Vascular activity of two silicon compounds, ALIS 409 and ALIS 421, novel multidrug-resistance reverting agents in cancer cells.
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.
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ABSTRACT: Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) are problematic to manage, especially in patients with acquired immune deficiency syndrome (AIDS). There is therefore a dire need for effective anti-MDR/XDR-TB agents. We have previously shown that agents that inhibit the efflux pumps of MDR bacteria and cancer cells also enhance killing of intracellular mycobacteria, possibly by increasing the availability of K(+) and Ca(2+) needed for the activation of lysosomal enzymes of the phagolysosomal unit. In this study, the newly synthesised and recently patented SILA 409 and 421 were tested for in vitro and ex vivo activity against XDR-TB. The minimum inhibitory concentration (MIC) of SILA compounds was determined by the BACTEC 460 TB system. The effect of each compound on the killing activity of human macrophages infected with XDR-TB was determined by exposing the macrophage that had phagocytosed the bacterium to the compounds and assessing the killing activity by colony-forming unit counting. Amongst the two compounds tested, SILA 421 was shown to have in vitro activity against XDR-TB (MIC<3.5mg/L) and to transform non-killing macrophages into effective killers of phagocytosed bacteria, without any cytotoxic activity. Because SILA 421 revealed good in vitro and ex vivo activities and is devoid of any cytotoxic activity, it is a potential candidate as an anti-MDR/XDR-TB drug.International journal of antimicrobial agents 01/2009; 33(5):479-82. · 3.03 Impact Factor
Article: Metalloid compounds as drugs.[Show abstract] [Hide abstract]
ABSTRACT: The six elements commonly known as metalloids are boron, silicon, germanium, arsenic, antimony, and tellurium. Metalloid containing compounds have been used as antiprotozoal drugs. Boron-based drugs, the benzoxaboroles have been exploited as potential treatments for neglected tropical diseases. Arsenic has been used as a medicinal agent and arsphenamine was the main drug used to treat syphilis. Arsenic trioxide has been approved for the treatment of acute promyelocytic leukemia. Pentavalent antimonials have been the recommended drug for visceral leishmaniasis and cutaneous leishmaniasis. Tellurium (IV) compounds may have important roles in thiol redox biological activity in the human body, and ammonium trichloro (dioxoethylene-O, O'-)tellurate (AS101) may be a promising agent for the treatment of Parkinson's disease. Organosilicon compounds have been shown to be effective in vitro multidrug-resistance reverting agents.Research in pharmaceutical sciences 01/2013; 8(3):145-158.
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ABSTRACT: Morpholino-disiloxane (ALIS-409) and piperazino-disiloxane (ALIS-421) compounds were developed as inhibitors of multidrug resistance of various types of cancer cells. In the present study, the effects of ALIS-409 and ALIS-421 compounds were investigated on cancer promotion and on co-existence of tumor and normal cells. The two compounds were evaluated for their inhibitory effects on Epstein-Barr virus immediate-early antigen (EBV-EA) expression induced by tetradecanoyl-phorbol-acetate (TPA) in Raji cell cultures. The method is known as a primary screening test for antitumor effect, below the (IC50) concentration. ALIS-409 was more effective in inhibiting EBV-EA (100 μg/ml) and tumor promotion, than ALIS-421, in the concentration range up to 1000 μg/ml. However, neither of the compounds were able to reduce tumor promotion significantly, expressed as inhibition of TPA-induced tumor antigen activation. Based on the in vitro results, the two disiloxanes were investigated in vivo for their effects on mouse skin tumors in a two-stage mouse skin carcinogenesis study. The application of dimethyl-benzanthracene (DMBA; 390 nmol) as a tumor initiator was followed by exposure to TPA (1.7 nmol/l) as a tumor promoter. The experiments showed that ALIS-409 at a concentration of 85 nmol/l had a weak EBV-EA inhibitory effect in vitro and a moderate antitumor activity, compared to the positive control of DMBA plus TPA-treated mice. Flow cytometry by differential staining demonstrated interactions in co-cultures of MCF7 breast cancer and MRC5 human lung fibroblasts. The growth rate of tumor cells in mixed populations of MCF7 breast cancer and MRC5 normal fibroblast cells was reduced in the presence of ALIS-409, as compared to the control non-treated cell populations. The two disiloxanes were moderately-effective in chemoprevention in DMBA-induced and TPA-promoted in vivo tumor formation. Authors suggest that the inhibition of tumor cell and fibroblast interaction by ALIS409 might have some perspective in the development of anti-stromal therapy.Anticancer research 05/2013; 33(5):2021-7. · 1.71 Impact Factor