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1.
Nutrients ; 15(17)2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37686755

RESUMO

Several studies utilizing Rhodiola rosea, which contains a complex mixture of phytochemicals, reported some positive drug-drug interaction (DDI) findings based on in vitro CYP450's enzyme inhibition, MAO-A and MAO-B inhibition, and preclinical pharmacokinetic studies in either rats or rabbits. However, variation in and multiplicity of constituents present in Rhodiola products is a cause for concern for accurately evaluating drug-drug interaction (DDI) risk. In this report, we examined the effects of bioengineered, nature-identical salidroside on the inhibition potential of salidroside on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 utilizing human liver microsomes, the induction potential of salidroside on CYP1A2, CYP2B6 and CYP3A4 in cryopreserved human hepatocytes, the inhibitory potential of salidroside against recombinant human MAO-A and MAO-B, and the OATP human uptake transport inhibitory potential of salidroside using transfected HEK293-OATP1B1 and OATP1B3 cells. The results demonstrate that the bioengineered salidroside at a concentration exceeding the predicted plasma concentrations of <2 µM (based on 60 mg PO) shows no risk for drug-drug interaction due to CYP450, MAO enzymes, or OATP drug transport proteins. Our current studies further support the safe use of salidroside in combination with other drugs cleared by CYP or MAO metabolism or OATP-mediated disposition.


Assuntos
Sistema Enzimático do Citocromo P-450 , Interações Medicamentosas , Glucosídeos , Animais , Coelhos , Ratos , Células HEK293
2.
Nutrients ; 14(11)2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35684130

RESUMO

Bioactive phytochemicals such as salidroside have been studied to understand the beneficial effects of Rhodiola rosea, an herbaceous plant used in traditional medicine to increase energy and treat a variety of health issues. However, Rhodiola plants are often slow-growing, and many are endangered in their native habitats. Thus, there is a need for safe, alternative supplies of key phytochemicals from Rhodiola. The salidroside subject of this safety study is a synthetic biology product from fermentation of a bioengineered E. coli that produces salidroside. Here, we present comprehensive test results that support the safety of salidroside manufactured via a patented sustainable bioengineering manufacturing process. In vitro bacterial reverse mutation assays with the bioengineered salidroside show no mutagenicity in any of the concentrations tested. In vivo toxicity studies in rats show no adverse effects from the salidroside product. Based on the results of these studies, we conclude that the bioengineered salidroside discussed here is not genotoxic and demonstrates a no-observed-adverse-effect level (NOAEL) at least 2000 mg/kg bw/day in male and female Sprague-Dawley rats. This study supports that the salidroside compound produced using bioengineered E. coli is a viable alternative to salidroside produced from harvested Rhodiola plants for use as a dietary supplement, food ingredient, or potentially as a pharmaceutical product.


Assuntos
Escherichia coli , Rhodiola , Animais , Escherichia coli/genética , Feminino , Glucosídeos/farmacologia , Masculino , Fenóis , Ratos , Ratos Sprague-Dawley , Rhodiola/química
3.
Int J Cancer ; 124(6): 1449-56, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19065668

RESUMO

CDC25 phosphatases are key actors in cyclin-dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy. Here, we report the identification and the characterization of IRC-083864, an original bis-quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC-083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT-116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC-083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent.


Assuntos
Benzotiazóis/uso terapêutico , Benzoxazóis/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Quinonas/uso terapêutico , Fosfatases cdc25/antagonistas & inibidores , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Quinases Ciclina-Dependentes/metabolismo , Citometria de Fluxo , Humanos , Camundongos , Camundongos Nus , Transplante Heterólogo
4.
Mol Cancer Ther ; 7(8): 2426-34, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18723488

RESUMO

Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on beta-tubulin and on alpha-tubulin and beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G(2)-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs.


Assuntos
Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Imidazóis/farmacologia , Sulfonamidas/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Ciclo Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Camundongos , Neovascularização Patológica , Transplante Heterólogo
5.
Cancer Res ; 66(18): 9227-34, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16982767

RESUMO

A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq). BIM-46174 inhibits the growth of a large panel of human cancer cell lines, including anticancer drug-resistant cells. Exposure of cancer cells to BIM-46174 leads to caspase-3-dependent apoptosis and poly(ADP-ribose) polymerase cleavage. National Cancer Institute COMPARE analysis for BIM-46174 supports its novel pharmacologic profile compared with 12,000 anticancer agents. The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors. Our data validate the feasibility of targeting heterotrimeric G-protein functions downstream the GPCRs to improve anticancer chemotherapy.


Assuntos
Cisteína/análogos & derivados , Proteínas Heterotriméricas de Ligação ao GTP/antagonistas & inibidores , Imidazóis/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisteína/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades beta da Proteína de Ligação ao GTP/antagonistas & inibidores , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/antagonistas & inibidores , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Células HL-60 , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Humanos , Camundongos , Invasividade Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Med Chem ; 61(3): 1031-1044, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29227648

RESUMO

Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure-activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αß-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αß-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Quinazolinonas/química , Estereoisomerismo , Relação Estrutura-Atividade , Moduladores de Tubulina/química
7.
J Med Chem ; 50(18): 4431-43, 2007 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-17696419

RESUMO

Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI(50) = 0.38 microM) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI(50) = 0.22 microM) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI(50) = 0.21 microM). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents.


Assuntos
Antineoplásicos/síntese química , Carbamatos/síntese química , Estradiol/análogos & derivados , Estradiol/síntese química , Ácidos Sulfônicos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbamatos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Estradiol/farmacologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Relação Estrutura-Atividade , Ácidos Sulfônicos/farmacologia
8.
Cancer Res ; 64(14): 4942-9, 2004 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15256467

RESUMO

BN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered beta-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition. Moreover, a Topo I-altered cell line (KBSTP2), resistant to SN38, remains sensitive to BN80927, suggesting that a part of the antiproliferative effects of BN80927 are mediated by a Topo I-independent pathway. This hypothesis is also supported by in vitro data showing an antiproliferative activity of BN80927 on a model of resistance related to the noncycling state of cells (G(0)-G(1) synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC(50) values consistently lower than those of SN38 in tumor cell lines as well as in their related drug-resistant lines. BN80927 shows high efficiency in vivo in tumor xenograft studies using human androgen-independent prostate tumors PC3 and DU145. Altogether, these data strongly support the clinical development of BN80927.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Animais , Camptotecina/sangue , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , DNA Super-Helicoidal/efeitos dos fármacos , DNA Super-Helicoidal/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Inibidores Enzimáticos/farmacologia , Células HL-60 , Humanos , Células K562 , Masculino , Camundongos , Camundongos Nus , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cancer Res ; 64(9): 3320-5, 2004 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15126376

RESUMO

CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models. BN82002 inhibits the phosphatase activity of recombinant human CDC25A, B, and C in vitro. It impairs the proliferation of tumoral cell lines and increases cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, BN82002 delays cell cycle progression at G1-S, in S phase and at the G2-M transition. In contrast, BN82002 arrests U2OS cell cycle mostly in the G1 phase. Selectivity of this inhibitor is demonstrated: (a) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and (b) by the partial reversion of cell cycle arrest in U2OS expressing CDC25. We also show that BN82002 reduces growth rate of human tumor xenografts in athymic nude mice. BN82002 is a original CDC25 inhibitor that is active both in cell and animal models. This greatly reinforces the interest in CDC25 as an anticancer target.


Assuntos
Inibidores Enzimáticos/farmacologia , Fosfatases cdc25/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Etilaminas , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Nus , Mitose/efeitos dos fármacos , Nitrocompostos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Fosfatases cdc25/biossíntese , Fosfatases cdc25/genética
10.
Mol Cancer Ther ; 4(9): 1378-87, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16170030

RESUMO

Cell cycle regulators, such as the CDC25 phosphatases, are potential targets for the development of new anticancer drugs. Here we report the identification and the characterization of BN82685, a quinone-based CDC25 inhibitor that is active in vitro and in vivo. BN82685 inhibits recombinant CDC25A, B, and C phosphatases in vitro. It inhibits the growth of human tumor cell lines with an IC(50) in the submicromolar range, independently of their resistance to chemotherapeutic agents. This inhibitory effect is irreversible on both the purified CDC25 enzyme in vitro and on tumor cell proliferation. The specificity of BN82685 towards the CDC25 phosphatases is shown by an increase in cyclin-dependent kinase 1 tyrosine 15 phosphorylation, by the reversion of the mitosis-inducing effect of CDC25B overexpression in HeLa cells, and by the lack of a growth inhibitory effect in an assay based on the use of a CDC25-independent fission yeast model. Finally, when administered p.o., BN82685 is shown to inhibit the growth of the human pancreatic tumor Mia PaCa-2 xenografted in athymic nude mice. BN82685 is therefore a promising new compound targeting CDC25, which confirms the interest of the inhibition of these enzymes as an anticancer therapeutic strategy.


Assuntos
Benzoquinonas/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Pancreáticas/patologia , Tiazóis/farmacologia , Fosfatases cdc25/antagonistas & inibidores , Administração Oral , Animais , Benzoquinonas/administração & dosagem , Benzoquinonas/síntese química , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Nus , Mitose/efeitos dos fármacos , Neoplasias Pancreáticas/enzimologia , Schizosaccharomyces/genética , Schizosaccharomyces/crescimento & desenvolvimento , Schizosaccharomyces/metabolismo , Tiazóis/administração & dosagem , Tiazóis/síntese química , Transplante Heterólogo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
ChemMedChem ; 9(1): 85-108, 1, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24124095

RESUMO

A structure-activity relationship (SAR) translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)-based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B-ring-mimicking THIQ core was connected to methoxyaryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g., 7-methoxy-2-(3- methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (20 c) GI50=2.1 µM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ-based A,B-mimic with the trimethoxyaryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (GI50=40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 7-methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline relative to a benchmark steroidal bis- sulfamate in an in vivo model of multiple myeloma.


Assuntos
Antineoplásicos/química , Compostos de Benzil/química , Isoquinolinas/química , Microtúbulos/metabolismo , Tetra-Hidroisoquinolinas/química , Moduladores de Tubulina/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos de Benzil/farmacologia , Compostos de Benzil/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Camundongos , Camundongos Nus , Microtúbulos/química , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico
12.
ChemMedChem ; 9(2): 350-70, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24436228

RESUMO

The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl-substituted sulfamate (±)-7-methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (6 b), for example, was found to be ∼10-fold more potent than the corresponding non-methylated compound 7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (4 b) against DU-145 prostate cancer cells (GI50 values: 220 nM and 2.1 µM, respectively). Such compounds were also found to be active against a drug-resistant MCF breast cancer cell line. The position and nature of substitution of the N-benzyl group in the C3-substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3-gem-dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/uso terapêutico , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Mieloma Múltiplo/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/farmacologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
13.
PLoS One ; 8(12): e80305, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24324595

RESUMO

Despite paclitxael's clinical success, treating hormone-refractory breast cancer remains challenging. Paclitaxel has a poor pharmacological profile, characterized by a low therapeutic index (TIX) caused by severe dose limiting toxicities, such as neutropenia and peripheral neuropathy. Consequently, new drugs are urgently required. STX140, a compound previously shown to have excellent efficacy against many tumors, is here compared to paclitaxel in three translational in vivo breast cancer models, a rat model of peripheral neuropathy, and through pharmacological testing. Three different in vivo mouse models of breast cancer were used; the metastatic 4T1 orthotopic model, the C3(1)/SV40 T-Ag model, and the MDA-MB-231 xenograft model. To determine TIX and pharmacological profile of STX140, a comprehensive dosing regime was performed in mice bearing MDA-MD-231 xenografts. Finally, peripheral neuropathy was examined using a rat plantar thermal hyperalgesia model. In the 4T1 metastatic model, STX140 and paclitaxel significantly inhibited primary tumor growth and lung metastases. All C3(1)/SV40 T-Ag mice in the control and paclitaxel treated groups developed palpable mammary cancer. STX140 blocked 47% of tumors developing and significantly inhibited growth of tumors that did develop. STX140 treatment caused a significant (P<0.001) survival advantage for animals in early and late intervention groups. Conversely, in C3(1)/SV40 T-Ag mice, paclitaxel failed to inhibit tumor growth and did not increase survival time. Furthermore, paclitaxel, but not STX140, induced significant peripheral neuropathy and neutropenia. These results show that STX140 has a greater anti-cancer efficacy, TIX, and reduced neurotoxicity compared to paclitaxel in C3(1)/SV40 T-Ag mice and therefore may be of significant benefit to patients with breast cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Estrenos/farmacologia , Hiperalgesia/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Animais , Antígenos Transformantes de Poliomavirus/genética , Antígenos Transformantes de Poliomavirus/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Progressão da Doença , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Hiperalgesia/imunologia , Hiperalgesia/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/mortalidade , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Análise de Sobrevida , Transplante Heterólogo
14.
Breast Cancer Res Treat ; 111(2): 251-60, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17957467

RESUMO

Breast cancer is the leading cause of cancer deaths among women worldwide. The theory of targeting both cancer cells directly and their blood supply has significant therapeutic potential. However, to date, there are few clinically successful single agents that meet these criteria. 2-Methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE) and 2-ethylestradiol-3,17-O,O-bis-sulfamate (2-EtE2bisMATE) are potent inhibitors of proliferation in a range of cancer cells. The work presented here demonstrates the potent in vitro and in vivo effects of these compounds. They cause apoptosis via the intrinsic mitochondrial pathway in both MDA-MB-231 breast cancer cells and endothelial cells. Furthermore, they are potent anti-angiogenic inhibitors in vivo, as shown by their ability to reduce endothelial staining in MDA-MB-231 xenograft tumors. We have developed a novel, flow cytometry based, ex vivo method which shows in cells recovered from MDA-MB-231 tumors treated with 2-MeOE2bisMATE and 2-EtE2bisMATE an increase in intra-tumoral G(2)-M arrest and apoptosis. The degree of apoptosis inversely correlates to tumor volume. Further in vivo studies reveal that both 2-MeOE2bisMATE and 2-EtE2bisMATE are orally bioavailable and extremely efficacious when compared to clinically tested drugs. As these compounds are anti-proliferative against breast cancer and endothelial cells they have the potential to be potent, dual acting clinical drugs of the future.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Estradiol/análogos & derivados , Ácidos Sulfônicos/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Estradiol/farmacocinética , Estradiol/farmacologia , Estradiol/uso terapêutico , Estradiol/toxicidade , Feminino , Humanos , Camundongos , Transplante de Neoplasias , Ácidos Sulfônicos/farmacocinética , Ácidos Sulfônicos/toxicidade , Transplante Heterólogo
15.
Mol Pharmacol ; 67(2): 531-40, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15531732

RESUMO

Most drugs currently used for human therapy interact with proteins, altering their activity to modulate the pathological cell physiology. In contrast, 2-hydroxy-9-cis-octadecenoic acid (Minerval) was designed to modify the lipid organization of the membrane. Its structure was deduced following the guidelines of the mechanism of action previously proposed by us for certain antitumor drugs. The antiproliferative activity of Minerval supports the above-mentioned hypothesis. This molecule augments the propensity of membrane lipids to organize into nonlamellar (hexagonal H(II)) phases, promoting the subsequent recruitment of protein kinase C (PKC) to the cell membrane. The binding of the enzyme to membranes was marked and significantly elevated by Minerval in model (liposomes) and cell (A549) membranes and in heart membranes from animals treated with this drug. In addition, Minerval induced increased PKCalpha expression (mRNA and protein levels) in A549 cells. This drug also induced PKC activation, which led to a p53-independent increase in p21(CIP) expression, followed by a decrease in the cellular concentrations of cyclins A, B, and D3 and cdk2. These molecular changes impaired the cell cycle progression of A549 cells. At the cellular and physiological level, administration of Minerval inhibited the growth of cancer cells and exerted antitumor effects in animal models of cancer without apparent histological toxicity. The present results support the potential use of Minerval and related compounds in the treatment of tumor pathologies.


Assuntos
Antineoplásicos/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Ácidos Oleicos/farmacologia , Proteína Quinase C/metabolismo , Ácidos Esteáricos/farmacologia , Animais , Bovinos , Linhagem Celular Tumoral , Membrana Celular/patologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores do Crescimento/farmacologia , Humanos , Lipossomos , Ácidos Oleicos/química , Proteína Quinase C-alfa
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