| Anticancer Effects of the Organosilicon Multidrug Resistance Modulator SILA 421. | |
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MedLine Citation:
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PMID: 22263791 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis{3-[1(4-butylpiperazinyl)]-propyl}-disiloxan-tetrahydrochlorid (SILA 421) is a compound that was developed as modulator of the ABC cassette transporter P-glycoprotein. Furthermore, it exerted antimicrobial toxicity, vascular effects, downregulation of chaperone induction and plasmid curing in bacterial cells. Here, this drug was found to possess cytotoxic activity against a panel of human cancer cell lines that do not overexpress P-gp, with 50% inhibitory concentrations ranging between 1.75±0.38 µM for GLC14 small cell lung cancer and 34.00±4.75 µM for PC-3 prostate cancer cells. HL-60 leukemia and MDA-MB-435 breast cancer cells exhibited cell cycle arrest and apoptotic cell death in response to SILA 421. Assessment of global gene expression of SILA 421-treated HL-60 cells was employed to identify cellular pathways affected by the compound and revealed disturbance of DNA replication, transcription and production of apparently misfolded proteins. Endoplasmatic reticulum stress and downregulation of cell cycle, repair mechanisms and growth factor circuits eventually resulted in induction of apoptosis in this cell line. Reversal of resistance to taxanes, which had been reported for SILA 421 and the related molecule SILA 409 may be linked to downregulation of gene expression of kinesins in addition to the well-established P-gp-inhibitory effect. Interference with DNA replication and transcription seem to be the common denominator of antimicrobial activity, plasmid curing and anticancer toxicity in human cell lines. Thus, in consideration of the full range of putative cellular targets found in the present work, the application of these SILA compounds for treatment of tumors should be further evaluated. |
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Authors:
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Ulrike Olszewski-Hamilton; Robert Zeillinger; Meltem Demirel Kars; Attila Zalatnai; Jozsef Molnar; Gerhard Hamilton |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-19 |
Journal Detail:
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Title: Anti-cancer agents in medicinal chemistry Volume: - ISSN: 1875-5992 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101265649 Medline TA: Anticancer Agents Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Cluster of Translational Oncology, Ludwig Boltzmann Society, Nussdorferstrasse 64/6, A-1090 Vienna, Austria. u.olszewski@gmx.net. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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