Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells

Müller, Joachim; Sidler, Daniel; Nachbur, Ueli; Wastling, Jonathan; Brunner, Thomas; Hemphill, Andrew

Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells

Dateien

2008_Mueller-Thiaszolides inhibit GSTP1.pdfGröße: 573.47 KBDownloads: 458

Datum

2008

Autor:innen

Müller, Joachim

Sidler, Daniel

Nachbur, Ueli

Wastling, Jonathan

Brunner, Thomas

Hemphill, Andrew

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

International Journal of Cancer. 2008, 123(8), pp. 1797-1806. ISSN 0020-7136. eISSN 1097-0215. Available under: doi: 10.1002/ijc.23755

Zusammenfassung

Thiazolides are a novel class of broad-spectrum anti-infective drugs with promising in vitro and in vivo activities against intracellular and extracellular protozoan parasites. The nitrothiazole-analogue nitazoxanide (NTZ; 2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide) represents the thiazolide parent compound, and a number of bromo- and carboxy-derivatives with differing activities have been synthesized. Here we report that NTZ and the bromo-thiazolide RM4819, but not the carboxy-thiazolide RM4825, inhibited proliferation of the colon cancer cell line Caco2 and nontransformed human foreskin fibroblasts (HFF) at or below concentrations the compounds normally exhibit anti-parasitic activity. Thiazolides induced typical signs of apoptosis, such as nuclear condensation, DNA fragmentation and phosphatidylserine exposure. Interestingly, the apoptosis-inducing effect of thiazolides appeared to be cell cycle-dependent and induction of cell cycle arrest substantially inhibited the cell death-inducing activity of these compounds. Using affinity chromatography and mass spectrometry glutathione-S-transferase P1 (GSTP1) from the GST class Pi was identified as a major thiazolide-binding protein. GSTP1 expression was more than 10 times higher in the thiazolide-sensitive Caco2 cells than in the less sensitive HFF cells. The enzymatic activity of recombinant GSTP1 was strongly inhibited by thiazolides. Silencing of GSTP1 using siRNA rendered cells insensitive to RM4819, while overexpression of GSTP1 increased sensitivity to RM4819-induced cell death. Thiazolides may thus represent an interesting novel class of future cancer therapeutics.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

Apoptosis, Colon cancer, Cell cycle, Oncogene

Zitieren

ISO 690

MÜLLER, Joachim, Daniel SIDLER, Ueli NACHBUR, Jonathan WASTLING, Thomas BRUNNER, Andrew HEMPHILL, 2008. Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells. In: International Journal of Cancer. 2008, 123(8), pp. 1797-1806. ISSN 0020-7136. eISSN 1097-0215. Available under: doi: 10.1002/ijc.23755

BibTex

@article{Muller2008-10-15Thiaz-14268,
  year={2008},
  doi={10.1002/ijc.23755},
  title={Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells},
  number={8},
  volume={123},
  issn={0020-7136},
  journal={International Journal of Cancer},
  pages={1797--1806},
  author={Müller, Joachim and Sidler, Daniel and Nachbur, Ueli and Wastling, Jonathan and Brunner, Thomas and Hemphill, Andrew}
}

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