RESUMEN
Three simplified "non-natural" natural taxanes, related to taxuspine X, were synthetized and assayed as P-glycoprotein (P-gp) inhibitors. One of them (6) proved to be a very efficient P-gp inhibitor with an IC50 = 7.2 × 10(-6) M. In addition, to rationalize biological data, a pharmacophoric model was built through a ligand-based approach. This model represents the first example of a pharmacophore, which describes interactions of taxanes with P-gp.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/síntesis química , Taxoides/síntesis química , Adenosina Trifosfatasas/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Humanos , Taxoides/químicaRESUMEN
We investigated whether a combination of static electromagnetic field (EMF) at a flux density of 4.75 T together with pulsed EMF at a flux density of 0.7 mT generated by an NMR apparatus (NMRF), could promote movements of Ca(2+), cell proliferation, and the eventual production of proinflammatory cytokines in human lymphocytes as well as in Jurkat cells, after exposure to the field for 1 h. The same study was also performed after activation of cells with 5 micro g/ml phytohaemagglutinin (PHA) immediately before the exposure period. Our results clearly demonstrate that NMRF exposure increases the [Ca(2+)](i), without any proliferative, or activating, or proinflammatory effect on both normal and PHA stimulated lymphocytes. Accordingly, the levels of interferon gamma, tumor necrosis factor alpha, interleukin-1beta, interleukin-2, and interleukin-6 remained unvaried after exposure. Exposure of Jurkat cells statistically decreased the [Ca(2+)](i) and the proliferation. This is consistent with the low levels of IL-2 measured in supernatants of these cells after exposure. On the whole our data suggest that static and pulsed NMRF exposure contribute synergistically in the increase of the [Ca(2+)](i) without any activating or proinflammatory effect either in normal or in PHA challenged lymphocytes. In Jurkat cells, by changing the properties of cell membranes, NMRF exposure can influence Ca(2+) transport processes and hence Ca(2+) homeostasis, causing a marked decrease of proliferation.
Asunto(s)
Calcio/metabolismo , Citocinas/metabolismo , Campos Electromagnéticos , Linfocitos/fisiología , Linfocitos/efectos de la radiación , Espectroscopía de Resonancia Magnética , División Celular/efectos de los fármacos , División Celular/fisiología , División Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Humanos , Células Jurkat , Linfocitos/citología , Linfocitos/efectos de los fármacos , Fitohemaglutininas/farmacología , Dosis de RadiaciónRESUMEN
We investigated whether static electromagnetic fields (EMFs) at a flux density of 4.75 T, generated by an NMR apparatus (NMRF), could promote movements of Ca2+, cell proliferation, and the eventual production of proinflammatory cytokines in human peripheral blood mononuclear cells (PBMC) as well as in Jurkat cells, after exposure to the field for 1 h. The same study was also performed after activation of cells with 5 mg/ml phytohaemagglutinin (PHA). Our results clearly demonstrate that static NMRF exposure has neither proliferative, nor activating, nor proinflammatory effects on both normal and PHA activated PBMC. Moreover, the concentration of interleukin-1beta, interleukin-2, interleukin-6, interferon, and tumour necrosis factor alpha (TNFalpha) remained unvaried in exposed cells. Exposure of Jurkat cells statistically decreased the proliferation and the proliferation indexes, which 24 and 48 h after exposure were 0.7 +/- 0.29 and 0.87 +/- 0.12, respectively. Moreover, in Jurkat cells the [Ca2+]i was higher than in PBMC and was reduced significantly to about one half after exposure. This is consistent with the decrease of proliferation and with the low levels of IL-2 measured. On the whole, our data suggest that NMRF exposure failed to affect the physiologic behaviour of normal lymphomonocytes. Instead in Jurkat cells, by changing the properties of cell membranes, NMRF can influence Ca2+ transport processes, and hence Ca2+ homeostasis with improvement of proliferation.