Exploration of p53 plus interferon-beta gene transfer for the sensitization of human colorectal cancer cell lines to cell death

While treatments for colorectal cancer continue to improve, some 50% of patients succumb within 5 years, pointing to the need for additional therapeutic options. We have developed a modified non-replicating adenoviral vector for gene transfer, called AdRGD-PG, which offers improved levels of transduction and transgene expression. Here, we employ the p53-responsive PG promoter to drive expression of p53 or human interferon-beta (hIFN beta) in human colorectal cancer cell lines HCT116(wt) (wtp53), HCT116(-/-) (p53 deficient) and HT29 (mutant p53). The HCT116 cell lines were both easily killed with p53 gene transfer, while combined p53 and hIFN beta cooperated for the induction of HT29 cell death and emission of immunogenic cell death (ICD) markers. Elevated annexinV staining and caspase 3/7 activity point to cell death by a mechanism consistent with apoptosis. P53 gene transfer alone or in combination with hIFN beta sensitized all cell lines to chemotherapy, permitting the application of low drug doses while still achieving significant loss of viability. While endogenous p53 status was not sufficient to predict response to treatment, combined p53 and hIFN beta provided an additive effect in HT29 cells. We propose that this approach may prove effective for the treatment of colorectal cancer, permitting the use of limited drug doses.

Automated summary

A modified non-replicating adenoviral vector was developed for gene transfer in colorectal cancer cells, showing enhanced sensitivity to chemotherapy and increased cell death rates. The approach may be effective for the treatment of colorectal cancer, allowing for the use of limited drug doses.