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1.
Invest New Drugs ; 26(3): 205-13, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17943230

RESUMO

Clinically relevant resistance to the currently approved camptothecins, irinotecan and topotecan, is poorly understood but may involve increased expression of ATP-dependent drug transporters such as ABCG2 (breast cancer resistant protein, BCRP). Gimatecan (ST1481) is a lipophilic 7-substituted camptothecin derivative that exhibits potent anti-tumor activity in a variety of preclinical cancer models and is under investigation in the clinic. Previous studies reported that gimatecan cytotoxicity was not affected by expression of ABCG2. To confirm and extend this finding, we assessed the cytotoxicity of gimatecan in pairs of isogenic cell lines consisting of transfectants expressing either ABCG2 (including wild-type, R482T, or R482G mutants), ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2), or ABCC4 (MRP4). Expression of wild-type or mutant ABCG2 in human cell lines conferred resistance to topotecan but not to gimatecan. Similarly, intracellular accumulation of gimatecan was unaffected by expression of wild-type ABCG2. Furthermore, expression of P-glycoprotein or MRP2 did not alter gimatecan cytotoxicity. Whereas expression of MRP1 had a minor effect on gimatecan cytotoxicity, expression of ABCC4 was found to significantly reduce the anti-proliferative effects of this drug. Cells containing resistance-conferring mutations in topoisomerase I were also resistant to gimatecan. These results suggest that gimatecan may be more effective than irinotecan or topotecan in cancers that express ABCG2, but not in cancers that express high levels of ABCC4 or contain certain topoisomerase I (TOP1) mutations.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Animais , Camptotecina/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/genética , DNA Topoisomerases Tipo I/metabolismo , Cães , Expressão Gênica , Humanos , Irinotecano , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação , Topotecan/farmacologia , Transfecção
2.
Mol Cancer Ther ; 6(12 Pt 1): 3307-13, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18089724

RESUMO

Lipophilic camptothecin derivatives are considered to have negligible affinity for breast cancer resistance protein (BCRP; ABCG2). Gimatecan, a new orally available 7-t-butoxyiminomethyl-substituted lipophilic camptothecin derivative, has been previously reported to be not a substrate for BCRP. Using a panel of in vitro models, we tested whether gimatecan is a substrate for BCRP as well as for P-glycoprotein (MDR1) or multidrug resistance protein 2 (MRP2; ABCC2), ATP-binding cassette drug efflux transporters involved in anticancer drug resistance, and able to affect the pharmacokinetics of substrate drugs. Cell survival, drug transport, accumulation, and efflux were studied in IGROV1 and (human BCRP overexpressing) T8 cells, Madin-Darby canine kidney II (MDCKII-WT, MDCKII-Bcrp1, MDCKII-MDR1, and MDCKII-MRP2), and LLCPK (LLCPK-WT and LLCPK-MDR1) cells. Competition with methotrexate uptake was studied in Sf9-BCRP membrane vesicles. In vitro, expression of BCRP resulted in 8- to 10-fold resistance to gimatecan. In Transwell experiments, gimatecan was transported by Bcrp1 and transport was inhibited by the BCRP/P-glycoprotein inhibitors elacridar and pantoprazole. Efflux of gimatecan from MDCKII-Bcrp1 cells was faster than in WT cells. In Sf9-BCRP membrane vesicles, gimatecan significantly inhibited BCRP-mediated transport of methotrexate. In contrast, gimatecan was not transported by MDR1 or MRP2. Gimatecan is transported by BCRP/Bcrp1 in vitro, although to a lesser extent than the camptothecin analogue topotecan. Implications of BCRP expression in the gut for the oral development of gimatecan and the interaction between gimatecan and other BCRP substrate drugs and/or inhibitors warrant further clinical investigation.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Camptotecina/análogos & derivados , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Antimetabólitos Antineoplásicos/metabolismo , Transporte Biológico , Camptotecina/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Cães , Interações Medicamentosas , Humanos , Metotrexato/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla
3.
Cancer Res ; 64(9): 2984-7, 2004 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15126329

RESUMO

Inhibition of endothelial cell growth by fumagillin has been assumed to be mediated by inhibition of the molecular target methionine aminopeptidase 2 (MetAp2). New data show that depletion of MetAp2 by siRNA does not inhibit endothelial cell growth. Moreover, MetAp2-depleted endothelial cells remain responsive to inhibition by either fumagillin or a newly identified MetAp2 enzyme inhibitor. These data suggest that MetAp2 function is not required for endothelial cell proliferation.


Assuntos
Aminopeptidases/deficiência , Azepinas/farmacologia , Ácidos Graxos Insaturados/farmacologia , Metaloendopeptidases/deficiência , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/genética , Aminopeptidases/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Cicloexanos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias Pulmonares/enzimologia , Metaloendopeptidases/antagonistas & inibidores , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , RNA Interferente Pequeno/genética , Sesquiterpenos , Especificidade por Substrato , Transfecção
4.
Cancer Res ; 64(2): 689-95, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14744786

RESUMO

We have synthesized a histone deacetylase inhibitor, NVP-LAQ824, a cinnamic hydroxamic acid, that inhibited in vitro enzymatic activities and transcriptionally activated the p21 promoter in reporter gene assays. NVP-LAQ824 selectively inhibited growth of cancer cell lines at submicromolar levels after 48-72 h of exposure, whereas higher concentrations and longer exposure times were required to retard the growth of normal dermal human fibroblasts. Flow cytometry studies revealed that both tumor and normal cells arrested in the G(2)-M phase of the cell cycle after compound treatment. However, an increased sub-G(1) population at 48 h (reminiscent of apoptotic cells) was observed only in the cancer cell line. Annexin V staining data supported our hypothesis that NVP-LAQ824 induced apoptosis in tumor and transformed cells but not in normal cells. Western blotting experiments showed an increased histone H3 and H4 acetylation level in NVP-LAQ824-treated cancer cells, suggesting that the likely in vivo target of NVP-LAQ824 was histone deacetylase(s). Finally, NVP-LAQ824 exhibited antitumor effects in a xenograft animal model. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel histone deacetylase inhibitor is currently in clinical trials as an anticancer agent.


Assuntos
Antineoplásicos/toxicidade , Neoplasias do Colo/tratamento farmacológico , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/toxicidade , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Inibidores Enzimáticos/toxicidade , Fluoruracila/uso terapêutico , Histona Desacetilases/isolamento & purificação , Humanos , Cinética , Masculino , Camundongos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Transplante Heterólogo
5.
J Med Chem ; 46(21): 4609-24, 2003 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-14521422

RESUMO

A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.


Assuntos
Acetiltransferases/antagonistas & inibidores , Acrilamidas/síntese química , Acrilamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histona Acetiltransferases , Humanos , Indicadores e Reagentes , Camundongos , Camundongos Nus , Conformação Molecular , Transplante de Neoplasias
6.
J Biol Chem ; 278(52): 52964-71, 2003 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-14534293

RESUMO

LAF389 is a synthetic analogue of bengamides, a class of marine natural products that produce inhibitory effects on tumor growth in vitro and in vivo. A proteomics-based approach has been used to identify signaling pathways affected by bengamides. LAF389 treatment of cells resulted in altered mobility of a subset of proteins on two-dimensional gel electrophoresis. Detailed analysis of one of the proteins, 14-3-3gamma, showed that bengamide treatment resulted in retention of the amino-terminal methionine, suggesting that bengamides directly or indirectly inhibited methionine aminopeptidases (MetAps). Both known MetAps are inhibited by LAF389. Short interfering RNA suppression of MetAp2 also altered amino-terminal processing of 14-3-3gamma. A high resolution structure of human MetAp2 co-crystallized with a bengamide shows that the compound binds in a manner that mimics peptide substrates. Additionally, the structure reveals that three key hydroxyl groups on the inhibitor coordinate the di-cobalt center in the enzyme active site.


Assuntos
Aminopeptidases/química , Azepinas/farmacologia , Proteínas 14-3-3 , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/genética , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Sítios de Ligação , Divisão Celular , Linhagem Celular Tumoral , Clonagem Molecular , Cobalto/química , Cristalografia por Raios X , Cicloexanos , Relação Dose-Resposta a Droga , Eletroforese em Gel Bidimensional , Inibidores Enzimáticos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Glicoproteínas/química , Glicoproteínas/genética , Humanos , Metionil Aminopeptidases , Modelos Químicos , Modelos Moleculares , Peptídeos/química , Ligação Proteica , Isoformas de Proteínas , Estrutura Terciária de Proteína , Proteoma , RNA Interferente Pequeno/metabolismo , Sesquiterpenos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tirosina 3-Mono-Oxigenase/metabolismo
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