The combination of 5-Fluorouracil plus p53 pathway restoration is associated with depletion of p53-deficient or mutant p53-expressing putative colon cancer stem cells

Catherine Huang, Xiang M. Zhang, Raluca T. Tavaluc, Lori S. Hart, David T. Dicker, Wenge Wang, Wafik S. El-Deiry

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The cancer stem cell hypothesis suggests that rare populations of tumor-initiating cells may be resistant to therapy, lead to tumor relapse and contribute to poor prognosis for cancer patients. We previously demonstrated the feasibility of p53 pathway restoration in p53-deficient tumor cell populations using small molecules including ellipticine or its derivatives. We now establish a single cell p53-regulated green fluorescent protein (EGFP)-reporter system in human DLD1 colon tumor cells expressing mutant p53 protein. We use these p53-EGFP reporter DLD1 cells to investigate the status of p53 transcriptional activity in putative colon cancer stem cell populations following exposure to p53 pathway-restoring drugs and/or classical chemotherapy. We demonstrate induction of p53-specific EGFP reporter fluorescence following overexpression of p53 family member p73 by an Adenovirus vector. We further show that p53-reporter activity is induced in DLD1 putative cancer stem cell side-populations analyzed by their Hoechst dye efflux properties following treatment with the p53 pathway restoring drug ellipticine. Combination of ellipticine with the cytotoxic agent 5-fluorouracil resulted in increased cytotoxicity as compared to either agent alone and this was associated with depletion of putative cancer stem cell populations as compared with 5-FU alone treatment. Our results support the feasibility of therapeutic targeting of mutant p53 in putative cancer stem cells as well as the potential to enhance cytotoxic chemotherapy.

Original languageEnglish (US)
Pages (from-to)2185-2192
Number of pages8
JournalCancer Biology and Therapy
Volume8
Issue number22
DOIs
StatePublished - Nov 15 2009

Keywords

  • 5-fluorouracil
  • ALDH
  • Cancer stem cell
  • Cytotoxicity
  • Ellipticine
  • Flow cytometry
  • Mutant p53
  • p53
  • Side-population

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