Apoptosis induction by sennoside laxatives in man; escape from a protective mechanism during chronic sennoside use?

Gorkom, B A van; Karrenbeld, Arend; Sluis, Tineke van der; Zwart, Nynke; Vries, Elisabeth G.E. de; Kleibeuker, Jan H.

doi:10.1002/path.914

Cited by 29 publications

(22 citation statements)

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“…However, recent data, including those from large-scale retrospective, prospective and experimental studies, did not show any increased cancer risk. It is widely accepted that increase in the incidence of adenomas is probably due to easier detection of small adenomas against the black background [2,[19][20][21]. We had only one patient with adenoma and did not see any MC in proximal segments of patients with colon cancer.…”

Section: Discussionmentioning

confidence: 89%

Herbal remedies are the main etiologic factor in melanosis coli, a case series study

Kav

Bayraktar

2010

Open Medicine

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AbstractMelanosis coli is a brown to black discoloration of the colon mucosa usually associated with long-term ingestion of laxatives. However, melanosis coli can be found in patients with no history of laxative use. Regular use of herbal remedies could be the major source of anthranoid laxatives in such patients. We designed a prospective case series study to identify the clinical characteristics and etiology of melanosis coli in affected patients. This study took place in Ankara, Turkey, between 08/2005 and 11/2006. Patients with endoscopic diagnosis of melanosis coli were interviewed for demographical data and use of herbal remedies. A total of 380 colonoscopies were performed during this period. Melanosis coli was diagnosed endoscopically in 12 patients (3.17%), 11 of whom were found to have characteristic pigment-laden macrophages in histopathological examination. Herbal remedies were the main etiological factor in the development of melanosis coli in 10 out of 11 patients. Diffuse involvement was found in 2 patients who had a history of long-term use. In 8 patients, melanosis coli was located in the left side of the colon. Although melanosis coli is a harmless discoloration of colonic mucosa resulting from complementary or alternative medicine, we believe that this association with herbals was overlooked or not inquired in patients. Therefore, it should be emphasized that “natural” or “alternative” is not equal to “safe”.

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Section: Discussionmentioning

confidence: 89%

Herbal remedies are the main etiologic factor in melanosis coli, a case series study

Kav

Bayraktar

2010

Open Medicine

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“…As has already been indicated, the chronic use of sennoside laxatives on some occasions causes pseudomelanosis coli [40] and this has been associated to an increase in the risk of colorectal cancer [41]. In patients subjected to enemas containing senna extracts, it was observed that the sennosides induce an acute massive loss of intestinal cells, possibly because of apoptosis, and alter the length of the colonic crypts causing the appearance of shorter crypts and an increase of the cellular proliferation and inhibition of the restoring apoptosis of the cellular function.…”

Section: Melanosis Coli and Apoptosismentioning

confidence: 99%

“…In conditions where severe melanosis coli was observed, apoptosis seems to be delayed, causing longer crypts without an increase of the proliferating activity or the expression of bcl-2, antiapoptotic gene. It has been suggested that the loss of a possible protective mechanism may increase the risk of carcinogenesis during the chronic use of sennosides [41]. …”

Section: Melanosis Coli and Apoptosismentioning

confidence: 99%

Is Senna Laxative Use Associated to Cathartic Colon, Genotoxicity, or Carcinogenicity?

Morales

Hernández

Bustamante

et al. 2009

Journal of Toxicology

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Due to their natural origin, apparent low oral toxicity, effectiveness, and accessibility without a medical prescription, the anthranoid laxatives are a popular remedy for constipation and are frequently used abusively. Therefore, it is important to characterize its harmful and/or toxic effects. The sennosides, main active metabolites of senna, exhibit a very low toxicity in rats, and its genotoxic activity in bacterial strains as well as mammal cells was classified as weak in those cases where it was shown to be significant. The toxicological and mutagenic status of the crude extract of senna, however, is not as well characterized, and it is necessary to do so since it is frequently, and at the same time incorrectly, believed that the chronic use of anthranoid laxatives is a risk factor for the development of colorectal cancer. The objective of this article was to review the information that arises in various scientific medical databases using key words such as senna, sen, Senna alexandrina, Cassia angustifolia, sennosides, laxative toxicity, mainly ISI and non-ISI articles of journals with an editorial committee. Web pages of products or companies that publicize or commercialize this type of laxative were not included. This analysis establishes that (1) there is no convincing evidence that the chronic use of senna has, as a consequence, a structural and/or functional alteration of the enteric nerves or the smooth intestinal muscle, (2) there is no relation between long-term administration of a senna extract and the appearance of gastrointestinal tumors or any other type in rats, (3) senna is not carcinogenic in rats even after a two-year daily dose of up to 300 mg/kg/day, and (4) the current evidence does not show that there is a genotoxic risk for patients who take laxatives containing senna extracts or sennosides.

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“…Anthranoid laxatives have been shown to induce apoptosis of colonic epithelial cells in man within 6 h after ingestion (Van Gorkom et al, 2001). Animal studies also demonstrated increased apoptosis 6 h after danthron administration (Walker et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of rhein, the active metabolite of sennoside laxatives, is reduced by multidrug resistance-associated protein 1

et al. 2002

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Anthranoid laxatives, belonging to the anthraquinones as do anthracyclines, possibly increase colorectal cancer risk. Anthracyclines interfere with topoisomerase II, intercalate DNA and are substrates for P-glycoprotein and multidrug resistanceassociated protein 1. P-glycoprotein and multidrug resistance-associated protein 1 protect colonic epithelial cells against xenobiotics. The aim of this study was to analyse the interference of anthranoids with these natural defence mechanisms and the direct cytotoxicity of anthranoids in cancer cell lines expressing these mechanisms in varying combinations. A cytotoxicity profile of rhein, aloe emodin and danthron was established in related cell lines exhibiting different levels of topoisomerases, multidrug resistance-associated protein 1 and P-glycoprotein. Interaction of rhein with multidrug resistance-associated protein 1 was studied by carboxy fluorescein efflux and direct cytotoxicity by apoptosis induction. Rhein was less cytotoxic in the multidrug resistance-associated protein 1 overexpressing GLC4/ADR cell line compared to GLC4. Multidrug resistanceassociated protein 1 inhibition with MK571 increased rhein cytotoxicity. Carboxy fluorescein efflux was blocked by rhein. No P-glycoprotein dependent rhein efflux was observed, nor was topoisomerase II responsible for reduced toxicity. Rhein induced apoptosis but did not intercalate DNA. Aloe emodin and danthron were no substrates for MDR mechanisms. Rhein is a substrate for multidrug resistance-associated protein 1 and induces apoptosis. It could therefore render the colonic epithelium sensitive to cytotoxic agents, apart from being toxic in itself.

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Apoptosis induction by sennoside laxatives in man; escape from a protective mechanism during chronic sennoside use?

Cited by 29 publications

References 29 publications

Herbal remedies are the main etiologic factor in melanosis coli, a case series study

Herbal remedies are the main etiologic factor in melanosis coli, a case series study

Is Senna Laxative Use Associated to Cathartic Colon, Genotoxicity, or Carcinogenicity?

Cytotoxicity of rhein, the active metabolite of sennoside laxatives, is reduced by multidrug resistance-associated protein 1

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