Human DNA polymerase ≤ (pol α) plays a key role in replicating across the UV radiation induced cyclobutane pyrimidine dimers (CPD) in DNA and mutations in pol ≤ gene result in a syndrome called Xeroderma Pigmentosum Variant (XP-V). In the absence of pol β, the DNA replication forks collapse after prolonged stalling at CPD sites, which consequently lead to DNA breakages and cell death. Therefore, pol ≤ has been considered to serve as a cellular protection mechanism to enhance cell survival and reduce mutagenesis. In addition to UV-induced CPD lesion, pol ≤ has the ability to handle DNA lesions introduced by chemotherapeutic anticancer agents, such as platinum based compounds and nucleoside analogs. Such damage tolerance ability of pol ≤ has been shown to reduce cell sensitivity to these DNA targeting agents. D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is a selenophene compounds that demonstrated promising antitumor activity against various human cancer cells and in vivo xenograft mouse model. Mechanistic studies have shown that D-501036 induced DNA adduct(s) and caused genome instability, which result in cell cycle accumulation in the S-phase, DNA breakage, and subsequently lead to cell death. Interestingly, the IC50 for human fibroblast XP30RO cells derived from XP-V patients was >50 fold higher than the XP30RO cells that stably transfected with a pol ≤ expressing vector (XP30RO-EGFP-pol α). In addition, D-501036 caused an increased amount of DNA breakage in the XP30RO-EGFP-pol ≤ cells as compared to its parental XP30RO cells in both DNA fragmentation and comet assays. These results revealed a novel role of pol ≤ in the action of D-501036 that is very different from its protective role against UV irradiation or cisplatin.
日期:
2012-04
關聯:
Cancer Research. 2012 Apr;72:Abstract number 3813.
