Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase–Bim axis and reveals glutathione-S-transferase P1 as Achilles’ heel

Sidler, Daniel; Brockmann, Anette; Mueller, Joachim D.; Nachbur, Ueli; Corazza, Nadia; Renzulli, Pietro; Hemphill, Andrew; Brunner, Thomas

doi:10.1038/onc.2011.575

Cited by 30 publications

(51 citation statements)

References 48 publications

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“…The fact that RM-5038 is not effective against anaerobic bacteria should theoretically improve the clinical tolerance of the drug when it is given for a prolonged period of time. However, it should be mentioned that some halogeno-thiazolides have been shown to induce apoptosis in some proliferative human cells, which could affect the overall safety of the new compound (5,6). RM-5038 is in early clinical trials in the United States, and the present study supports clinical trials of the compound against cryptosporidial diarrhea.…”

supporting

confidence: 66%

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Gargala

Audigier

Favennec

et al. 2013

Antimicrob Agents Chemother

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cNitazoxanide and three halogeno-thiazolides, RM-4850, RM-4865, and RM-5038, were tested against Cryptosporidium parvum in experimentally infected immunosuppressed Mongolian gerbils. Daily 400-mg/kg doses of the four test drugs for 5 to 8 consecutive days produced similar reductions of oocyst shedding. Using early-infected gerbils, a shorter 4-day treatment with RM-5038 reduced oocyst shedding by 95%, compared to 47% for nitazoxanide (P ‫؍‬ 0.02), suggesting that RM-5038 is more effective than nitazoxanide under the experimental conditions used. We have previously reported the in vitro activities of several thiazolides against Cryptosporidium parvum and Sarcocystis neurona, two apicomplexan protozoa (1, 2). Recent tests of RM-5038 showed the same level of activity as its active circulating metabolite RM-4848, which, with RM-4850 and RM-4865, had exhibited the highest level of in vitro activity against C. parvum development. These compounds deserved to be tested in vivo to confirm their anticryptosporidial activity.The in vivo activities of nitazoxanide and three halogenothiazolides were studied in experimentally Cryptosporidium parvum-infected gerbils (Meriones unguiculatus). Animals weighing 30 to 40 g at the beginning of the study were individually housed in plastic cages equipped with a grill ceiling providing rodent food granules and water ad libitum. The cage was protected by another top wrapped with sterile paper in order to comply with level II contamination requirements. Animals were handled according to the technical and ethical regulations of the French Ministry of Agriculture. Gerbils were immunosuppressed by injection of dexamethasone (Qualimed, Puteaux, France) at 0.8 mg every 2 days and fed a low-protein diet (white bread) for at least 10 consecutive days before infection, and dexamethasone was administered until the end of the experiment. Prior to the start of treatment, each gerbil was inoculated by oral gavage with C. parvum oocysts. The test compounds were suspended in pure dimethyl sulfoxide (DMSO) and administered at a dose of 200 mg/kg of body weight twice daily by oral gavage in a constant volume. One to 3 days after the cessation of treatment, all of the animals were killed by deep sodium thiopental anesthesia. To assess C. parvum infection, the volume of the cecal and colonic contents collected from each sacrificed gerbil was suspended in a 10% (wt/vol) formalin solution and homogenized. The suspension was vortexed for 30 s and allowed to settle for an additional 30 s. Ten percent of the suspension was diluted in phosphate-buffered saline (PBS) and centrifuged at 1,800 ϫ g for 30 min. After washing, the pellet was resuspended in PBS and half of the oocyst-containing pellet was incubated with an oocyst-specific monoclonal antibody conjugated with fluorescein isothiocyanate (Crypt-aGlo; Waterborne, New Orleans, LA) in the dark at 37°C for 30 min. A CytoSpin was prepared for each specimen, and oocysts were counted by epifluorescence microscopy at a magnification of ϫ400. The number of oocyst...

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supporting

confidence: 66%

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Gargala

Audigier

Favennec

et al. 2013

Antimicrob Agents Chemother

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“…COLO205 colorectal cells have reduced levels of glutathione-S-transferase P1 (GSTP1), an enzyme which detoxifies drugs by conjugating them to glutathione (GSH) often limiting the efficacy of anticancer agents. 12 Without this enzyme, there may be less conjugation and inactivation by GSH, which could increase the sensitivity of cells towards anticancer compounds. The breast cell line, MDA-MB-468 showed a consistently high sensitivity in the NCI-60 screen (IC 50 values 17 nM to 1.8 mM).…”

Section: Antiproliferative Activitymentioning

confidence: 99%

Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action

et al. 2018

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“…Of note, we demonstrated that luteolin activated some enzymes of a DNA damage pathway resulting in significant toxicity for OSCC cells. Moreover, although nitazoxanide was previously shown to be efficient against other cancer cells, such as colorectal (31)(32)(33)(34) and breast cancers (35), the antitumoral activity of metixene hydrochloride and nitazoxanide had not previously been demonstrated against oral cancer cells. We report here that luteolin, metixene hydrochloride, and nitazoxanide exhibit dose-and time-dependent selective toxicity in SCC-25 cells.…”

Section: Discussionmentioning

confidence: 97%

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

Tjioe

Oliveira

Gavard

2016

Nutrition and Cancer

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Oral squamous cell carcinoma (OSCC) exhibited high chemoresistance to current treatments. Here we aimed at identifying and repositioning approved drugs that could be selectively toxic toward OSCC cells. Through a cell-based drug screening of 1,280 chemical molecules, we selected compounds lethal to oral cancer SCC-25 cells, while sparing normal keratinocyte HaCaT cells. Within the chemical library, the natural flavonoid luteolin was identified as a potent cytotoxic agent against oral cancer cells in vitro, along with metixene hydrochloride and nitazoxanide. Of note, they exhibit low toxicity and high efficiency compared to the standard-of-care, such as cisplatin and the epidermal growth factor receptor inhibitor tyrphostin. From a molecular standpoint, luteolin causes phosphorylation of ataxia telangiectasia mutated (ATM) and H2AX in a DNA repair pathway and can be efficiently combined with a checkpoint kinase (CHK) pharmacological inhibitor. Thus, luteolin emerges as a potent cytotoxic and/or adjuvant therapy in oral cancer, as it is a natural compound presenting better effects in vitro compared to conventional chemotherapeutic agents. Future in vivo exploration is next required to provide the proof-of-concept that luteolin could be an efficient anticancer molecule.

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Thiazolide-induced apoptosis in colorectal cancer cells is mediated via the Jun kinase–Bim axis and reveals glutathione-S-transferase P1 as Achilles’ heel

Cited by 30 publications

References 48 publications

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

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