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Specific repression of mutant K-RAS by 10–23 DNAzyme: Sensitizing cancer cell to anti-cancer therapies
Ist Teil von
Biochemical and biophysical research communications, 2009-01, Vol.378 (2), p.230-234
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2009
Quelle
ScienceDirect
Beschreibungen/Notizen
Point mutations of the
Ras family are frequently found in human cancers at a prevalence rate of 30%. The most common mutation
K-Ras(G12V), required for tumor proliferation, survival, and metastasis due to its constitutively active GTPase activity, has provided an ideal target for cancer therapy. 10–23 DNAzyme, an oligodeoxyribonucleotide-based ribonuclease consisting of a 15-nucleotide catalytical domain flanked by two target-specific complementary arms, has been shown to effectively cleave the target mRNA at purine–pyrimidine dinucleotide. Taking advantage of this specific property, 10–23 DNAzyme was designed to cleave mRNA of
K-Ras(G12V)(
GGU
→
GUU) at the GU dinucleotide while left the wild-type (WT)
K-Ras mRNA intact. The
K-Ras(G12V)-specific 10–23 DNAzyme was able to reduce
K-Ras(G12V) at both mRNA and protein levels in SW480 cell carrying homozygous
K-Ras(G12V). No effect was observed on the WT
K-Ras in HEK cells. Although
K-Ras(G12V)-specific DNAzymes alone did not inhibit proliferation of SW480 or HEK cells, pre-treatment of this DNAzyme sensitized the
K-Ras(G12V) mutant cells to anti-cancer agents such as doxorubicin and radiation. These results offer a potential of using allele-specific 10–23 DNAzyme in combination with other cancer therapies to achieve better effectiveness on cancer treatment.