Norcantharidin-induced post-G(2)/M apoptosis is dependent on wild-type p53gene

Norcantharidin (NCTD), a synthetic analogue of phosphatase type 2A inhibito rs, cantharidin, was shown to have limited effects in treating human and an imal tumors. The tumor cell killing mechanisms by norcantharidin, however, remain unclear. In this report, we wished to investigate the mechanisms of norcantharidin-mediated cytotoxicity. Effort was made to investigate whethe r norcantharidin exerted its cytotoxicity through a p53-dependent or -indep endent mechanism. RT-2 (wtp53) and U251 (mutant p53) glioblastoma cell line s were exposed to norcantharidin at different dosages. Time-course fluoresc ent-activated cell sorting (FACS) analysis showed that high doses of norcan tharidin arrested the cells at the G(2)/M phase and subsequent post-G(2)/M apoptosis in RT-2 cell line. In comparison, the U251 cell line was found re sistant to norcantharidin-induced cytotoxicity. Restoring wild-type p53 gen e function in the U251 cell line after adenoviral infections induced tumor cell cytotoxicity after exposure to norcantharidin. These results showed th at norcantharidin kills tumor cells efficiently corresponding to their endo genous p53 gene status. The results also showed the feasibility of using ad enoviral p53 gene therapy to enhance chemosensitivity of tumor cells to nor cantharidin. (C) 2000 Academic Press.