CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death.
CP-31398 is a prototype small molecule that stabilizes the active conformation of p53 and promotes p53 activity in cancer cell lines with mutant or wild-type p53. Here, we report that CP-31398 induces p53 reporter gene activity and p21 expression in all of 11 glioma cell lines harboring wild-type or mutant p53, but not in p53-null LN-308 cells. Upon prolonged exposure to CP-31398, all glioma cell lines undergo caspase-independent and bcl-x(L)-insensitive cell death with EC(50) concentrations of 10-36 microM. By comparing p53 wild-type U87MG and p53-null LN-308 cells expressing the temperature-sensitive p53(V135A) mutant, we delineate two pathways of CP-31398-induced cell death: an early, p53-dependent pathway that requires (new p53) protein synthesis and a late, p53-independent pathway characterized by aurintricarboxylic acid -sensitive calcium release and epiphenomenal free radical formation. Post-transcriptional repression of p53 synthesis by an intracellularly transcribed short interfering RNA confirmed the presence of these two pathways of cell death. These observations point out some of the liabilities of CP-31398 as a prototype p53-based therapeutic and define a rationale for further refinement of small molecules that specifically target the p53 pathway, but lack the p53-independent effects.
Wischhusen
J
J
Laboratory of Molecular Neuro-Oncology, Department of Neurology, Medical School, University of Tübingen, D-72076 Tübingen, Germany.
Naumann
U
U
Ohgaki
H
H
Rastinejad
F
F
Weller
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D005434:Flow Cytometry; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007700:Kinetics; D011743:Pyrimidines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000502:physiology
D000970:Antineoplastic Agents; D017931:DNA Primers; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C402665:CP 31398