Pifithrin-alpha enhancing anticancer effect of topotecan on p53-expressing cancer cells

摘要

p53 is generally known as an effective anti-cancer molecular, but it is lost or mutated in more than 50% of human tumors. It is still a controversial issue whether the activity of p53 really benefits for treating cancers, we wondered what would happen if the endogenous p53 was inhibited before treated with topotecan (TPT) on p53 positive tumor cells. In this study, pifithrin-alpha (PFT alpha), a p53 inhibitor, was used 2 h before treated with TPT on three kinds of cancer cell lines including MCF7, BGC823 and HepG2 cells. The IC(50)s of TPT for MCF7, BGC823 and HepG2 cells after 10 mu M PFT alpha pretreated, was 4.8 to 14.4 folds lower than the effect of TPT alone. It was demonstrated that PFT alpha decreases the p-p53 levels and p-p53 activity, not affects p53 expression in p53 positive tumor cells. PFT alpha enhanced anticancer effect of TPT on cells was found mainly by two ways. Firstly, it increased the TPT accumulation in cells and nucleus and promoted the inhibition of TPT on activity of Topo I, and induced more DNA damage. Secondly, PFT alpha decreased formation of p53/mdm2 complex responsible for p53 degradation by inhibiting the protein expression of mdm2, so p53 degradation was decreased in cytoplasm and p53 accumulation was increased in nucleus, which induced more cells undergo apoptosis. So, the crosstalk between p53 and TPT played a pivotal role for enhancing anticancer effects of PFT alpha and TPT on p53 positive cancer cells. These findings provide a new idea for drug design and combination chemotherapy of cancers.