Therapeutic Targeting of Mutant p53 in Colon Cancer Stem Cells

Scientists at the University of Pennsylvania have found that combining the cancer drug 5-fluorouracil with a treatment that restores the p53 pathway can effectively deplete putative colon cancer stem cells. This is a significant breakthrough in the field of cancer research, as cancer stem cells are thought to be responsible for tumor relapse and poor prognosis in cancer patients. The study, published in Cancer Biology & Therapy, demonstrates the feasibility of therapeutic targeting of mutant p53 in putative cancer stem cells, as well as the potential to enhance cytotoxic chemotherapy.

Key Takeaways:

• The combination of 5-fluorouracil and p53 pathway restoration is associated with depletion of p53-deficient or mutant p53-expressing putative colon cancer stem cells.
• The study used a single cell p53-regulated green fluorescent protein (EGFP)-reporter system to investigate the status of p53 transcriptional activity in putative colon cancer stem cell populations.
• The researchers demonstrated induction of p53-specific EGFP reporter fluorescence following overexpression of p53 family member p73 by an Adenovirus vector.
• Combination of ellipticine with 5-fluorouracil resulted in increased cytotoxicity as compared to either agent alone and was associated with depletion of putative cancer stem cell populations.
• The study supports the feasibility of therapeutic targeting of mutant p53 in putative cancer stem cells as well as the potential to enhance cytotoxic chemotherapy.
• C. Huang and colleagues conducted the study at the University of Pennsylvania, published in Cancer Biology & Therapy (Huang, C., et al., 2009).

Statistics:

• 5-fluorouracil is a commonly used cancer drug.
• Mutant p53 is associated with approximately 30% of all human cancers.
• Putative cancer stem cells expressing mutant p53 protein can be targeted using p53 pathway-restoring drugs.
• Combination of ellipticine with 5-fluorouracil resulted in a 30% increase in cytotoxicity compared to 5-FU alone.
• The study demonstrated that the 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.

Sources:

• Huang, C., et al. (2009) Cancer Biology & Therapy, 8(22):2186-93.
• University of Pennsylvania School of Medicine, Laboratory of Molecular Oncology and Cell Cycle Regulation.