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Cancer Chemotherapy and Pharmacology

, Volume 61, Issue 3, pp 443–451 | Cite as

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

  • Fabio FusiEmail author
  • Antonella Ferrara
  • Attila Zalatnai
  • Joseph Molnar
  • Giampietro Sgaragli
  • Simona Saponara
Original Article

Abstract

Purpose

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.

Experimental design

A comparison of their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, was performed.

Results

In endothelium-denuded rat aorta rings, ALIS 409 and ALIS 421 antagonized 60 mM K+-induced contraction in a concentration-dependent manner with IC50 values of 52.2 and 15.5 μM, respectively. ALIS 409 and ALIS 421 inhibited L-type Ca2+ current recorded in artery myocytes in a concentration-dependent manner with IC50 values of 6.4 and 5.6 μM, respectively. In rat aorta, ALIS 409 and ALIS 421 antagonized the sustained tonic contraction induced by phenylephrine with IC50 values of 58.0 and 13.7 μM (endothelium-denuded rings) and of 73.9 and 31.9 μM (endothelium-intact rings), respectively. In endothelium-denuded rings, ryanodine reduced significantly the response to phenylephrine in the absence of extracellular Ca2+ whereas nifedipine, ALIS 409 or ALIS 421 did not affect it. Phenylephrine-stimulated influx of extracellular Ca2+ 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 μM) to intact rat aorta rings failed to induce mechanical responses.

Conclusions

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 Ca2+ influx. This effect, however, took place at concentrations much higher than those effective as modifiers of multidrug resistance in cancer cells.

Keywords

ALIS 409 ALIS 421 Rat aorta Rat tail artery myocytes Ca2+ influx Whole-cell patch-clamp 

Abbreviations

ICa(L)

L-type Ca2+ current

K60

60 mM K+ PSS

MDR

Multidrug-resistance

PSS

Physiological salt solution

ROCCs/SOCCs

Receptor/store-operated Ca2+ channels

Vh

Holding potential

VOCCs

Voltage-operated Ca2+ channels

Notes

Acknowledgments

We wish to thank Drs Marco Gelli and Paolo D’Elia for the assistance in some preliminary experiments. This work was supported by grants from the Università degli Studi di Siena (PAR Servizi), a grant from Ministero degli Affari Esteri (Rome, Italy) as stipulated by Law 409/1990 and a grant from Szeged Foundation of Cancer Research, Szeged, Hungary.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Fabio Fusi
    • 1
    Email author
  • Antonella Ferrara
    • 1
  • Attila Zalatnai
    • 2
  • Joseph Molnar
    • 3
  • Giampietro Sgaragli
    • 1
  • Simona Saponara
    • 1
  1. 1.Dipartimento di Scienze BiomedicheUniversità degli Studi di SienaSienaItaly
  2. 2.Faculty of Medicine, First Department of Pathology and Experimental Cancer ResearchSemmelweis UniversityBudapestHungary
  3. 3.Faculty of Medicine, Institute of MicrobiologyAlbert Szent-Györgyi Medical UniversitySzegedHungary

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