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1.
J Med Chem ; 49(9): 2731-4, 2006 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-16640333

RESUMEN

In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.


Asunto(s)
Antimaláricos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Artemisininas/química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Plasmodium falciparum/efectos de los fármacos , Sesquiterpenos/química , Administración Oral , Animales , Antimaláricos/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Dimerización , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/síntesis química , Humanos , Estructura Molecular
2.
Cancer Res ; 65(23): 10854-61, 2005 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-16322232

RESUMEN

Nearly all cervical cancers are etiologically attributable to human papillomavirus (HPV) infection and pharmaceutical treatments targeting HPV-infected cells would be of great medical benefit. Because many neoplastic cells (including cervical cancer cells) overexpress the transferrin receptor to increase their iron uptake, we hypothesized that iron-dependent, antimalarial drugs such as artemisinin might prove useful in treating HPV-infected or transformed cells. We tested three different artemisinin compounds and found that dihydroartemisinin (DHA) and artesunate displayed strong cytotoxic effects on HPV-immortalized and transformed cervical cells in vitro with little effect on normal cervical epithelial cells. DHA-induced cell death involved activation of the mitochondrial caspase pathway with resultant apoptosis. Apoptosis was p53 independent and was not the consequence of drug-induced reductions in viral oncogene expression. Due to its selective cytotoxicity, hydrophobicity, and known ability to penetrate epithelial surfaces, we postulated that DHA might be useful for the topical treatment of mucosal papillomavirus lesions. To test this hypothesis, we applied DHA to the oral mucosa of dogs that had been challenged with the canine oral papillomavirus. Although applied only intermittently, DHA strongly inhibited viral-induced tumor formation. Interestingly, the DHA-treated, tumor-negative dogs developed antibodies against the viral L1 capsid protein, suggesting that DHA had inhibited tumor growth but not early rounds of papillomavirus replication. These findings indicate that DHA and other artemisinin derivatives may be useful for the topical treatment of epithelial papillomavirus lesions, including those that have progressed to the neoplastic state.


Asunto(s)
Artemisininas/farmacología , Papillomaviridae/fisiología , Sesquiterpenos/farmacología , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/virología , Animales , Apoptosis/efectos de los fármacos , Perros , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/virología , Femenino , Células HeLa , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Mucosa Bucal/virología , Papillomaviridae/genética , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/virología , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Replicación Viral/efectos de los fármacos
3.
J Virol ; 78(11): 5720-7, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15140969

RESUMEN

Human ectocervical cells, following retroviral transduction with the human papillomavirus type 16 E6/E7 oncogenes, are altered in their array of transcribed cellular genes, including increased mRNA for the insulin-like growth factor binding protein 3 (IGFBP-3). IGFBP-3 expression is associated with cellular senescence, and its addition to many cell types inhibits growth or induces apoptosis. By immunoblotting and enzyme-linked immunosorbent assay methods, we demonstrate that late-passage, immortalized E6/E7-transduced cells secrete high levels of IGFBP-3 (25 ng/ml), which represent a 500-fold increase compared to levels in early-passage, nonimmortalized transduced cells (<0.05 ng/ml). Concomitantly, these late-passage cervical cells exhibit an increase in sensitivity to IGF-1, including enhanced phosphorylation of the IGF receptor (IGF-R) and insulin receptor substrate as well as increased DNA synthesis (5-fold) and cell proliferation (3.7-fold). However, there was no change in the level of IGF-R in these cells (surface or total), and the cells did not synthesize IGF-1, indicating that these arms of the IGF pathway were independently regulated and not responsible for the augmented signaling. Consistent with a causal relationship between IGFBP-3 expression and enhanced IGF-1 responses, we found that early-passage cells could be converted to the late-passage, IGF-1-responsive phenotype by preincubation with IGFBP-3. Thus, in contrast to findings with some cell types, IGFBP-3 expression in cervical cells is associated with augmented IGF-1 signaling and cell proliferation and correlates with the timing of cellular immortalization.


Asunto(s)
Senescencia Celular , Cuello del Útero/virología , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Factor I del Crecimiento Similar a la Insulina/farmacología , Proteínas Oncogénicas Virales/genética , Proteínas Represoras , División Celular/efectos de los fármacos , Células Cultivadas , ADN/biosíntesis , Femenino , Humanos , Proteínas Oncogénicas Virales/fisiología , Proteínas E7 de Papillomavirus , Receptor IGF Tipo 1/análisis
4.
Am J Pathol ; 160(4): 1251-7, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11943710

RESUMEN

Cervical carcinoma cells display high telomerase activity and usually contain and express integrated copies of the human papillomavirus (HPV) genome. Recent studies have demonstrated that the E6 oncogene of malignancy-associated HPVs increases cellular telomerase activity, predominantly via transcriptional activation of the catalytic subunit of telomerase, hTERT. To examine the relationship between E6 oncoprotein expression and telomerase expression during cellular immortalization, we transduced primary human cervical epithelial cells with the HPV E6/E7 genes and monitored temporal changes in viral oncoprotein expression, cellular hTERT RNA expression, and cellular telomerase activity. Quantitation of the individual E6 and E7 proteins, using a newly developed immunoprecipitation/immunoblotting technique, demonstrated that both oncoproteins were expressed at stable levels during successive passages of cervical cells. In contrast, the levels of hTERT mRNA and telomerase activity increased progressively and dramatically during passaging. Late-passage immortalized cells (passage 30) showed a 25-fold increase in hTERT mRNA and a 300-fold increase in telomerase activity compared to early-passage (passage 4) cells. Thus, neither hTERT mRNA expression nor telomerase activity are directly proportional to the level of E6 oncoprotein, indicating that E6 is not the sole determinant of the high levels of telomerase in cervical cells during immortalization.


Asunto(s)
Cuello del Útero/metabolismo , Proteínas Oncogénicas/metabolismo , Oncogenes , Papillomaviridae/genética , Telomerasa/metabolismo , Transducción Genética , División Celular/fisiología , Células Cultivadas , Senescencia Celular/fisiología , Cuello del Útero/fisiología , Proteínas de Unión al ADN , Células Epiteliales/metabolismo , Células Epiteliales/fisiología , Femenino , Expresión Génica , Humanos , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/metabolismo , Telomerasa/genética
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