The invention concerns a double-stranded oligonucleotide characterized in that it consists of two complementary oligonucleotide sequences forming a hybrid comprising each at one of their 3' or 5' ends one to five non-matched nucleotides forming single-stranded ends overlapping from the hybrid, one of said oligonucleotide sequences being substantially complementary of a target sequence belonging to a DNA or RNA molecule to be specifically repressed. The invention also concerns the use of said oligonucleotides in pharmaceutical compositions for treating cancers.