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Patricio Aller - One of the best experts on this subject based on the ideXlab platform.
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Effects of etomoxir in combination with other metabolic inhibitors, in different cell models.
2014Co-Authors: Maria Cristina Estan, Elena De ,blas, Eva Calvino, Susana Calvo, Beatriz Guillén-guío, María Del Carmen Boyano-adánez, Eduardo Rial, Patricio AllerAbstract:(A) Changes in viability, as evidenced by the MTT assay, in HL60 cells treated with 5 and 10 mM 2-DG, alone and in combination with 100 µM etomoxir. Absorption values are indicated in relation to untreated (Cont) cultures. (B) Frequency of HL60 cells at the different growth cycle phases and with sub-G1 DNA content (apoptotic) upon incubation with 5–20 mM 2-DG, alone or with 100 µM etomoxir. (C–E) Frequency of apoptosis in HL60 cell cultures upon incubation with: (C) 100 µM etomoxir and 5–20 mM 2-DG, alone or in combination; (D) the same, using etomoxir and Lonidamine (Lon, 50–150 µM); (E) the same, using etomoxir and metformin (Metf, 4 mM). Metformin plus 2-DG was included as a positive control. (F) Frequency of apoptosis in HL60 cell cultures incubated with 2 µM ATO in combination with 50 µM etomoxir plus 5 mM 2-DG, in relation to ATO plus 2-DG alone and ATO plus etomoxir alone; and in cultures incubated with 2 µM ATO in combination with 50 µM etomoxir plus 50 µM Lonidamine, in relation to ATO plus Lonidamine alone and ATO plus etomoxir alone. (G) Frequency of apoptosis in NBA cell cultures treated with 1–5 mM 2-DG, alone and in combination with 50–100 µM etomoxir. (H) The same in mitogen-stimulated PBLs, using 10 mM 2-DG and 100 µM etomoxir. All treatments lasted for 24 h. All values are the mean ± S.D. of at least four determinations. Symbols in A and F indicate significant differences between the indicated pairs of values. Symbols in C, D, E, G, H, indicate significant differences between the combined treatment and the corresponding individual treatments (n.s., non-significant). For other conditions see legend of Fig. 1.
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Scheme summarizing the main results in this work.
2014Co-Authors: Maria Cristina Estan, Elena De ,blas, Eva Calvino, Susana Calvo, Beatriz Guillén-guío, María Del Carmen Boyano-adánez, Eduardo Rial, Patricio AllerAbstract:Etomoxir decreases respiration while increasing glycolytic activity. In addition, it causes oxidative stress (ROS over-production, GSH depletion) which, together with AMPK activation, may explain the potentiation of ATO-provoked apoptosis. Etomoxir may also cooperate in some cell models with glycolytic inhibitors (2-DG, Lonidamine) to cause apoptosis. This response is further enhanced by co-incubation with ATO, due to the capacity of this agent to attenuate the 2-DG/etomoxir-provoked Akt and ERK activation.
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increased apoptotic efficacy of Lonidamine plus arsenic trioxide combination in human leukemia cells reactive oxygen species generation and defensive protein kinase mek erk akt mtor modulation
Biochemical Pharmacology, 2011Co-Authors: Eva Calvino, Elena De ,blas, Maria Cristina Estan, Gloria P Simon, Pilar Sancho, Maria Del Carmen Boyanoadanez, Jacqueline Breard, Patricio AllerAbstract:Abstract Lonidamine is a safe, clinically useful anti-tumor drug, but its efficacy is generally low when used in monotherapy. We here demonstrate that Lonidamine efficaciously cooperates with the anti-leukemic agent arsenic trioxide (ATO, Trisenox™) to induce apoptosis in HL-60 and other human leukemia cell lines, with low toxicity in non-tumor peripheral blood lymphocytes. Apoptosis induction by Lonidamine/ATO involves mitochondrial dysfunction, as indicated by early mitochondrial permeability transition pore opening and late mitochondrial transmembrane potential dissipation, as well as activation of the intrinsic apoptotic pathway, as indicated by Bcl-X L and Mcl-1 down-regulation, Bax translocation to mitochondria, cytochrome c and Omi/HtrA2 release to the cytosol, XIAP down-regulation, and caspase-9 and -3 cleavage/activation, with secondary (Bcl-2-inhibitable) activation of the caspase-8/Bid axis. Lonidamine stimulates reactive oxygen species production, and Lonidamine/ATO toxicity is attenuated by antioxidants. Lonidamine/ATO stimulates JNK phosphorylation/activation, and apoptosis is attenuated by the JNK inhibitor SP600125. In addition, Lonidamine elicits ERK and Akt/mTOR pathway activation, as indicated by increased ERK, Akt, p70S6K and rpS6 phosphorylation, and these effects are reduced by co-treatment with ATO. Importantly, co-treatment with MEK/ERK inhibitor (U0126) and PI3K/Akt (LY294002) or mTOR (rapamycin) inhibitors, instead of ATO, also potentiates Lonidamine-provoked apoptosis. These results indicate that: (i) Lonidamine efficacy is restrained by drug-provoked activation of MEK/ERK and Akt/mTOR defensive pathways, which therefore represent potential therapeutic targets. (ii) Co-treatment with ATO efficaciously potentiates Lonidamine toxicity via defensive pathway inhibition and JNK activation. And (iii) conversely, the pro-oxidant action of Lonidamine potentiates the apoptotic efficacy of ATO as an anti-leukemic agent.
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curcumin stimulates reactive oxygen species production and potentiates apoptosis induction by the antitumor drugs arsenic trioxide and Lonidamine in human myeloid leukemia cell lines
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Yolanda Sanchez, Elena De ,blas, Eva Calvino, Gloria P Simon, Patricio AllerAbstract:Arsenic trioxide (ATO, Trisenox) is an important antileukemic drug, but its efficacy is frequently low when used as a single agent. Here, we demonstrate that the apoptotic action of ATO is greatly increased when combined with subcytotoxic curcumin concentrations in U937 and HL60 human acute myeloid leukemia cells, and with lower efficacy in K562 chronic myelogenous leukemia cells. Curcumin exerts similar cooperative effect with the mitochondria-targeting drug Lonidamine, whereas the response is negligible in combination with the DNA-targeting drug cisplatin. Curcumin plus ATO or Lonidamine stimulates typical events of the mitochondrial executioner pathway (Bax and Bid activation, cytochrome c release, X-linked inhibitor of apoptosis down-regulation, and caspase-9/-3 activation) and causes mitochondrial transmembrane potential dissipation, which nevertheless represents a late event in the apoptotic response. Curcumin increases anion superoxide production, and its proapoptotic action in combination with ATO and Lonidamine is mimicked by pro-oxidant agents (2-methoxyestradiol and H(2)O(2)) and prevented by antioxidant agents [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride and N-acetyl-l-cysteine]. Within the assayed time period (16-24 h), curcumin does not significantly modify p38-mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase phosphorylation/activation or nuclear factor-κB activity, but it greatly stimulates extracellular signal-regulated kinase (ERK) phosphorylation, and decreases Akt phosphorylation. Experiments using mitogen-activated protein kinase kinase/ERK inhibitors [2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126)] and phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) indicate that ERK activation does not mediate and even restrains apoptosis potentiation, whereas Akt down-regulation facilitates apoptosis generation. In summary, cotreatment with curcumin may represent a useful manner of increasing the efficacy of ATO and Lonidamine as antitumor drugs in myeloid leukemia cells.
Mansoor M Amiji - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic efficacy and safety of paclitaxel/Lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer. PLoS ONE 2011; 6:24075; PMID:21931642; DOI:10.1371/journal. pone.0024075. molecular targets of adjudin, an anti-s
2015Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M Amiji, Lara S. Duan, Mansoor M, Therapeutic EfficacyAbstract:Therapeutic efficacy and safety of paclitaxel/ Lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cance
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Therapeutic efficacy and safety of paclitaxel/Lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer
2013Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M AmijiAbstract:The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and Lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor). Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase) and LDH (lactate dehydrogenase), and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/Lonidamine) drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted Lonidamine/paclitaxel nanoparticles decreased tumor density an
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therapeutic efficacy and safety of paclitaxel Lonidamine loaded egfr targeted nanoparticles for the treatment of multi drug resistant cancer
PLOS ONE, 2011Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M AmijiAbstract:The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and Lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor). Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase) and LDH (lactate dehydrogenase), and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/Lonidamine) drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted Lonidamine/paclitaxel nanoparticles decreased tumor density and altered the MDR phenotype of the tumor xenografts. These EGFR-targeted combination nanoparticles were considerably less toxic than solution treatments. Due to the flexible design and simple conjugation chemistry, this nanocarrier system could be used as a platform for the development of other MDR cancer therapies; the use of this system for EGFR-targeted, combination paclitaxel/Lonidamine therapy is an advance in personalized medicine.
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pharmacokinetics and biodistribution of Lonidamine paclitaxel loaded egfr targeted nanoparticles in an orthotopic animal model of multi drug resistant breast cancer
Nanomedicine: Nanotechnology Biology and Medicine, 2011Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M AmijiAbstract:Abstract The aim of this study was to assess the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)–targeted polymer-blend nanoparticles loaded with the anticancer drugs Lonidamine and paclitaxel. Plasma, tumor, and tissue distribution profiles were quantified in an orthotopic animal model of multidrug-resistant breast cancer and were compared to treatment with nontargeted nanoparticles and to treatment with drug solution. A poly(d,l-lactide- co -glycolide)–poly(ethylene glycol)–EGFR targeting peptide (PLGA-PEG-EFGR peptide) construct was synthesized for incorporation in poly( ɛ -caprolactone) particles to achieve active EGFR targeting. An isocratic high-pressure liquid chromatography method was developed to quantify Lonidamine and paclitaxel in mice plasma, tumors, and vital organs. The targeted nanoparticles demonstrated a superior pharmacokinetic profile relative to drug solution and nontargeted nanoparticles, particularly for Lonidamine delivery. The first target site of accumulation was the liver, followed by the kidneys, and then the tumor mass; maximal tumor accumulation occured at 3 hours after administration. Lonidamine-paclitaxel combination therapy administered via EGFR-targeted polymer-blend nanocarriers may become a viable platform for the future treatment of multidrug-resistant cancer. From the Clinical Editor In this study the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)–targeted polymer-blend nanoparticles loaded with Lonidamine and paclitaxel were assessed. The targeted nanoparticles demonstrated a superior pharmacokinetic profile relative to drug solution and nontargeted nanoparticles, paving the way to new therapeutic approaches for multidrug-resistant malignancies.
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development of egfr targeted polymer blend nanocarriers for combination paclitaxel Lonidamine delivery to treat multi drug resistance in human breast and ovarian tumor cells
Molecular Pharmaceutics, 2011Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M AmijiAbstract:Multi-drug resistant (MDR) cancer is a significant clinical obstacle and is often implicated in cases of recurrent, nonresponsive disease. Targeted nanoparticles were made by synthesizing a poly(d,l-lactide-co-glycolide)/poly(ethylene glycol)/epidermal growth factor receptor targeting peptide (PLGA/PEG/EGFR-peptide) construct for incorporation in poly(epsilon-caprolactone) (PCL) nanoparticles. MDR was induced in a panel of nine human breast and ovarian cancer cell lines using hypoxia. EGFR-targeted polymer blend nanoparticles were shown to actively target EGFR overexpressing cell lines, especially upon induction of hypoxia. The nanoparticles were capable of sustained drug release. Combination therapy with Lonidamine and paclitaxel significantly improved the therapeutic index of both drugs. Treatment with a nanoparticle dose of 1 μM paclitaxel/10 μM Lonidamine resulted in less than 10% cell viability for all hypoxic/MDR cell lines and less than 5% cell viability for all normoxic cell lines. Comparatively, ...
Elena De ,blas - One of the best experts on this subject based on the ideXlab platform.
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Effects of etomoxir in combination with other metabolic inhibitors, in different cell models.
2014Co-Authors: Maria Cristina Estan, Elena De ,blas, Eva Calvino, Susana Calvo, Beatriz Guillén-guío, María Del Carmen Boyano-adánez, Eduardo Rial, Patricio AllerAbstract:(A) Changes in viability, as evidenced by the MTT assay, in HL60 cells treated with 5 and 10 mM 2-DG, alone and in combination with 100 µM etomoxir. Absorption values are indicated in relation to untreated (Cont) cultures. (B) Frequency of HL60 cells at the different growth cycle phases and with sub-G1 DNA content (apoptotic) upon incubation with 5–20 mM 2-DG, alone or with 100 µM etomoxir. (C–E) Frequency of apoptosis in HL60 cell cultures upon incubation with: (C) 100 µM etomoxir and 5–20 mM 2-DG, alone or in combination; (D) the same, using etomoxir and Lonidamine (Lon, 50–150 µM); (E) the same, using etomoxir and metformin (Metf, 4 mM). Metformin plus 2-DG was included as a positive control. (F) Frequency of apoptosis in HL60 cell cultures incubated with 2 µM ATO in combination with 50 µM etomoxir plus 5 mM 2-DG, in relation to ATO plus 2-DG alone and ATO plus etomoxir alone; and in cultures incubated with 2 µM ATO in combination with 50 µM etomoxir plus 50 µM Lonidamine, in relation to ATO plus Lonidamine alone and ATO plus etomoxir alone. (G) Frequency of apoptosis in NBA cell cultures treated with 1–5 mM 2-DG, alone and in combination with 50–100 µM etomoxir. (H) The same in mitogen-stimulated PBLs, using 10 mM 2-DG and 100 µM etomoxir. All treatments lasted for 24 h. All values are the mean ± S.D. of at least four determinations. Symbols in A and F indicate significant differences between the indicated pairs of values. Symbols in C, D, E, G, H, indicate significant differences between the combined treatment and the corresponding individual treatments (n.s., non-significant). For other conditions see legend of Fig. 1.
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Scheme summarizing the main results in this work.
2014Co-Authors: Maria Cristina Estan, Elena De ,blas, Eva Calvino, Susana Calvo, Beatriz Guillén-guío, María Del Carmen Boyano-adánez, Eduardo Rial, Patricio AllerAbstract:Etomoxir decreases respiration while increasing glycolytic activity. In addition, it causes oxidative stress (ROS over-production, GSH depletion) which, together with AMPK activation, may explain the potentiation of ATO-provoked apoptosis. Etomoxir may also cooperate in some cell models with glycolytic inhibitors (2-DG, Lonidamine) to cause apoptosis. This response is further enhanced by co-incubation with ATO, due to the capacity of this agent to attenuate the 2-DG/etomoxir-provoked Akt and ERK activation.
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increased apoptotic efficacy of Lonidamine plus arsenic trioxide combination in human leukemia cells reactive oxygen species generation and defensive protein kinase mek erk akt mtor modulation
Biochemical Pharmacology, 2011Co-Authors: Eva Calvino, Elena De ,blas, Maria Cristina Estan, Gloria P Simon, Pilar Sancho, Maria Del Carmen Boyanoadanez, Jacqueline Breard, Patricio AllerAbstract:Abstract Lonidamine is a safe, clinically useful anti-tumor drug, but its efficacy is generally low when used in monotherapy. We here demonstrate that Lonidamine efficaciously cooperates with the anti-leukemic agent arsenic trioxide (ATO, Trisenox™) to induce apoptosis in HL-60 and other human leukemia cell lines, with low toxicity in non-tumor peripheral blood lymphocytes. Apoptosis induction by Lonidamine/ATO involves mitochondrial dysfunction, as indicated by early mitochondrial permeability transition pore opening and late mitochondrial transmembrane potential dissipation, as well as activation of the intrinsic apoptotic pathway, as indicated by Bcl-X L and Mcl-1 down-regulation, Bax translocation to mitochondria, cytochrome c and Omi/HtrA2 release to the cytosol, XIAP down-regulation, and caspase-9 and -3 cleavage/activation, with secondary (Bcl-2-inhibitable) activation of the caspase-8/Bid axis. Lonidamine stimulates reactive oxygen species production, and Lonidamine/ATO toxicity is attenuated by antioxidants. Lonidamine/ATO stimulates JNK phosphorylation/activation, and apoptosis is attenuated by the JNK inhibitor SP600125. In addition, Lonidamine elicits ERK and Akt/mTOR pathway activation, as indicated by increased ERK, Akt, p70S6K and rpS6 phosphorylation, and these effects are reduced by co-treatment with ATO. Importantly, co-treatment with MEK/ERK inhibitor (U0126) and PI3K/Akt (LY294002) or mTOR (rapamycin) inhibitors, instead of ATO, also potentiates Lonidamine-provoked apoptosis. These results indicate that: (i) Lonidamine efficacy is restrained by drug-provoked activation of MEK/ERK and Akt/mTOR defensive pathways, which therefore represent potential therapeutic targets. (ii) Co-treatment with ATO efficaciously potentiates Lonidamine toxicity via defensive pathway inhibition and JNK activation. And (iii) conversely, the pro-oxidant action of Lonidamine potentiates the apoptotic efficacy of ATO as an anti-leukemic agent.
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Increased apoptotic efficacy of Lonidamine plus arsenic trioxide combination in human leukemia cells. Reactive oxygen species generation and defensive protein kinase (MEK/ERK, Akt/mTOR) modulation
'Elsevier BV', 2011Co-Authors: Calviño Eva, Simón, Gloria P., Elena De ,blas, Estañ, María Cristina, Sancho Pilar, Boyano-adánez, María Del Carmen, Bréard Jacqueline, Aller PatricioAbstract:11 páginas, 7 figuras, 3 figuras suplementarias -- PAGS nros. 1619-1629Lonidamine is a safe, clinically useful anti-tumor drug, but its efficacy is generally low when used in monotherapy. We here demonstrate that Lonidamine efficaciously cooperates with the anti-leukemic agent arsenic trioxide (ATO, Trisenox™) to induce apoptosis in HL-60 and other human leukemia cell lines, with low toxicity in non-tumor peripheral blood lymphocytes. Apoptosis induction by Lonidamine/ATO involves mitochondrial dysfunction, as indicated by early mitochondrial permeability transition pore opening and late mitochondrial transmembrane potential dissipation, as well as activation of the intrinsic apoptotic pathway, as indicated by Bcl-XL and Mcl-1 down-regulation, Bax translocation to mitochondria, cytochrome c and Omi/HtrA2 release to the cytosol, XIAP down-regulation, and caspase-9 and -3 cleavage/activation, with secondary (Bcl-2-inhibitable) activation of the caspase-8/Bid axis. Lonidamine stimulates reactive oxygen species production, and Lonidamine/ATO toxicity is attenuated by antioxidants. Lonidamine/ATO stimulates JNK phosphorylation/activation, and apoptosis is attenuated by the JNK inhibitor SP600125. In addition, Lonidamine elicits ERK and Akt/mTOR pathway activation, as indicated by increased ERK, Akt, p70S6K and rpS6 phosphorylation, and these effects are reduced by co-treatment with ATO. Importantly, co-treatment with MEK/ERK inhibitor (U0126) and PI3K/Akt (LY294002) or mTOR (rapamycin) inhibitors, instead of ATO, also potentiates Lonidamine-provoked apoptosis. These results indicate that: (i) Lonidamine efficacy is restrained by drug-provoked activation of MEK/ERK and Akt/mTOR defensive pathways, which therefore represent potential therapeutic targets. (ii) Co-treatment with ATO efficaciously potentiates Lonidamine toxicity via defensive pathway inhibition and JNK activation. And (iii) conversely, the pro-oxidant action of Lonidamine potentiates the apoptotic efficacy of ATO as an anti-leukemic agentThis work was supported by the Ministerio de Ciencia e Innovación, Spain, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Dirección General de Investigación (Grants SAF2007-64721 and SAF-2010-20256) and Programa Consolider-Ingenio 2010 (Grant CSD-00020); and by the Consejo Superior de Investigaciones Científicas (Grant 201020E037). M.C.E. is recipient of a JAE-Predoc fellowship from de Consejo Superior de Investigaciones Científicas. G.P.S. is the recipient of a “Contrato de Personal Investigador de Apoyo”, Dirección General de Universidades e Investigación, Consejería de Educación, Comunidad de Madrid. The authors are very grateful to Dr. M. De las Casas (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas) for supply of freshly isolated lymphocytesPeer reviewe
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curcumin stimulates reactive oxygen species production and potentiates apoptosis induction by the antitumor drugs arsenic trioxide and Lonidamine in human myeloid leukemia cell lines
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Yolanda Sanchez, Elena De ,blas, Eva Calvino, Gloria P Simon, Patricio AllerAbstract:Arsenic trioxide (ATO, Trisenox) is an important antileukemic drug, but its efficacy is frequently low when used as a single agent. Here, we demonstrate that the apoptotic action of ATO is greatly increased when combined with subcytotoxic curcumin concentrations in U937 and HL60 human acute myeloid leukemia cells, and with lower efficacy in K562 chronic myelogenous leukemia cells. Curcumin exerts similar cooperative effect with the mitochondria-targeting drug Lonidamine, whereas the response is negligible in combination with the DNA-targeting drug cisplatin. Curcumin plus ATO or Lonidamine stimulates typical events of the mitochondrial executioner pathway (Bax and Bid activation, cytochrome c release, X-linked inhibitor of apoptosis down-regulation, and caspase-9/-3 activation) and causes mitochondrial transmembrane potential dissipation, which nevertheless represents a late event in the apoptotic response. Curcumin increases anion superoxide production, and its proapoptotic action in combination with ATO and Lonidamine is mimicked by pro-oxidant agents (2-methoxyestradiol and H(2)O(2)) and prevented by antioxidant agents [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride and N-acetyl-l-cysteine]. Within the assayed time period (16-24 h), curcumin does not significantly modify p38-mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase phosphorylation/activation or nuclear factor-κB activity, but it greatly stimulates extracellular signal-regulated kinase (ERK) phosphorylation, and decreases Akt phosphorylation. Experiments using mitogen-activated protein kinase kinase/ERK inhibitors [2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126)] and phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) indicate that ERK activation does not mediate and even restrains apoptosis potentiation, whereas Akt down-regulation facilitates apoptosis generation. In summary, cotreatment with curcumin may represent a useful manner of increasing the efficacy of ATO and Lonidamine as antitumor drugs in myeloid leukemia cells.
Eva Calvino - One of the best experts on this subject based on the ideXlab platform.
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Effects of etomoxir in combination with other metabolic inhibitors, in different cell models.
2014Co-Authors: Maria Cristina Estan, Elena De ,blas, Eva Calvino, Susana Calvo, Beatriz Guillén-guío, María Del Carmen Boyano-adánez, Eduardo Rial, Patricio AllerAbstract:(A) Changes in viability, as evidenced by the MTT assay, in HL60 cells treated with 5 and 10 mM 2-DG, alone and in combination with 100 µM etomoxir. Absorption values are indicated in relation to untreated (Cont) cultures. (B) Frequency of HL60 cells at the different growth cycle phases and with sub-G1 DNA content (apoptotic) upon incubation with 5–20 mM 2-DG, alone or with 100 µM etomoxir. (C–E) Frequency of apoptosis in HL60 cell cultures upon incubation with: (C) 100 µM etomoxir and 5–20 mM 2-DG, alone or in combination; (D) the same, using etomoxir and Lonidamine (Lon, 50–150 µM); (E) the same, using etomoxir and metformin (Metf, 4 mM). Metformin plus 2-DG was included as a positive control. (F) Frequency of apoptosis in HL60 cell cultures incubated with 2 µM ATO in combination with 50 µM etomoxir plus 5 mM 2-DG, in relation to ATO plus 2-DG alone and ATO plus etomoxir alone; and in cultures incubated with 2 µM ATO in combination with 50 µM etomoxir plus 50 µM Lonidamine, in relation to ATO plus Lonidamine alone and ATO plus etomoxir alone. (G) Frequency of apoptosis in NBA cell cultures treated with 1–5 mM 2-DG, alone and in combination with 50–100 µM etomoxir. (H) The same in mitogen-stimulated PBLs, using 10 mM 2-DG and 100 µM etomoxir. All treatments lasted for 24 h. All values are the mean ± S.D. of at least four determinations. Symbols in A and F indicate significant differences between the indicated pairs of values. Symbols in C, D, E, G, H, indicate significant differences between the combined treatment and the corresponding individual treatments (n.s., non-significant). For other conditions see legend of Fig. 1.
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Scheme summarizing the main results in this work.
2014Co-Authors: Maria Cristina Estan, Elena De ,blas, Eva Calvino, Susana Calvo, Beatriz Guillén-guío, María Del Carmen Boyano-adánez, Eduardo Rial, Patricio AllerAbstract:Etomoxir decreases respiration while increasing glycolytic activity. In addition, it causes oxidative stress (ROS over-production, GSH depletion) which, together with AMPK activation, may explain the potentiation of ATO-provoked apoptosis. Etomoxir may also cooperate in some cell models with glycolytic inhibitors (2-DG, Lonidamine) to cause apoptosis. This response is further enhanced by co-incubation with ATO, due to the capacity of this agent to attenuate the 2-DG/etomoxir-provoked Akt and ERK activation.
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increased apoptotic efficacy of Lonidamine plus arsenic trioxide combination in human leukemia cells reactive oxygen species generation and defensive protein kinase mek erk akt mtor modulation
Biochemical Pharmacology, 2011Co-Authors: Eva Calvino, Elena De ,blas, Maria Cristina Estan, Gloria P Simon, Pilar Sancho, Maria Del Carmen Boyanoadanez, Jacqueline Breard, Patricio AllerAbstract:Abstract Lonidamine is a safe, clinically useful anti-tumor drug, but its efficacy is generally low when used in monotherapy. We here demonstrate that Lonidamine efficaciously cooperates with the anti-leukemic agent arsenic trioxide (ATO, Trisenox™) to induce apoptosis in HL-60 and other human leukemia cell lines, with low toxicity in non-tumor peripheral blood lymphocytes. Apoptosis induction by Lonidamine/ATO involves mitochondrial dysfunction, as indicated by early mitochondrial permeability transition pore opening and late mitochondrial transmembrane potential dissipation, as well as activation of the intrinsic apoptotic pathway, as indicated by Bcl-X L and Mcl-1 down-regulation, Bax translocation to mitochondria, cytochrome c and Omi/HtrA2 release to the cytosol, XIAP down-regulation, and caspase-9 and -3 cleavage/activation, with secondary (Bcl-2-inhibitable) activation of the caspase-8/Bid axis. Lonidamine stimulates reactive oxygen species production, and Lonidamine/ATO toxicity is attenuated by antioxidants. Lonidamine/ATO stimulates JNK phosphorylation/activation, and apoptosis is attenuated by the JNK inhibitor SP600125. In addition, Lonidamine elicits ERK and Akt/mTOR pathway activation, as indicated by increased ERK, Akt, p70S6K and rpS6 phosphorylation, and these effects are reduced by co-treatment with ATO. Importantly, co-treatment with MEK/ERK inhibitor (U0126) and PI3K/Akt (LY294002) or mTOR (rapamycin) inhibitors, instead of ATO, also potentiates Lonidamine-provoked apoptosis. These results indicate that: (i) Lonidamine efficacy is restrained by drug-provoked activation of MEK/ERK and Akt/mTOR defensive pathways, which therefore represent potential therapeutic targets. (ii) Co-treatment with ATO efficaciously potentiates Lonidamine toxicity via defensive pathway inhibition and JNK activation. And (iii) conversely, the pro-oxidant action of Lonidamine potentiates the apoptotic efficacy of ATO as an anti-leukemic agent.
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curcumin stimulates reactive oxygen species production and potentiates apoptosis induction by the antitumor drugs arsenic trioxide and Lonidamine in human myeloid leukemia cell lines
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Yolanda Sanchez, Elena De ,blas, Eva Calvino, Gloria P Simon, Patricio AllerAbstract:Arsenic trioxide (ATO, Trisenox) is an important antileukemic drug, but its efficacy is frequently low when used as a single agent. Here, we demonstrate that the apoptotic action of ATO is greatly increased when combined with subcytotoxic curcumin concentrations in U937 and HL60 human acute myeloid leukemia cells, and with lower efficacy in K562 chronic myelogenous leukemia cells. Curcumin exerts similar cooperative effect with the mitochondria-targeting drug Lonidamine, whereas the response is negligible in combination with the DNA-targeting drug cisplatin. Curcumin plus ATO or Lonidamine stimulates typical events of the mitochondrial executioner pathway (Bax and Bid activation, cytochrome c release, X-linked inhibitor of apoptosis down-regulation, and caspase-9/-3 activation) and causes mitochondrial transmembrane potential dissipation, which nevertheless represents a late event in the apoptotic response. Curcumin increases anion superoxide production, and its proapoptotic action in combination with ATO and Lonidamine is mimicked by pro-oxidant agents (2-methoxyestradiol and H(2)O(2)) and prevented by antioxidant agents [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride and N-acetyl-l-cysteine]. Within the assayed time period (16-24 h), curcumin does not significantly modify p38-mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase phosphorylation/activation or nuclear factor-κB activity, but it greatly stimulates extracellular signal-regulated kinase (ERK) phosphorylation, and decreases Akt phosphorylation. Experiments using mitogen-activated protein kinase kinase/ERK inhibitors [2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126)] and phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) indicate that ERK activation does not mediate and even restrains apoptosis potentiation, whereas Akt down-regulation facilitates apoptosis generation. In summary, cotreatment with curcumin may represent a useful manner of increasing the efficacy of ATO and Lonidamine as antitumor drugs in myeloid leukemia cells.
Lara Milane - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic efficacy and safety of paclitaxel/Lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer. PLoS ONE 2011; 6:24075; PMID:21931642; DOI:10.1371/journal. pone.0024075. molecular targets of adjudin, an anti-s
2015Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M Amiji, Lara S. Duan, Mansoor M, Therapeutic EfficacyAbstract:Therapeutic efficacy and safety of paclitaxel/ Lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cance
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Therapeutic efficacy and safety of paclitaxel/Lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer
2013Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M AmijiAbstract:The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and Lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor). Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase) and LDH (lactate dehydrogenase), and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/Lonidamine) drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted Lonidamine/paclitaxel nanoparticles decreased tumor density an
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therapeutic efficacy and safety of paclitaxel Lonidamine loaded egfr targeted nanoparticles for the treatment of multi drug resistant cancer
PLOS ONE, 2011Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M AmijiAbstract:The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and Lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor). Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase) and LDH (lactate dehydrogenase), and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/Lonidamine) drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted Lonidamine/paclitaxel nanoparticles decreased tumor density and altered the MDR phenotype of the tumor xenografts. These EGFR-targeted combination nanoparticles were considerably less toxic than solution treatments. Due to the flexible design and simple conjugation chemistry, this nanocarrier system could be used as a platform for the development of other MDR cancer therapies; the use of this system for EGFR-targeted, combination paclitaxel/Lonidamine therapy is an advance in personalized medicine.
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pharmacokinetics and biodistribution of Lonidamine paclitaxel loaded egfr targeted nanoparticles in an orthotopic animal model of multi drug resistant breast cancer
Nanomedicine: Nanotechnology Biology and Medicine, 2011Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M AmijiAbstract:Abstract The aim of this study was to assess the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)–targeted polymer-blend nanoparticles loaded with the anticancer drugs Lonidamine and paclitaxel. Plasma, tumor, and tissue distribution profiles were quantified in an orthotopic animal model of multidrug-resistant breast cancer and were compared to treatment with nontargeted nanoparticles and to treatment with drug solution. A poly(d,l-lactide- co -glycolide)–poly(ethylene glycol)–EGFR targeting peptide (PLGA-PEG-EFGR peptide) construct was synthesized for incorporation in poly( ɛ -caprolactone) particles to achieve active EGFR targeting. An isocratic high-pressure liquid chromatography method was developed to quantify Lonidamine and paclitaxel in mice plasma, tumors, and vital organs. The targeted nanoparticles demonstrated a superior pharmacokinetic profile relative to drug solution and nontargeted nanoparticles, particularly for Lonidamine delivery. The first target site of accumulation was the liver, followed by the kidneys, and then the tumor mass; maximal tumor accumulation occured at 3 hours after administration. Lonidamine-paclitaxel combination therapy administered via EGFR-targeted polymer-blend nanocarriers may become a viable platform for the future treatment of multidrug-resistant cancer. From the Clinical Editor In this study the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)–targeted polymer-blend nanoparticles loaded with Lonidamine and paclitaxel were assessed. The targeted nanoparticles demonstrated a superior pharmacokinetic profile relative to drug solution and nontargeted nanoparticles, paving the way to new therapeutic approaches for multidrug-resistant malignancies.
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development of egfr targeted polymer blend nanocarriers for combination paclitaxel Lonidamine delivery to treat multi drug resistance in human breast and ovarian tumor cells
Molecular Pharmaceutics, 2011Co-Authors: Lara Milane, Zhenfeng Duan, Mansoor M AmijiAbstract:Multi-drug resistant (MDR) cancer is a significant clinical obstacle and is often implicated in cases of recurrent, nonresponsive disease. Targeted nanoparticles were made by synthesizing a poly(d,l-lactide-co-glycolide)/poly(ethylene glycol)/epidermal growth factor receptor targeting peptide (PLGA/PEG/EGFR-peptide) construct for incorporation in poly(epsilon-caprolactone) (PCL) nanoparticles. MDR was induced in a panel of nine human breast and ovarian cancer cell lines using hypoxia. EGFR-targeted polymer blend nanoparticles were shown to actively target EGFR overexpressing cell lines, especially upon induction of hypoxia. The nanoparticles were capable of sustained drug release. Combination therapy with Lonidamine and paclitaxel significantly improved the therapeutic index of both drugs. Treatment with a nanoparticle dose of 1 μM paclitaxel/10 μM Lonidamine resulted in less than 10% cell viability for all hypoxic/MDR cell lines and less than 5% cell viability for all normoxic cell lines. Comparatively, ...
