Vascular activity of two silicon compounds, ALIS 409 and ALIS 421, novel multidrug-resistance reverting agents in cancer cells

ArticleinCancer Chemotherapy and Pharmacology 61(3):443-51 · April 2008with6 Reads
Impact Factor: 2.77 · DOI: 10.1007/s00280-007-0488-6 · Source: PubMed

    Abstract

    The aim of this study was to investigate the effects of two novel multidrug-resistance reverting agents, ALIS 409 [1,3-dimethyl-1,3-p-fluorophenyl-1,3(3-morfolinopropyl)-1,3-disiloxan dihydrochloride] and ALIS 421 [1,3-dimethyl-1,3-(4-fluorophenyl)-1,3[3(4-buthyl)-(1-piperazinyl)-propyl]-1,3-disiloxan tetrahydrochloride], on vascular functions in vitro.
    A comparison of their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, was performed.
    In endothelium-denuded rat aorta rings, ALIS 409 and ALIS 421 antagonized 60 mM K(+)-induced contraction in a concentration-dependent manner with IC(50) values of 52.2 and 15.5 microM, respectively. ALIS 409 and ALIS 421 inhibited L-type Ca(2+) current recorded in artery myocytes in a concentration-dependent manner with IC(50) values of 6.4 and 5.6 microM, respectively. In rat aorta, ALIS 409 and ALIS 421 antagonized the sustained tonic contraction induced by phenylephrine with IC(50) values of 58.0 and 13.7 microM (endothelium-denuded rings) and of 73.9 and 31.9 microM (endothelium-intact rings), respectively. In endothelium-denuded rings, ryanodine reduced significantly the response to phenylephrine in the absence of extracellular Ca(2+) whereas nifedipine, ALIS 409 or ALIS 421 did not affect it. Phenylephrine-stimulated influx of extracellular Ca(2+) was markedly reduced when tissues were pretreated with ALIS 409, ALIS 421 or nifedipine, and stimulated when they were pretreated with ryanodine. Application of ALIS 409 (up to 100 microM) to intact rat aorta rings failed to induce mechanical responses.
    Our results provide functional evidence that the myorelaxing effect elicited either by ALIS 409 or by ALIS 421 involved mainly the direct blockade of extracellular Ca(2+) influx. This effect, however, took place at concentrations much higher than those effective as modifiers of multidrug resistance in cancer cells.