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[PMID]: 27777381 [Au] Autor: Ghaly PE; Abou El-Magd RM; Churchill CD; Tuszynski JA; West FG [Ad] Endereço: Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada. [Ti] Título: A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation. [So] Source: Oncotarget;7(26):40518-40530, 2016 Jun 28. [Is] ISSN: 1949-2553 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,ß-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Avaliação Pré-Clínica de Medicamentos Noscapina/análogos & derivados [Mh] Termos MeSH secundário: Alcaloides/farmacologia Sítios de Ligação Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Cristalografia por Raios X Desenho de Drogas Seres Humanos Cinética Microtúbulos/efeitos dos fármacos Modelos Moleculares Noscapina/química Paclitaxel/farmacologia Ligação Proteica Tubulina (Proteína)/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Alkaloids); 0 (Antineoplastic Agents); 0 (Tubulin); 8V32U4AOQU (Noscapine); P88XT4IS4D (Paclitaxel) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180117 [Lr] Data última revisão: 180117 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161026 [St] Status: MEDLINE [do] DOI: 10.18632/oncotarget.9642

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[PMID]: 28622054 [Au] Autor: Tian X; Liu M; Zhu Q; Tan J; Liu W; Wang Y; Chen W; Zou Y; Cai Y; Han Z; Huang X [Ad] Endereço: a Department of Gastroenterology , Tongren Hospital of Wuhan University (Wuhan Third Hospital) , Wuhan , China. [Ti] Título: Down-regulation of liver-intestine cadherin enhances noscapine-induced apoptosis in human colon cancer cells. [So] Source: Expert Rev Anticancer Ther;17(9):857-863, 2017 Sep. [Is] ISSN: 1744-8328 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: The aim of the present study was to explore the signaling pathway of noscapine which induces apoptosis by blocking liver-intestine cadherin (CDH17) gene in colon cancer SW480 cells. METHODS: Human colon cancer SW480 cells were transfected with CDH17 interference vector and treatment with 10 µmol/L noscapine. The proliferation and apoptosis of SW480 cells were detected by MTT assay and AnnexinV-FITC/PI flow cytometry kit (BD), respectively. Cell invasion were assessed by transwell assays. Apoptosis related proteins (Cyt-c, Bax, Bcl-2 and Bcl-xL) levels were evaluated by western blot. RESULTS: Compared to the noscapine group, the proliferation was decreased significantly and the apoptosis was increased significantly in SW480 cells of the siCDH17+noscapine group. Cyt-c and Bax protein levels in siCDH17+noscapine group was higher than that of the noscapine group, but Bcl-2 and Bcl-xL protein levels in siCDH17+noscapine group were lower than that of the noscapine group. Moreover, up-expression of CDH17 inhibited the efficacy of noscapine-induced apoptosis in SW480 cells. CONCLUSIONS: We inferred that down-expression of extrinsic CDH17 gene can conspicuously promote apoptosis-inducing effects of noscapine on human colon cancer SW480 cells, which is a novel strategy to improve chemotherapeutic effects on colon cancer. [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Caderinas/genética Neoplasias do Colo/tratamento farmacológico Noscapina/farmacologia [Mh] Termos MeSH secundário: Western Blotting Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Neoplasias do Colo/genética Neoplasias do Colo/patologia Regulação para Baixo/efeitos dos fármacos Citometria de Fluxo Regulação Neoplásica da Expressão Gênica Seres Humanos Intestinos/efeitos dos fármacos Intestinos/metabolismo Fígado/efeitos dos fármacos Fígado/metabolismo Transdução de Sinais/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CDH17 protein, human); 0 (Cadherins); 8V32U4AOQU (Noscapine) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170822 [Lr] Data última revisão: 170822 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170617 [St] Status: MEDLINE [do] DOI: 10.1080/14737140.2017.1344097

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[PMID]: 28502297 [Au] Autor: Han Z; Huang X; Liu M; Tan J; Zhu Q; Wang Y; Cai Y; Chen A; Tian X [Ad] Endereço: Department of Gastroenterology, Wuhan Third Hospital, Wuhan 430060, China. [Ti] Título: [Knock-down of cadherin 17 inhibits proliferation and promote apoptosis in noscapine-resistant human SW480 colon cancer cells]. [So] Source: Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi;33(5):606-610, 2017 May. [Is] ISSN: 1007-8738 [Cp] País de publicação: China [La] Idioma: chi [Ab] Resumo: Objective To investigate the effects of cadherin 17 (CDH17) on the proliferation and apoptosis of noscapine-resistant human SW480 colon cancer cells. Methods The level of CDH17 in noscapine-resistant human SW480 colon cancer cells was knocked down by small interfering RNA (siRNA), and the silence was confirmed by Western blotting and real-time quantitative PCR. Transfected SW480 cells were treated with noscapine, and then the proliferation and cell viability of SW480 cells were measured by MTT assay and plate clone formation assay, respectively; the apoptosis of SW480 cells was detected by flow cytometry combined with annexinV-FITC/PI staining; the expressions of poly-ADP-ribose polymerase (PARP) and caspase-3 were determined by Western blotting. Results Compared with NC-siRNA group and control group, the expression levels of CDH17 protein and mRNA were down-regulated in the CDH17-siRNA-transfected SW480 cell lines. After noscapine treatment, compared with NC-siRNA and control group, the colony-forming ratio and cell viability were significantly lower in CDH17-siRNA -transfected cell lines, and the expression levels of cleaved-PARP and cleaved- caspase-3 were up-regulated in CDH17-siRNA group, and the cell apoptosis rate increased. Conclusion Knock-down of CDH17 in SW480 cells can effectively inhibit cell proliferation and promote cell apoptosis as well as improve SW480 cell sensitivity to narcotine. [Mh] Termos MeSH primário: Apoptose/genética Caderinas/genética Proliferação Celular/genética Neoplasias do Colo/tratamento farmacológico Neoplasias do Colo/genética Resistência a Medicamentos Antineoplásicos/genética Noscapina/farmacologia [Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cadherins); 8V32U4AOQU (Noscapine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171004 [Lr] Data última revisão: 171004 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170516 [St] Status: MEDLINE

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[PMID]: 28056737 [Au] Autor: Pradhan S; Mahaddalkar T; Choudhary S; Manhcukonda N; Nagireddy PR; Kantevari S; Lopus M [Ad] Endereço: Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences, Kalina, Mumbai, India. [Ti] Título: Elucidation of the Tubulin-targeted Mechanism of Action of 9-(3-pyridyl) Noscapine. [So] Source: Curr Top Med Chem;17(22):2569-2574, 2017. [Is] ISSN: 1873-4294 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: We have recently reported the synthesis and antiproliferative potential of a series of biaryl type α-noscapine congeners. Among them, 9-(3-pyridyl) noscapine 3f (9-PyNos, henceforth), which was synthesized by adding pyridine unit to the tetrahydroisoquinoline part of natural α-noscapine core, was found to be the most effective one to inhibit proliferation of a variety of cancer cell lines. However, details of its interactions with its cellular target, tubulin, remain poorly understood. In this report, we examined the nature of interactions of 9-PyNos with tubulin based on the methodologies of spectrofluorimetry, circular dichroism, and turbidimetry techniques. Far-UV circular dichroism spectra indicated perturbation of tubulin secondary structure in the presence of 9-PyNos, not amounting, however, to the perturbation induced by noscapine. The noscapinoid nevertheless altered the surface configuration of the protein considerably, as indicated by an anilinonaphthalene sulphonate binding assay, and promoted colchicine binding to tubulin, the latter indicating its adjacent binding site with colchicine. 9-PyNos however, did not alter microtubule assembly considerably. Investigating the possible reason behind this apparent lack of strong inhibition of microtubule assembly, we found that the binding interactions of tubulin with 9-PyNos do not involve modification of cysteine residues of tubulin. Taken together, our data suggest that the antiproliferative mechanism of action of 9-PyNos involves disruption of structural integrity of tubulin without strong inhibition of tubulin assembly. [Mh] Termos MeSH primário: Noscapina/análogos & derivados Moduladores de Tubulina/farmacologia Tubulina (Proteína)/metabolismo [Mh] Termos MeSH secundário: Seres Humanos Estrutura Molecular Noscapina/síntese química Noscapina/química Noscapina/farmacologia Relação Estrutura-Atividade Tubulina (Proteína)/química Moduladores de Tubulina/síntese química Moduladores de Tubulina/química [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (9-(3-pyridyl)noscapine); 0 (Tubulin); 0 (Tubulin Modulators); 8V32U4AOQU (Noscapine) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170825 [Lr] Data última revisão: 170825 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170107 [St] Status: MEDLINE [do] DOI: 10.2174/1568026617666170104150304

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[PMID]: 27939522 [Au] Autor: Cheriyamundath S; Mahaddalkar T; Kantevari S; Lopus M [Ad] Endereço: Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai Kalina Campus, Mumbai-400098, India. [Ti] Título: Induction of acetylation and bundling of cellular microtubules by 9-(4-vinylphenyl) noscapine elicits S-phase arrest in MDA-MB-231 cells. [So] Source: Biomed Pharmacother;86:74-80, 2017 Feb. [Is] ISSN: 1950-6007 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Noscapine is an alkaloid present in the latex of Papaver somniferum. It has been known for its anticancer efficacy and lack of severe toxicities to normal tissues. Structural alterations in noscapine core architecture have produced a number of potent analogues of noscapine. Here, we report an unusual activity of a novel noscapine analogue, 9-(4-vinylphenyl)noscapine (VinPhe-Nos) on cancer cells. As we reported earlier, VinPhe-Nos inhibited MDA-MB-231 cell proliferation with an IC of 6µM. The present study elucidated a possible antiproliferative mechanism of action of VinPhe-Nos. The noscapinoid significantly inhibited clonogenic propagation of MDA-MB-231 cells. However, unlike the majority of tubulin-binding agents, it did not induce mitotic arrest; instead, it prolonged S-phase. Although prolonged presence of the drug show some disruption of cellular microtubule architecture, it did not affect microtubule recovery after cold-induced depolymerization. VinPhe-Nos, nevertheless, induced acetylation and bundling of microtubules. Our data suggest that rational modification of parent compound can alter its mechanism of action on cell cycle and that VinPhe-Nos can be investigated further as a less-toxic, S-phase-preferred, cytostatic anticancer agent. [Mh] Termos MeSH primário: Pontos de Checagem do Ciclo Celular/fisiologia Microtúbulos/fisiologia Noscapina/análogos & derivados Noscapina/farmacologia Pontos de Checagem da Fase S do Ciclo Celular/fisiologia [Mh] Termos MeSH secundário: Acetilação/efeitos dos fármacos Pontos de Checagem do Ciclo Celular/efeitos dos fármacos Linhagem Celular Tumoral Seres Humanos Microtúbulos/efeitos dos fármacos Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 8V32U4AOQU (Noscapine) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170209 [Lr] Data última revisão: 170209 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161213 [St] Status: MEDLINE

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[PMID]: 27237331 [Au] Autor: Tomar V; Kukreti S; Prakash S; Madan J; Chandra R [Ti] Título: Noscapine and its Analogs as Chemotherapeutic Agent: Current updates. [So] Source: Curr Top Med Chem;17(2):174-188, 2017. [Is] ISSN: 1873-4294 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Recently, noscapine was reported as anticancer drug. Unlike, colchicine and podophyllotoxin, noscapine did not depolymerize microtubules even at stoichiometric concentrations but rather only mitigated their dynamics. Other microtubule-interacting chemotherapeutics, although quite effective, have therapy-limiting toxicities including immunosuppression and peripheral neuropathies. Recurrent cancers often become resistant. Noscapine however remains effective in some such instances, e.g., taxane-resistant ovarian cancer. Noscapine and analogs also do not show signs of neurotoxicity or immunosuppression. In addition, 9-bromo noscapine, Red-9-Br-Nos and other analogs were characterized for their structure and further studied in detail. On the other hand, noscapine was shown to be neuroprotective in mouse model of neurodegenerative disease and in stroke patients. Like low doses of colchicine, noscapine and its analog 9-Br-Noscapine also show anti-inflammatory activities. There are indications of a preventive use of noscapine in ischemiareperfusion injury and fibrosis. The entire biosynthetic pathway of noscapine is encoded as gene cluster within 401 kilo bases of genomic DNA, opening up opportunities for the large-scale biotechnological production of noscapine for medicinal needs. Thus, noscapine and its derivatives (noscapinoids) might be cost-effective and safe components for cancer chemotherapy. Owing to its low toxicity, it also might be useful for preventive use in high-risk situations. This brief review is an update of current research activity and patents on noscapine and its analogs. [Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico Noscapina/uso terapêutico [Mh] Termos MeSH secundário: Antineoplásicos/química Antineoplásicos/farmacologia Antitussígenos/química Antitussígenos/farmacologia Antitussígenos/uso terapêutico Apoptose/efeitos dos fármacos Seres Humanos Noscapina/química Noscapina/farmacologia Acidente Vascular Cerebral/tratamento farmacológico Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Antitussive Agents); 8V32U4AOQU (Noscapine) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170209 [Lr] Data última revisão: 170209 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160531 [St] Status: MEDLINE

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[PMID]: 27213192 [Ti] Título: Noscapine: angioedema. [So] Source: Prescrire Int;25(169):71, 2016 Mar. [Is] ISSN: 1167-7422 [Cp] País de publicação: France [La] Idioma: eng [Mh] Termos MeSH primário: Angioedema/induzido quimicamente Antitussígenos/efeitos adversos Noscapina/efeitos adversos [Mh] Termos MeSH secundário: Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antitussive Agents); 8V32U4AOQU (Noscapine) [Em] Mês de entrada: 1606 [Cu] Atualização por classe: 160506 [Lr] Data última revisão: 160506 [Sb] Subgrupo de revista: T [Da] Data de entrada para processamento: 160524 [St] Status: MEDLINE

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[PMID]: 27177833 [Au] Autor: Doddapaneni R; Patel K; Chowdhury N; Singh M [Ad] Endereço: College of Pharmacy and Pharmaceuical Sciences, Florida A&M University, Tallahassee, FL 32307, USA. [Ti] Título: Noscapine chemosensitization enhances docetaxel anticancer activity and nanocarrier uptake in triple negative breast cancer. [So] Source: Exp Cell Res;346(1):65-73, 2016 Aug 01. [Is] ISSN: 1090-2422 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Chemosensitization and enhanced delivery to solid tumor are widely explored strategies to augment the anticancer efficacy of existing chemotherapeutics agents. The aim of current research was to investigate the role of low dose Noscapine (Nos) in potentiating docetaxel cytotoxicity and enhancing tumor penetration of nanocarriers. The objectives are; (1) To evaluate the chemo-sensitizing effect of Nos in combination with docetaxel (DTX), and to elucidate the possible mechanism (2) To investigate the effect of low dose Nos on tumor stroma and enhancing nanocarrier uptake in triple negative breast cancer (TNBC) bearing nude mice. Cytotoxicity and flow cytometry analysis of DTX in Nos (4µM) pre-treated MDA-MB-231 cells showed 3.0-fold increase in cell killing and 30% increase in number of late apoptotic cells, respectively. Stress transducer p38 phosphorylation was significantly upregulated with Nos exposure. DTX showed remarkable downregulation in expression of bcl-2, survivin and pAKT in Nos pre-treated MDA-MB-231 cells. Nos pre-sensitization significantly (p<0.02) enhanced the anti-migration effect of DTX. In vivo studies in orthotopic TNBC tumor bearing mice showed marked reduction in tumor collagen-I levels and significantly (p<0.03) higher intra-tumoral uptake of coumarin-6 loaded PEGylated liposomes (7-fold) in Nos treated group. Chemo-sensitization and anti-fibrotic effect of Nos could be a promising approach to increase anticancer efficacy of DTX which can be used for other nanomedicinal products. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Portadores de Fármacos/química Nanopartículas/química Noscapina/farmacologia Taxoides/farmacologia Neoplasias de Mama Triplo Negativas/patologia [Mh] Termos MeSH secundário: Animais Apoptose/efeitos dos fármacos Linhagem Celular Tumoral Ensaios de Migração Celular Movimento Celular/efeitos dos fármacos Cumarínicos/metabolismo Ativação Enzimática/efeitos dos fármacos Imunofluorescência Seres Humanos Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo Lipossomos Camundongos Microtúbulos/efeitos dos fármacos Microtúbulos/metabolismo Fosforilação/efeitos dos fármacos Polimerização/efeitos dos fármacos Coloração e Rotulagem Tiazóis/metabolismo Tubulina (Proteína)/metabolismo Ensaios Antitumorais Modelo de Xenoenxerto Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Coumarins); 0 (Drug Carriers); 0 (Liposomes); 0 (Taxoids); 0 (Thiazoles); 0 (Tubulin); 0 (coumarin 6); 15H5577CQD (docetaxel); 8V32U4AOQU (Noscapine); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 170517 [Lr] Data última revisão: 170517 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160515 [St] Status: MEDLINE

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[PMID]: 27081867 [Au] Autor: Quisbert-Valenzuela EO; Calaf GM [Ad] Endereço: Institute for Advanced Research, University of Tarapacá, Arica 8097877, Chile. [Ti] Título: Apoptotic effect of noscapine in breast cancer cell lines. [So] Source: Int J Oncol;48(6):2666-74, 2016 Jun. [Is] ISSN: 1791-2423 [Cp] País de publicação: Greece [La] Idioma: eng [Ab] Resumo: Cancer is a public health problem in the world and breast cancer is the most frequently cancer in women. Approximately 15% of the breast cancers are triple-negative. Apoptosis regulates normal growth, homeostasis, development, embryogenesis and appropriate strategy to treat cancer. Bax is a protein pro-apoptotic enhancer of apoptosis in contrast to Bcl-2 with antiapoptotic properties. Initiator caspase-9 and caspase-8 are features of intrinsic and extrinsic apoptosis pathway, respectively. NF-κB is a transcription factor known to be involved in the initiation and progression of breast cancer. Noscapine, an alkaloid derived from opium is used as antitussive and showed antitumor properties that induced apoptosis in cancer cell lines. The aim of the present study was to determine the apoptotic effect of noscapine in breast cancer cell lines compared to breast normal cell line. Three cell lines were used: i) a control breast cell line MCF-10F; ii) a luminal-like adenocarcinoma triple-positive breast cell line MCF-7; iii) breast cancer triple-negative cell line MDA-MB-231. Our results showed that noscapine had lower toxicity in normal cells and was an effective anticancer agent that induced apoptosis in breast cancer cells because it increases Bax gene and protein expression in three cell lines, while decreases Bcl-xL gene expression, and Bcl-2 protein expression decreased in breast cancer cell lines. Therefore, Bax/Bcl-2 ratio increased in the three cell lines. This drug increased caspase-9 gene expression in breast cancer cell lines and caspase-8 gene expression increased in MCF-10F and MDA-MB-231. Furthermore, it increased cleavage of caspase-8, suggesting that noscapine-induced apoptosis is probably due to the involvement of extrinsic and intrinsic apoptosis pathways. Antiapoptotic gene and protein expression diminished and proapoptotic gene and protein expression increased noscapine-induced expression, probably due to decrease in NF-κB gene and protein expression and also by increase of IκBα gene expression induced by this drug. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Neoplasias da Mama/genética NF-kappa B/genética Noscapina/farmacologia Proteína X Associada a bcl-2/genética [Mh] Termos MeSH secundário: Apoptose Neoplasias da Mama/tratamento farmacológico Neoplasias da Mama/metabolismo Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Relação Dose-Resposta a Droga Feminino Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Seres Humanos Células MCF-7 NF-kappa B/metabolismo Transdução de Sinais/efeitos dos fármacos Proteína X Associada a bcl-2/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (NF-kappa B); 0 (bcl-2-Associated X Protein); 8V32U4AOQU (Noscapine) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170310 [Lr] Data última revisão: 170310 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160416 [St] Status: MEDLINE [do] DOI: 10.3892/ijo.2016.3476

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[PMID]: 26757437 [Au] Autor: Andey T; Patel A; Marepally S; Chougule M; Spencer SD; Rishi AK; Singh M [Ad] Endereço: Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences University, 19 Foster Street, Worcester, MA, United States of America. [Ti] Título: Formulation, Pharmacokinetic, and Efficacy Studies of Mannosylated Self-Emulsifying Solid Dispersions of Noscapine. [So] Source: PLoS One;11(1):e0146804, 2016. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PURPOSE: To formulate hydroxypropyl methylcellulose-stabilized self-emulsifying solid dispersible carriers of noscapine to enhance oral bioavailability. METHODS: Formulation of noscapine (Nos) self-emulsifying solid dispersible microparticles (SESDs) was afforded by emulsification using an optimized formula of Labrafil M1944, Tween-80, and Labrasol followed by spray-drying with hydroxypropyl methylcellulose (HPMC), with and without mannosamine (Mann-Nos_SESDs and Nos_SESDs respectively); self-microemulsifying liquid dispersions (SMEDDs) with and without mannosamine (Mann-Nos_SMEDDs and Nos_SMEDDs respectively) were also prepared. SMEDDs and SESDs were characterized for size, polydispersity, surface charge, entrapment efficiency, in vitro permeability, in vitro release kinetics, and oral pharmacokinetics in Sprague-Dawley rats (10 mg/kg p.o). The antitumor efficacy of Mann-Nos_SESDs on the basis of chemosensitization to cisplatin (2.0 mg/kg, i.v.) was investigated in a chemorefractory lung tumor Nu/Nu mouse model up to a maximal oral dose of 300 mg/kg. RESULTS: The oil/surfactant/co-surfactant mixture of Labrafil M1944, Tween-80, and Labrasol optimized at weight ratios of 62.8:9.30:27.90% produced stable self-microemulsifying dispersions (SMEDDs) at a SMEDD to water ratio of 1-3:7-9 parts by weight. SMEDDs had hydrodynamic diameters between 231 and 246 nm; surface charges ranged from -16.50 to -18.7 mV; and entrapment efficiencies were between 32 and 35%. SESDs ranged in size between 5.84 and 6.60 µm with surface charges from -10.62 to -12.40 mV and entrapment efficiencies of 30.96±4.66 and 32.05±3.72% (Nos_SESDs and Mann-Nos_SESDs respectively). Mann-Nos_SESDs exhibited saturating uptake across Caco-2 monolayers (Papp = 4.94±0.18 × 10(-6) cm/s), with controlled release of 50% of Nos in 6 hr at pH 6.8 following Higuchi kinetics. Mann-Nos_ SESDs was 40% more bioavailable compared to Nos_SESDs; and was effective in sensitizing H1650 SP cells to Cisplatin in vitro and in an orthotopic lung tumor model of H1650 SP origin. CONCLUSIONS: Mannosylated noscapine self-emulsifying solid dispersions (Mann-Nos_SESDs) are bioavailable and potentiate the antineoplastic effect of cisplatin-based chemotherapy in cisplatin-resistant NSCLC. [Mh] Termos MeSH primário: Antineoplásicos/química Antineoplásicos/farmacocinética Noscapina/química Noscapina/farmacocinética [Mh] Termos MeSH secundário: Administração Oral Animais Antineoplásicos/administração & dosagem Disponibilidade Biológica Linhagem Celular Tumoral Sobrevivência Celular/efeitos dos fármacos Química Farmacêutica Cisplatino/farmacologia Modelos Animais de Doenças Portadores de Fármacos Liberação Controlada de Fármacos Resistência a Medicamentos Antineoplásicos Estabilidade de Medicamentos Sinergismo Farmacológico Emulsões Seres Humanos Manose/química Camundongos Modelos Animais Nanopartículas/química Noscapina/administração & dosagem Ratos Fatores de Tempo Transcitose Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Drug Carriers); 0 (Emulsions); 8V32U4AOQU (Noscapine); PHA4727WTP (Mannose); Q20Q21Q62J (Cisplatin) [Em] Mês de entrada: 1607 [Cu] Atualização por classe: 161215 [Lr] Data última revisão: 161215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160113 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0146804

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