Systemic toxicity and tumor cell resistance still limit the efficacy of chemotherapy in colorectal cancer. Therefore, alternative treatments are desperately needed. The thiazolide Nitazoxanide (NTZ) is an FDA-approved drug for the treatment of parasite-mediated infectious diarrhea with a favorable safety profile. Interestingly, NTZ and the thiazolide RM4819-its bromo-derivative lacking antibiotic activity-are also promising candidates for cancer treatment. Yet the exact anticancer mechanism(s) of these compounds still remains unclear. In this study, we systematically investigated RM4819 and NTZ in 2D and 3D colorectal cancer culture systems. Both compounds strongly inhibited proliferation of colon carcinoma cell lines by promoting G1 phase cell cycle arrest. Thiazolide-induced cell cycle arrest was independent of the p53/p21 axis, but was mediated by inhibition of protein translation via the mTOR/c-Myc/p27 pathway, likely caused by inhibition of mitochondrial respiration. While both thiazolides demonstrated mitochondrial uncoupling activity, only RM4819 inhibited the mitochondrial respiratory chain complex III. Interestingly, thiazolides also potently inhibited the growth of murine colonic tumoroids in a comparable manner with cisplatin, while in contrast to cisplatin thiazolides did not affect the growth of primary intestinal organoids. Thus, thiazolides appear to have a tumor-selective antiproliferative activity, which offers new perspectives in the treatment of colorectal cancer.

18 Jul 2014·ACS Chemical BiologyQ2 · BIOLOGY

Structure–Function Relationship of Thiazolide-Induced Apoptosis in Colorectal Tumor Cells

Q2 · BIOLOGY

Article

Author: Stemmer, Kerstin ; Brockmann, Anette ; Strittmatter, Tobias ; Marx, Andreas ; Brunner, Thomas ; May, Sarah

Thiazolides are a novel class of anti-infectious agents against intestinal intracellular and extracellular protozoan parasites, bacteria, and viruses. While the parent compound nitazoxanide (NTZ; 2-(acetolyloxy)-N-(5-nitro-2-thiazolyl)benzamide) has potent antimicrobial activity, the bromo-thiazolide RM4819 (N-(5-bromothiazol-2-yl)-2-hydroxy-3-methylbenzamide) shows only reduced activity. Interestingly, both molecules are able to induce cell death in colon carcinoma cell lines, indicating that the molecular target in intestinal pathogens and in colon cancer cells is different. The detoxification enzyme glutathione S-transferase of class Pi 1 (GSTP1) is frequently overexpressed in various tumors, including colon carcinomas, and limits the efficacy of antitumor chemotherapeutic drugs due to its detoxifying activities. In colorectal tumor cells RM4819 has been shown to interact with GSTP1, and GSTP1 enzymatic activity is required for thiazolide-induced apoptosis. At present it is unclear which molecular structures of RM4819 are required to interact with GSTP1 and to induce cell death in colon carcinoma cell lines. Here, we demonstrate that novel thiazolide derivatives with variation in their substituents of the benzene ring do not significantly affect apoptosis induction in Caco-2 cells, whereas removal of the bromide atom on the thiazole ring leads to a strong reduction of cell death induction in colon cancer cells. We further show that active thiazolides require caspase activation and GSTP1 expression in order to induce apoptosis. We demonstrate that increased glutathione (GSH) levels sensitize colon cancer cells to thiazolides, indicating that both GSTP1 enzymatic activity as well as GSH levels are critical factors in thiazolide-induced cell death.

15 Oct 2008·International Journal of CancerQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

AbstractThiazolides 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. © 2008 Wiley‐Liss, Inc.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis C	Phase 1	-	Romark, L.C.	-

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