Activation of p53 for the treatment of cancer

Abstract

T umor suppressor p53 promotes cell death in response to environmental stress signals including DNA damage, hypoxia and aberrant proliferative signals like oncogene activation [Vazquez et al., 2008]. This molecule is important for combating carcinogenesis. A mutation inactivating p53 is found in about 50% of cancer including hepatoma, prostate cancer and lymphoma [Soussi and Wiman, 2007; Petitjean et al., 2007]. In cervical cancer cell line HelaS3, p53 activity is inhibited by human papillomavirus E6 and E7 proteins, which is demonstrated to be critical for the carcinogenesis of cervical cancer [Kessis et al., 1993]. Thus, activation of p53 is an appropriate approach for the treatment of cancers [Vazquez et al., 2008]. We read with great interest the paper ‘‘Roscovitine Up-Regulates p53 Protein and Induces Apoptosis in Human HeLaS3 Cervix Carcinoma Cells’’ published by WesieskaGadek et al. in your journal [Wesierska-Gadek et al., 2008]. Roscovitine increases p53 activity in HelaS3 cells through several mechanisms including increased protein expression, decreased degradation and protein activation of p53. The mechanism for the role of activated p53 in cancer treatment involves in both cell cycle arrest and apoptosis. Activation of p53 can increase p21 expression, which in turn inhibits a broad range of CDKs and PCNA-dependent DNA polymerase activity [Warbrick et al., 1997] and thus reduce cell cycle progression. Activation of p53 also causes cell apoptosis through activation of pro-apoptosis pathway and inhibition of IAPs (the inhibitors of apoptosis). Thus, activation of p53 can be used solely for the treatment of cancer. Roscovitine was compared with cisplatin and proved to be superior because roscovitine has no cytotoxicity. This research provided a new approach to activate p53. The authors showed that roscovitine phosphorylated p53 at Ser46 different from cisplatin which phosphorylated p53 at Ser15. The potency of roscovitine activating p53 is several folds lower than cisplatin. However, cisplatin at high dose causes cytotoxicity, neurotoxicity and nephrotoxicity because it makes DNA mutation. Roscovitine was