Anticancer Effects of the Organosilicon Multidrug Resistance Modulator SILA 421
Küçük Resim Yok
Tarih
2012
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
BENTHAM SCIENCE PUBL LTD
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
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 mu M for GLC14 small cell lung cancer and 34.00 +/- 4.75 mu M 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, cellular repair mechanisms and growth factor-related signaling cascades eventually resulted in induction of apoptosis in this cell line. In addition to the well established P-gp inhibitory effect of SILA compounds, 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. Interference with DNA replication and transcription seems to be the common denominator of antimicrobial activity and plasmid curing, as well as 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.
Açıklama
Anahtar Kelimeler
Annexin V, Cell lines, Cellular pathways, Cytotoxicity, Drug resistance, Gene expression, HL-60, MDR modulator, Organosilicon, P-glycoprotein, Phenothiazine, Reactome, SILA 421
Kaynak
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
WoS Q Değeri
Q2
Scopus Q Değeri
Q3
Cilt
12
Sayı
6
