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

BAP van Gorkom, H Timmer-Bosscha, S de Jong, JH Kleibeuker, EGE de Vries*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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 resistance-associated protein I. P-glycoprotein and multidrug resistance-associated protein I 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 men, aloe emodin and danthron was established in related cell lines exhibiting different levels of topoisomerases, multidrug resistance-associated protein I and P-glycoprotein. Interaction of rhein with multidrug resistance-associated protein I was studied by carboxy fluorescein efflux and direct cytotoxicity by apoptosis induction. Rhein was less cytotoxic in the multidrug resistance-associated protein I overexpressing GLC4/ADR cell line compared to GLC4. Multidrug resistance-associated protein I 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 I and induces apoptosis. It could therefore render the colonic epithelium sensitive to cytotoxic agents, apart from being toxic in itself, (C) 2002 Cancer Research UK.

Original languageEnglish
Pages (from-to)1494-1500
Number of pages7
JournalBritish Jounal of Cancer
Volume86
Issue number9
DOIs
Publication statusPublished - 6-May-2002

Keywords

  • anthranoids
  • multidrug resistance
  • apoptosis
  • colon
  • carcinogeresis
  • COLONIC EPITHELIAL-CELLS
  • HUMAN TUMOR-CELLS
  • ANTHRAQUINONE GLYCOSIDES
  • INDUCED APOPTOSIS
  • MELANOSIS-COLI
  • DRUG EFFLUX
  • EXPRESSION
  • MRP
  • LINE
  • TRANSPORT

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