Wild-type p53 gene transfer into mutated p53 HT29 cells improves sensitivity to photodynamic therapy via induction of apoptosis.
Photodynamic therapy (PDT) is an effective local cancer treatment that induces cytotoxicity through the intracellular generation of reactive oxygen species. It is generally thought that p53 regulates chemotherapy and radiation therapy responsiveness via apoptosis induction control. The current study investigated whether cellular sensitivity to PDT is increased when a wild-type (wt) p53 status is restored by gene transfer in the established HT9blk Ala273-mutant p53 human colon cancer cell line. The photosensitizer accumulation was similar in both cell lines, and survival measurements using MTT test and clonogenic assays demonstrated that wt p53 transfected cells (HT29A4) were significantly more sensitive to chlorin e6-mediated PDT. P53 protein expression and its functionality as a transcription factor demonstrated through the induction of mdm2 transactivation, were not found to be directly involved in this differential photosensitivity. However, induction of caspase 3 activation (2.6-fold), leading to significant apoptosis induction 24-h after PDT was observed in HT29A4 cells. These results suggest that the introduction of wt p53 in HT29A4 potentiates the cell sensitivity to PDT through the induction of apoptosis in relation to p53 mutational status, but independently of p53 expression level and transcriptional activity.
Barberi-Heyob
Muriel
M
Centre Alexis Vautrin, Laboratoire de Recherche en Oncologie, Unité de Recherche en Thérapie Photodynamique, 54511 Vandoeuvre-les-Nancy, France. m.barberi@nancy.fnclcc.fr
Védrine
Pierre-Olivier
PO
Merlin
Jean-Louis
JL
Millon
Régine
R
Abecassis
Joseph
J
Poupon
Marie-France
MF
Guillemin
François
F
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002735:Chlorophyllides; D016158:Genes, p53 / Q000235:genetics*; D019073:HT29 Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D010778:Photochemotherapy; D011166:Porphyrins / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002735:Chlorophyllides; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; C062985:phytochlorin