p53 Small-Molecule Inhibitor Enhances Temozolomide Cytotoxic Activity against Intracranial Glioblastoma Xenografts

Cocombination of temozolomide and a p53 small-molecule inhibitor precursor significantly enhanced tumor control in p53 wild-type glioblastoma xenografts (P < 0.001).

• The active form of the p53 inhibitor increased the cytotoxicity of temozolomide in p53 wild-type glioblastoma cells.
• Increased poly(ADP-ribose) polymerase cleavage and elevated phospho-H2AX levels were observed alongside heightened cytotoxic responses.
• In vivo, cotreatment with the p53 inhibitor precursor and temozolomide led to a significant survival benefit in three distinct p53 wild-type glioblastoma xenograft models.
• Mice with p53-null glioblastoma did not show a survival advantage from the p53 inhibitor precursor when treated with temozolomide.
• The findings suggest that the combination enhances temozolomide's effectiveness in a p53-dependent manner.

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