RESUMO
Toremifene (TOR) and Tamoxifen (TAM) are widely used as endocrine therapy for estrogen receptor positive breast cancer. Poor metabolizers of TAM are likely to have worse clinical outcomes than patients who exhibit normal TAM metabolism due to lower plasma level of its active metabolite, 4-hydroxy-N-desmethyl (4OH-NDM) tamoxifen (endoxifen). In this study, we examined the role of individual cytochrome P450 (CYP) isoforms in the metabolism of TOR to N-desmethyl (NDM), 4-hydroxy (4OH) and 4OH-NDM metabolites in comparison with TAM using human liver microsomes (HLMs) with selective chemical inhibitors for each CYP isoform and recombinant CYP proteins. Similar levels of NDM metabolites were formed for both TOR and TAM, and N-demethylation of both compounds was primarily carried out by CYP3A4. We found that the formation of 4OH-NDM-TOR was catalyzed both by CYP2C9 and CYP2D6, whereas the formation of 4OH-TAM and endoxifen was specifically catalyzed by CYP2D6 in HLMs. Our results suggest that the potential contribution of CYP2D6 in the bioactivation pathway of TOR may be lower compared to TAM, and may have a different impact on clinical outcome than CYP2D6 polymorphisms.
Assuntos
Microssomos Hepáticos/metabolismo , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Tamoxifeno/metabolismo , Toremifeno/metabolismo , Biotransformação , Linhagem Celular Tumoral , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Feminino , Humanos , Técnicas In Vitro , Microssomos Hepáticos/efeitos dos fármacos , Tamoxifeno/análogos & derivadosRESUMO
Antiestrogen agents are commonly used to treat patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen has been the mainstay of endocrine treatment for patients with early and advanced breast cancer for many years. Following tamoxifen treatment failure, however, there are still limited options for subsequent hormonal therapy. We discovered a novel compound, NK150460, that inhibits 17ß-estradiol (E2)-dependent transcription without affecting binding of E2 to ER. Against our expectations, NK150460 inhibited growth of not only most ER-positive, but also some ER-negative breast cancer cell lines, while never inhibiting growth of non-breast cancer cell lines. Cell-based screening using a random shRNA library, identified aryl hydrocarbon receptor nuclear translocator (ARNT) as a key gene involved in NK150460's antitumor mechanism. siRNAs against not only ARNT but also its counterpart aryl hydrocarbon receptor (AhR) and their target protein, CYP1A1, dramatically abrogated NK150460's growth-inhibitory activity. This suggests that the molecular cascade of AhR/ARNT plays an essential role in NK150460's antitumor mechanism. Expression of ERα was decreased by NK150460 treatment, and this was inhibited by an AhR antagonist. Unlike two other AhR agonists now undergoing clinical developmental stage, NK150460 did not induce histone H2AX phosphorylation or p53 expression, suggesting that it did not induce a DNA damage response in treated cells. Cell lines expressing epithelial markers were more sensitive to NK150460 than mesenchymal marker-expressing cells. These data indicate that NK150460 is a novel AhR agonist with selective antitumor activity against breast cancer cell lines, and its features differ from those of the other two AhR agonists.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Quinolinas/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Citocromo P-450 CYP1A1/metabolismo , Dano ao DNA , Células Epiteliais/metabolismo , Estrogênios/farmacologia , Feminino , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Camundongos Nus , Quinolinas/química , Ratos Nus , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genéticaRESUMO
Preliminary examination for the structure-activity relationship of quinone monooxime derivatives on cytotoxicity against HeLa S3 cell and further trials using eight different cell lines suggested that 2-aryl-6,7-methylenedioxy-1,4-naphthoquinone-1-oxime methyl ethers, carrying 2-methoxy-4,5-methylenedioxyphenyl, 7-methoxy-2-methylbenzofuran-4-yl, and 2-methoxycarbonyl-3,4-dimethoxyphenyl as the 2-aryl substituent, were potential candidates for anti-cancer drugs.
Assuntos
Antineoplásicos/química , Éteres Metílicos/química , Naftoquinonas/química , Oximas/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Naftoquinonas/toxicidade , Oximas/toxicidade , Relação Estrutura-AtividadeRESUMO
Our laboratory has been investigating the use of compounds which disrupt beta-catenin/T cell factor (TCF) binding to treat human colon cancer. There are several cysteine residues on the surface of beta-catenin where it binds to TCF. Some bis[2-(acylamino)phenyl] disulfides might have the ability to form a disulfide bond with the cysteine residues of beta-catenin, leading to inhibition of the growth of human colon cells. Bis[2-(acylamino)phenyl] disulfides were screened to inhibit the growth of cancer cells. Among them, bis[2-(2,2-dimethylpropanoylamino)phenyl] disulfide (1) had promising inhibitory effects (HCT116, IC50: 9.7 microM; DLD-1, IC50: 6.9 microM) on cell proliferation, and did not show any cytotoxicity among normal human fibroblast CCD-1059SK cells even at 200 microM. This derivative reduced the beta-catenin/TCF4 association in the HCT116 cells to ca. 50% at 150 microM. Furthermore, it activated markedly the phosphorylation of c-Jun N-terminal kinase (JNK) connected to stress-activated apoptosis at a lower concentration (30 microM). In view of cell cycle analyses, Hoechst staining, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin Nick end-labeling (TUNEL) assays along with the above results, it is likely that 1 inhibited the growth of HCT116 cells through pathways including the JNK-mediated apoptosis.
Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Dissulfetos/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Citometria de Fluxo , Corantes Fluorescentes , Células HCT116 , Humanos , Imunoprecipitação , Marcação In Situ das Extremidades Cortadas , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , beta Catenina/metabolismoRESUMO
4 OSW-1 analogues featuring modified carbohydrate moieties were prepared. The purpose of these modifications was to assess the importance of certain chemical functions with respect to biological activity. The synthesis and biological activity of the target molecules are shown.
Assuntos
Carboidratos/química , Colestenonas/química , Saponinas/química , Linhagem Celular Tumoral , Colestenonas/farmacologia , Humanos , Saponinas/farmacologiaRESUMO
The in vitro growth inhibitory activity of lissoclibadins and lissoclinotoxins isolated from the tropical ascidian Lissoclinum cf. badium against nine human cancer cell lines was examined to evaluate their potential anticancer efficacy. Lissoclibadins 1 (1) and 2 (2), and lissoclinotoxin F (4) showed the strongest activity of the six compounds tested, which were more potent than the anticancer drug cisplatin. Compound 1 has a trimeric structure, and compounds 2 and 4 are structural isomers possessing dimeric structures connected by disulfide and sulfide bonds of trans- and cis-orientations, respectively. Lissoclibadin 3 (3), a dimeric compound connected by two sulfide bonds, and two monomeric compounds (5, 6) were less active than 1, 2, and 4. Lissoclibadin 2 (2) was the most interesting compound possessing potent inhibitory activity against colon (DLD-1 and HCT116), breast (MDA-MB-231), renal (ACHN), and non-small-cell lung (NCI-H460) cancer cell lines and showing no toxicity following a 50 mg/kg single treatment to mice, and preferable stability in rat plasma.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Urocordados/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , HumanosRESUMO
To identify prodrugs of a thiolate histone deacetylase inhibitor NCH-31 that show potent antiproliferative activity and are stable in human plasma, we synthesized several candidate prodrugs of NCH-31. Among these compounds, S-2-methyl-3-phenylpropanoyl compound 2 showed more potent antiproliferative activity and higher stability in human plasma than S-isobutyryl compound NCH-51.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Tiazóis/farmacologia , Western Blotting , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , HumanosRESUMO
We report here that lysocellin, a polyether antibiotic from a streptomycete, induces G1 phase arrest in human osteosarcoma MG63 cells. Lysocellin up-regulates p21WAF1/Cip1 and down-regulates cyclin D1 at the mRNA level. In addition, cyclin D1 is down-regulated by the proteasome-dependent signal pathway in MG63 cells. In drug combination studies, we found that lysocellin treatment weakened the cytotoxic activity of etoposide in MG63 cells using a colony-formation assay. To study the in vivo efficacy of lysocellin, we isolated a novel compound related to lysocellin from the same streptomycete, and found that the novel drug is converted to lysocellin in vivo and decreases etoposide-induced alopecia in a neonatal rat model. We raise the possibility that this novel drug, named 'alopestatin', may be a promising agent against alopecia.
Assuntos
Proliferação de Células/efeitos dos fármacos , Etoposídeo/farmacologia , Fase G1/efeitos dos fármacos , Alopecia/induzido quimicamente , Alopecia/prevenção & controle , Animais , Animais Recém-Nascidos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Área Sob a Curva , Northern Blotting , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Etoposídeo/toxicidade , Feminino , Furanos/administração & dosagem , Furanos/sangue , Furanos/metabolismo , Furanos/farmacocinética , Furanos/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
To find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) was designed and synthesized. In this series, compound 7, in which the hydroxamic acid of SAHA is replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. In cancer cell growth inhibition assay, S-isobutyryl derivative 51 showed strong activity, and its potency was comparable to that of SAHA. The cancer cell growth inhibitory activity was verified to be the result of histone hyperacetylation and subsequent induction of p21(WAF1/CIP1) by Western blot analysis. Kinetical enzyme assay and molecular modeling suggest the thiol formed by enzymatic hydrolysis within the cell interacts with the zinc ion in the active site of HDACs.
Assuntos
Antineoplásicos/síntese química , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/síntese química , Tiazóis/síntese química , Acetilação , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Ligação Competitiva , Proteínas de Ciclo Celular/biossíntese , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21 , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilases/química , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Modelos Moleculares , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , VorinostatRESUMO
The screening tests of N-hydroxybenzamides for their HDAC-inhibitory activities led to the discovery of the promising compounds with a 2-naphthylcarbonyl group and with a 1,4-biphenylcarbonyl group. These compounds were further modified to optimize their physico-chemical profile. As a result, the inhibitor with a 6-amino-2-naphthylcarbonyl was obtained, which showed not only promising growth inhibitions against a panel of tumor cells, but also an improved water solubility. It exhibited the maximal 185% of survival rate (%T/C) in a in vivo experiment with P388 cell-inoculated mice.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores de Histona Desacetilases , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A concise total synthesis of 12-methoxydihydrochelerythrine (6), isolated from Bocconia integrifolia, is described. The synthesis features an efficient route to a 12-alkoxybenzo[c]phenanthridine skeleton via naphthoquinone monooxime 11 as a key compound. Starting from 7-methoxy-2-methylbenzo[b]furan (9), 3-aryl-1-tetralone 10 was synthesised, followed by aromatisation to 3-aryl-1-naphthol 17. After oxidative cleavage of the furan ring, basic nitrosation of naphthol 22 gave the naphthoquinone 11. The benzo[c]phenanthridine skeleton was formed by reductive cyclisation of 11. Deoxygenation of the lactam moiety in 23 afforded nor-base 32 and methylation of 32 under reductive conditions gave the target dihydro base 6 (23 steps from benzofuran 9 in 10% overall yield). The corresponding quaternary base 7 showed moderate anti-tumour activity against cancer cell lines; on NCI-H460: IC50 4.5 microM and on MDA-MB-231: IC50 1.2 microM. Introduction of a methoxy group into the 12-position of the benzo[c]phenanthridine skeleton could cause enhanced activity against MDA-MB-231 by comparison of 7 with chelerythrine (35) (IC50 5.3 microM).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzofuranos/química , Naftoquinonas/química , Oximas/química , Fenantridinas/síntese química , Tetralonas/química , Benzofenantridinas , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenantridinas/farmacologiaRESUMO
Effects of toremifene (TOR) in combination with paclitaxel (TXL) on various human breast cancer cell lines were evaluated. TOR and TXL exhibited additive effects on estrogen receptor (ER)-positive cancer cell lines, MCF-7 and T-47D, and a sub-additive effect on a tamoxifen (TAM)-resistant line, T-47D/TAM. To all three ER-negative cancer cell lines, the combined treatment also showed additive effects on MDA-MB-134VI, MDA-MB-231 and MDA-MB-453. Furthermore, a synergistic effect was observed on a multi-drug resistant (MDR) line, Adr. This synergistic effect was more potent in the combination with TOR than that with TAM. The combined treatment increased intracellular TXL, and the accumulation by TOR was 1.5-fold that by TAM. Consequently, the ratio of G2M arrested cells was higher, with statistical significance, in the TOR combination than in the TAM combination. In addition, these synergistic effects in MDR cells were also observed in the combination of TXL with major clinical active metabolites, N-desmethyl-TOR (TOR-1) and 4-hydroxy-TOR (TOR-2). These results suggest that the combination therapy of TOR and TXL might be an effective clinical treatment for breast cancer patients.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/patologia , Paclitaxel/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Toremifeno/farmacologia , Sinergismo Farmacológico , Humanos , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Four new chalcone derivatives (1, 4, 7, 10) were isolated from the stem bark of Millettia leucantha KURZ (Leguminosae) along with two known ones (2, 6) and five known flavones (3, 5, 8, 9, 11). Structure elucidation and unambiguous assignment of the isolates were achieved with the aid of 1D and 2D NMR extensive studies. Correlation of 10 to 4 was successfully done by reduction with Et(3)SiH/CF(3)CO(2)H. Moderate cytotoxic activity was observed in chalcones (1, 10), whereas dihydrochalcones (4, 6) showed moderate anti-Herpes Simplex Virus (HSV) activity. Interestingly, flavone 8 showed significant anti-inflammatory effects inhibiting both cyclooxygenase (COX)-1 and -2.