynthesis. Iron-depletion additionally reduced 3H-spermidine uptake in direct agreement with the lowered levels of the Polyamine importer, SLC22A16. Regarding mechanism, the "reprogramming" of Polyamine Metabolism by iron-depletion is consistent with the down-regulation of ADI1 and MAT2α, and the up-regulation of SAT1. Moreover, changes in ADI1 (biosynthetic) and SAT1 (catabolic) partially depended on the iron-regulated changes in c-Myc and/or p53. The ability of iron chelators to inhibit proliferation was rescuable by putrescine and spermidine, and under some conditions by spermine. Collectively, iron and Polyamine Metabolism are intimately coupled, which has significant ramifications for understanding the integrated role of iron and Polyamine Metabolism in proliferation.
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Curcumin mediates Polyamine Metabolism and sensitizes gastrointestinal cancer cells to antitumor Polyamine-targeted therapies
2018Co-Authors: Tracy Murray-stewart, Patrick M Woster, Matthew Dunworth, Yuan Lui, Francis M. Giardiello, Robert A CaseroAbstract:Curcumin, a natural polyphenol that contributes to the flavor and yellow pigment of the spice turmeric, is known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. Previous studies demonstrated that curcumin can inhibit ornithine decarboxylase (ODC) activity in human leukemia and breast cancer cells, and pretreatment with dietary curcumin blocks carcinogen-induced ODC activity in rodent models of skin, colon, and renal cancer. The current study investigated the regulation of Polyamine Metabolism in human gastric and colon carcinoma cell lines in response to curcumin. Curcumin treatment significantly induced spermine oxidase (SMOX) mRNA and activity, which results in the generation of hydrogen peroxide, a source of ROS. Simultaneously, curcumin down regulated spermidine/spermine N1-acetyltransferase (SSAT) activity and the biosynthetic enzymes ODC and S-adenosylmethionine decarboxylase (SAMDC), thereby diminishing intracellular Polyamine pools. Combination treatments using curcumin with the ODC inhibitor 2-difluoromethylornithine (DFMO), an agent currently in clinical chemoprevention trials, significantly enhanced inhibition of ODC activity and decreased growth of GI cancer cell lines beyond that observed with either agent alone. Similarly, combining curcumin with the Polyamine analogue bis(ethyl)norspermine enhanced growth inhibition that was accompanied by enhanced accumulation of the analogue and decreased intracellular Polyamine levels beyond those observed with either agent alone. Importantly, cotreatment with curcumin permitted the lowering of the effective dose of ODC inhibitor or Polyamine analogue. These studies provide insight into the Polyamine-related mechanisms involved in the cancer cell response to curcumin and its potential as a chemopreventive or chemotherapeutic agent in the GI tract.
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self immolative nanoparticles for simultaneous delivery of microrna and targeting of Polyamine Metabolism in combination cancer therapy
Journal of Controlled Release, 2017Co-Authors: Ying Xie, Laurence J Marton, Robert A Casero, Tracy Murraystewart, Yazhe Wang, David OupickyAbstract:Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated Polyamine Metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a Polyamine analog N1,N11-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in Polyamine catabolism (SMOX, SSAT) and depleted cellular natural Polyamines. Simultaneous regulation of Polyamine Metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated Polyamine Metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines.
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Biochemical evaluation of the anticancer potential of the Polyamine-based nanocarrier Nano11047
2017Co-Authors: Tracy Murray-stewart, Laurence J Marton, Elena Ferrari, Ying Xie, David Oupicky, Robert A CaseroAbstract:Synthesizing polycationic polymers directly from existing drugs overcomes the drug-loading limitations often associated with pharmacologically inert nanocarriers. We recently described nanocarriers formed from a first-generation Polyamine analogue, bis(ethyl)norspermine (BENSpm), that could simultaneously target Polyamine Metabolism while delivering therapeutic nucleic acids. In the current study, we describe the synthesis and evaluation of self-immolative nanocarriers derived from the second-generation Polyamine analogue PG-11047. Polyamines are absolutely essential for proliferation and their Metabolism is frequently dysregulated in cancer. Through its effects on Polyamine Metabolism, PG-11047 effectively inhibits tumor growth in cancer cell lines of multiple origins as well as in human tumor mouse xenografts. Promising clinical trials have been completed verifying the safety and tolerance of this rotationally restricted Polyamine analogue. We therefore used PG-11047 as the basis for Nano11047, a biodegradable, prodrug nanocarrier capable of targeting Polyamine Metabolism. Following exposure of lung cancer cell lines to Nano11047, uptake and intracellular degradation into the parent compound PG-11047 was observed. The release of PG-11047 highly induced the Polyamine catabolic enzyme activities of spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX). By contrast, the activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in Polyamine biosynthesis and a putative oncogene, was decreased. Consequently, intracellular levels of the natural Polyamines were depleted concurrent with tumor cell growth inhibition. This availability of Nano11047 as a novel drug form and potential nucleic acid delivery vector will potentially benefit and encourage future clinical studies.
Anthony E Pegg - One of the best experts on this subject based on the ideXlab platform.
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Polyamine Metabolism and cancer treatments challenges and opportunities
Nature Reviews Cancer, 2018Co-Authors: Robert A Casero, Tracy Murray Stewart, Anthony E PeggAbstract:Advances in our understanding of the Metabolism and molecular functions of Polyamines and their alterations in cancer have led to resurgence in the interest of targeting Polyamine Metabolism as an anticancer strategy. Increasing knowledge of the interplay between Polyamine Metabolism and other cancer-driving pathways, including the PTEN–PI3K–mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting Polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated Polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, Polyamine blocking therapy, a strategy that combines the inhibition of Polyamine biosynthesis with the simultaneous blockade of Polyamine transport, can be more effective than therapies based on Polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant Polyamine Metabolism for anticancer therapy. This Review discusses new insights into molecular mechanisms that link the dysregulation of Polyamine Metabolism with carcinogenesis and strategies for targeting this pathway for cancer therapy.
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mammalian Polyamine Metabolism and function
Iubmb Life, 2009Co-Authors: Anthony E PeggAbstract:Polyamines are ubiquitous small basic molecules that play multiple essential roles in mammalian physiology. Their cellular content is highly regulated and there is convincing evidence that altered Metabolism is involvement in many disease states. Drugs altering Polyamine levels may therefore have a variety of important targets. This review will summarize the current state of understanding of Polyamine Metabolism and function, the regulation of Polyamine content, and heritable pathological conditions that may be derived from altered Polyamine Metabolism.
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spermidine spermine n1 acetyltransferase the turning point in Polyamine Metabolism
The FASEB Journal, 1993Co-Authors: Robert A Casero, Anthony E PeggAbstract:Polyamines are thought to have several vital roles in cell growth and differentiation. The highly regulated Polyamine metabolic pathway provides cells with the ability to finely control the intracellular concentration of these ubiquitous polycations. Although earlier studies of regulation of Polyamine content were concentrated on the biosynthetic reactions, recently the importance of the catabolic processes, particularly the highly regulated acetylation step in Polyamine degradation, has become apparent. This work has led to an understanding of how a cell may, in a tightly controlled manner, facilitate the breakdown, excretion, cycling, and/or intracellular shuttling of the Polyamines. This myriad of possibilities appears to be regulated initially at a single rate-limiting enzymatic step, the N1-acetylation of spermidine or spermine, by spermidine/spermine N1-acetyltransferase (SSAT). Recent cloning of the human SSAT gene has facilitated a more detailed study of this enzyme. SSAT appears to have a role in the determination of tumor sensitivity to a new class of antineoplastic agents. The further study of SSAT and the associated Polyamine Metabolism should provide a better understanding of the regulation and function of these cations.
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spermidine spermine n1 acetyltransferase the turning point in Polyamine Metabolism
The FASEB Journal, 1993Co-Authors: Robert A Casero, Anthony E PeggAbstract:Polyamines are thought to have several vital roles in cell growth and differentiation. The highly regulated Polyamine metabolic pathway provides cells with the ability to finely control the intracellular concentration of these ubiquitous polycations. Although earlier studies of regulation of Polyamine content were concentrated on the biosynthetic reactions, recently the importance of the catabolic processes, particularly the highly regulated acetylation step in Polyamine degradation, has become apparent. This work has led to an understanding of how a cell may, in a tightly controlled manner, facilitate the breakdown, excretion, cycling, and/or intracellular shuttling of the Polyamines. This myriad of possibilities appears to be regulated initially at a single rate-limiting enzymatic step, the N1-acetylation of spermidine or spermine, by spermidine/spermine N1-acetyltransferase (SSAT). Recent cloning of the human SSAT gene has facilitated a more detailed study of this enzyme. SSAT appears to have a role in...
Des R Richardson - One of the best experts on this subject based on the ideXlab platform.
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coupling of the Polyamine and iron Metabolism pathways in the regulation of proliferation mechanistic links to alterations in key Polyamine biosynthetic and catabolic enzymes
Biochimica et Biophysica Acta, 2018Co-Authors: Darius J R Lane, Robert A Casero, Donghun Bae, Aritee R Siafakas, Yohan Suryo Rahmanto, Lina Alakra, Patric J Jansson, Des R RichardsonAbstract:Many biological processes result from the coupling of metabolic pathways. Considering this, proliferation depends on adequate iron and Polyamines, and although iron-depletion impairs proliferation, the metabolic link between iron and Polyamine Metabolism has never been thoroughly investigated. This is important to decipher, as many disease states demonstrate co-dysregulation of iron and Polyamine Metabolism. Herein, for the first time, we demonstrate that cellular iron levels robustly regulate 13 Polyamine pathway proteins. Seven of these were regulated in a conserved manner by iron-depletion across different cell-types, with four proteins being down-regulated (i.e., acireductone dioxygenase 1 [ADI1], methionine adenosyltransferase 2α [MAT2α], Antizyme and Polyamine oxidase [PAOX]) and three proteins being up-regulated (i.e., S-adenosyl methionine decarboxylase [AMD1], Antizyme inhibitor 1 [AZIN1] and spermidine/spermine-N1-acetyltransferase 1 [SAT1]). Depletion of iron also markedly decreased Polyamine pools (i.e., spermidine and/or spermine, but not putrescine). Accordingly, iron-depletion also decreased S-adenosylmethionine that is essential for spermidine/spermine biosynthesis. Iron-depletion additionally reduced 3H-spermidine uptake in direct agreement with the lowered levels of the Polyamine importer, SLC22A16. Regarding mechanism, the "reprogramming" of Polyamine Metabolism by iron-depletion is consistent with the down-regulation of ADI1 and MAT2α, and the up-regulation of SAT1. Moreover, changes in ADI1 (biosynthetic) and SAT1 (catabolic) partially depended on the iron-regulated changes in c-Myc and/or p53. The ability of iron chelators to inhibit proliferation was rescuable by putrescine and spermidine, and under some conditions by spermine. Collectively, iron and Polyamine Metabolism are intimately coupled, which has significant ramifications for understanding the integrated role of iron and Polyamine Metabolism in proliferation.
Francis Raul - One of the best experts on this subject based on the ideXlab platform.
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flavanols and procyanidins of cocoa and chocolate inhibit growth and Polyamine biosynthesis of human colonic cancer cells
Cancer Letters, 2002Co-Authors: S Carnesecchi, Yann Schneider, Sheryl A Lazarus, David Coehlo, Francine Gosse, Francis RaulAbstract:Abstract The effects of cocoa powder and extracts with different amounts of flavanols and related procyanidin oligomers were investigated on the growth of Caco-2 cells. Treatment of the cells with 50 μg/ml of procyanidin-enriched (PE) extracts caused a 70% growth inhibition with a blockade of the cell cycle at the G2/M phase. PE extracts caused a significant decrease of ornithine decarboxylase and S-adenosylmethionine decarboxylase activities, two key enzymes of Polyamine biosynthesis. This led to a decrease in the intracellular pool of the Polyamines. These observations indicate that Polyamine Metabolism might be an important target in the anti-proliferative effects of cocoa polyphenols.
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anti proliferative effect of resveratrol a natural component of grapes and wine on human colonic cancer cells
Cancer Letters, 2000Co-Authors: Yann Schneider, Francine Gosse, Florence Vincent, B Duranton, Lassina Badolo, Christian Bergmann, Nikolaus Seiler, Francis RaulAbstract:Resveratrol, a natural polyphenolic phytoalexine present in grapes and wines, has been reported to exert a variety of important pharmacological effects. We investigated the effects of resveratrol on the growth and Polyamine Metabolism of CaCo-2 human colon cancer cells. Treatment of the CaCo-2 cells with 25 μM resveratrol caused a 70% growth inhibition. The cells accumulated at the S/G2 phase transition of the cell cycle. No signs of cytotoxicity or apoptosis were detected. Resveratrol caused a significant decrease of ornithine decarboxylase (ODC) activity, a key enzyme of Polyamine biosynthesis, which is enhanced in cancer growth. ODC inhibition resulted in the reduction of the intracellular putrescine content, indicating that Polyamines might represent one of several targets involved in the anti-proliferative effects of resveratrol.
David Oupicky - One of the best experts on this subject based on the ideXlab platform.
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self immolative nanoparticles for simultaneous delivery of microrna and targeting of Polyamine Metabolism in combination cancer therapy
Journal of Controlled Release, 2017Co-Authors: Ying Xie, Laurence J Marton, Robert A Casero, Tracy Murraystewart, Yazhe Wang, David OupickyAbstract:Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated Polyamine Metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a Polyamine analog N1,N11-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in Polyamine catabolism (SMOX, SSAT) and depleted cellular natural Polyamines. Simultaneous regulation of Polyamine Metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated Polyamine Metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines.
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Biochemical evaluation of the anticancer potential of the Polyamine-based nanocarrier Nano11047
2017Co-Authors: Tracy Murray-stewart, Laurence J Marton, Elena Ferrari, Ying Xie, David Oupicky, Robert A CaseroAbstract:Synthesizing polycationic polymers directly from existing drugs overcomes the drug-loading limitations often associated with pharmacologically inert nanocarriers. We recently described nanocarriers formed from a first-generation Polyamine analogue, bis(ethyl)norspermine (BENSpm), that could simultaneously target Polyamine Metabolism while delivering therapeutic nucleic acids. In the current study, we describe the synthesis and evaluation of self-immolative nanocarriers derived from the second-generation Polyamine analogue PG-11047. Polyamines are absolutely essential for proliferation and their Metabolism is frequently dysregulated in cancer. Through its effects on Polyamine Metabolism, PG-11047 effectively inhibits tumor growth in cancer cell lines of multiple origins as well as in human tumor mouse xenografts. Promising clinical trials have been completed verifying the safety and tolerance of this rotationally restricted Polyamine analogue. We therefore used PG-11047 as the basis for Nano11047, a biodegradable, prodrug nanocarrier capable of targeting Polyamine Metabolism. Following exposure of lung cancer cell lines to Nano11047, uptake and intracellular degradation into the parent compound PG-11047 was observed. The release of PG-11047 highly induced the Polyamine catabolic enzyme activities of spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX). By contrast, the activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in Polyamine biosynthesis and a putative oncogene, was decreased. Consequently, intracellular levels of the natural Polyamines were depleted concurrent with tumor cell growth inhibition. This availability of Nano11047 as a novel drug form and potential nucleic acid delivery vector will potentially benefit and encourage future clinical studies.
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synthesis of bisethylnorspermine lipid prodrug as gene delivery vector targeting Polyamine Metabolism in breast cancer
Molecular Pharmaceutics, 2012Co-Authors: Yanmei Dong, Yu Zhu, Qing Hui Zhou, David OupickyAbstract:Progress in the development of nonviral gene delivery vectors continues to be hampered by low transfection activity and toxicity. Here we proposed to develop a lipid prodrug based on a Polyamine analogue bisethylnorspermine (BSP) that can function dually as gene delivery vector and, after intracellular degradation, as active anticancer agent targeting dysregulated Polyamine Metabolism. We synthesized a prodrug of BSP (LS-BSP) capable of intracellular release of BSP using thiolytically sensitive dithiobenzyl carbamate linker. Biodegradability of LS-BSP contributed to decreased toxicity compared with nondegradable control L-BSP. BSP showed a strong synergistic enhancement of cytotoxic activity of TNF-related apoptosis-inducing ligand (TRAIL) in human breast cancer cells. Decreased enhancement of TRAIL activity was observed for LS-BSP when compared with BSP. LS-BSP formed complexes with plasmid DNA and mediated transfection activity comparable to DOTAP and L-BSP. Our results show that BSP-based vectors are promising candidates for combination drug/gene delivery.