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Anticancer activity and chemoprevention of xenobiotic organosulfurs in preclinical model systems

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      Abstract

      There seems to be little doubt that xenobiotic and plant derived organosulfur compounds have enormous benefits for in vitro cellular functions and for a multitude of diseases, including cancer. Since there are numerous reviews on anticancer activities of plant organosulfurs, the focus herein will be on alterations associated with xenobiotic organosulfurs. Benefits of 2-mercaptoethanol (2-Me), N-Acetyl-cysteine, cysteamine, thioproline, piroxicam, disulfiram, amifostine, sulindac, celecoxib, oltipraz and their derivates on transplanted homologous tumors and on autochthonous cancers with a viral-, radiation-, chemical carcinogen-, and undefined-etiology are assessed. Because all organosulfurs were not tested for activity in each of the etiology categories, comparative evaluations are restricted. In general, all ‘appeared’ to lower the incidence of cancer irrespective of etiology; however, since most of these values were determined at ages much younger than at a natural-end-of-life-age, differences most likely, instead, reflect a delayed initiation and/or a slowed progression of tumorigenesis. The poorest, long-term benefits of early intervention protocols occurred for viral- and chemical carcinogen-induced cancers. In addition, once tumorigenesis was beyond the initiation stage, outcomes of organosulfur therapies were extremely poor, indicating that they will not be of significant value as stand alone treatments. More importantly, except for the lifetime prevention of spontaneous and radiation-induced mammary tumors by daily dietary 2-Me, similar life long prevention of tumorigenesis was not achieved with other xenobiotics or any of nature’s plant organosulfurs. These results raise an interesting question: Is the variability in incidence found for different organosulfurs associated with (a) their structure, (b) the length of the untreated latency period, (c) treatment duration/dose, and/or (d) the etiology-inducing agent?

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      Most cited references 166

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      Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues.

      Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents. NSAIDs restore normal apoptosis in human adenomatous colorectal polyps and in various cancer cell lines that have lost adenomatous polyposis coli gene function. NSAIDs also inhibit angiogenesis in cell culture and rodent models of angiogenesis. Many epidemiologic studies have found that long-term use of NSAIDs is associated with a lower risk of colorectal cancer, adenomatous polyps, and, to some extent, other cancers. Two NSAIDs, sulindac and celecoxib, have been found to inhibit the growth of adenomatous polyps and cause regression of existing polyps in randomized trials of patients with familial adenomatous polyposis (FAP). However, unresolved questions about the safety, efficacy, optimal treatment regimen, and mechanism of action of NSAIDs currently limit their clinical application to the prevention of polyposis in FAP patients. Moreover, the development of safe and effective drugs for chemoprevention is complicated by the potential of even rare, serious toxicity to offset the benefit of treatment, particularly when the drug is administered to healthy people who have low annual risk of developing the disease for which treatment is intended. This review considers generic approaches to improve the balance between benefits and risks associated with the use of NSAIDs in chemoprevention. We critically examine the published experimental, clinical, and epidemiologic literature on NSAIDs and cancer, especially that regarding colorectal cancer, and identify strategies to overcome the various logistic and scientific barriers that impede clinical trials of NSAIDs for cancer prevention. Finally, we suggest research opportunities that may help to accelerate the future clinical application of NSAIDs for cancer prevention or treatment.
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        Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.

        Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported. We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year. A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number of polyps had decreased to 44 percent of base-line values and the diameter of the polyps to 35 percent of base-line values (P = 0.014 and P < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at base line. No side effects from sulindac were noted. Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy.
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          H₂S signalling through protein sulfhydration and beyond.

          Hydrogen sulfide (H(2)S) has recently emerged as a mammalian gaseous messenger molecule, akin to nitric oxide and carbon monoxide. H(2)S is predominantly formed from Cys or its derivatives by the enzymes cystathionine β-synthase and cystathionine γ-lyase. One of the mechanisms by which H(2)S signals is by sulfhydration of reactive Cys residues in target proteins. Although analogous to protein nitrosylation, sulfhydration is substantially more prevalent and usually increases the catalytic activity of targeted proteins. Physiological actions of sulfhydration include the regulation of inflammation and endoplasmic reticulum stress signalling as well as of vascular tension.
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            Author and article information

            Affiliations
            Altick Associates, River Falls, WI, USA
            Author notes
            Contributors
            Altick Associates, River Falls, WI, USA
            Journal
            101627223
            42298
            Oncol Discov
            Oncol Discov
            Oncology discovery
            2052-6199
            14 March 2014
            2013
            06 November 2014
            : 1
            : 4
            4222532
            10.7243/2052-6199-1-4
            NIHMS555153
            © 2013 Robert E. Click licensee Herbert Publications Ltd

            This is an Open Access article distributed under the terms of Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0). This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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