Apoptosis induction by sennoside laxatives in man; escape from a protective mechanism during chronic sennoside use?
Chronic sennoside use induces melanosis coli (MC) and possibly increases colorectal cancer risk. Sennosides alter colonic crypt length, proliferative activity, and bcl-2 expression 18 h after administration. To investigate possible mechanisms for carcinogenesis, the effects of acute sennoside use and the presence of MC on colorectal epithelium were studied. Colorectal biopsies from 15 subjects receiving sennosides 6 h before sigmoidoscopy (Sen), 15 controls (NSen), and 27 with MC [11 moderate (MMC) and 16 severe (SMC)]. were analysed for degree of apoptosis (H&E staining), immunohistochemical p53, p21/WAF and bcl-2 expression, and proliferative activity (labelling index, LI). Apoptosis (p=0.0004), intensity of p53 staining (p=0.01), and p21/WAF expression (p=0.008) were increased in Sen and SMC compared with NSen and MMC. p53 expression was increased in Sen (p=0.004). No difference in bcl-2 expression or LI was observed. Crypts were shorter in Sen (p=0.05) and longer in SMC (p=0.04) than in NSen. It is concluded that sennosides acutely induce apoptosis of colonic epithelial cells, presumably by a p53, p21/WAF-mediated pathway, resulting in shorter crypts. In severe melanosis coli, apoptosis seems to be delayed, causing longer crypts without a rise in proliferative activity or bcl-2 expression. This escape from a presumably protective mechanism may enhance the risk of carcinogenesis during chronic sennoside use.
van Gorkom
B A
BA
Department of Gastroenterology, University Hospital, 9700 RB Groningen, The Netherlands.
Karrenbeld
A
A
van der Sluis
T
T
Zwart
N
N
de Vries
E G
EG
Kleibeuker
J H
JH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000880:Anthraquinones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D002400:Cathartics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012676:Senna Extract; D000081226:Sennosides; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000880:Anthraquinones; C493956:CDKN1A protein, human; D002400:Cathartics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D000081226:Sennosides; D016159:Tumor Suppressor Protein p53; D012676:Senna Extract