Cytotoxic chemotherapy upregulates pro-apoptotic Bax and Bak in the small intestine of rats and humans

Pathology. 2005 Feb;37(1):56-62. doi: 10.1080/00313020400023461.


Aims: Small intestinal crypt cells rapidly undergo apoptosis in response to cytotoxic drug treatment that results in gastrointestinal toxicity. The Bcl-2 family have been implicated in both positive and negative regulation of intestinal cell apoptosis. The aim of this study was to examine the effect of cytotoxic treatment on Bcl-2 protein expression in patients and rats with tumours.

Methods: Four pro- and four anti-apoptotic members of the Bcl-2 family, caspase-3 and p53 were examined in small intestinal crypts before and after treatment in rats and humans. Immunohistochemistry identified changes in protein expression over time, while relative RT-PCR was used to investigate mRNA expression in rat small intestine.

Results: Cytotoxic treatment increased p53 and caspase-3 which coincided with elevated levels of apoptosis. Bax and Bak protein and mRNA expression also significantly increased at 6 hours following treatment in rats. Bax and Bak protein increased at day 1 after treatment in humans. Anti-apoptotic Mcl-1 protein decreased within 24hours. Other Bcl-2 family members showed only modest changes.

Conclusion: Increased expression of Bax and Bak but not other Bcl-2 family members is associated with apoptosis in small intestinal crypts and may amplify the sensitivity and susceptibility of crypt cells to chemotherapy-induced enteropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Caspase 3
  • Caspases / drug effects
  • Female
  • Humans
  • Immunohistochemistry
  • Intestinal Mucosa / drug effects*
  • Intestinal Neoplasms / drug therapy
  • Membrane Proteins / drug effects*
  • Proto-Oncogene Proteins c-bcl-2 / drug effects*
  • RNA, Messenger / analysis
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Protein p53 / drug effects
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein


  • Antineoplastic Agents
  • BAK1 protein, human
  • BAX protein, human
  • Bak1 protein, rat
  • Bax protein, rat
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • CASP3 protein, human
  • Casp3 protein, rat
  • Caspase 3
  • Caspases