MicroRNAs are short non-coding RNAs that function as sequence-directed post-transcriptional inhibitors of gene expression. The cellular response to ten drugs including actinomycin-D (ACT-D) was examined in a genetically modified HCT116 colon cancer cell line with a deletion in the gene encoding a critical miRNA processing enzyme called DROSHA. We found that the DROSHA-null subline was more susceptible than the parental cells expressing wild-type DROSHA to apoptosis induced by several drugs, most prominently ACT-D. This increase in susceptibility to apoptosis was characterized by increased DNA-fragmentation, increased caspase-3/7 activity, and loss of membrane integrity. The increased susceptibility to apoptosis was not associated with differences in DNA-synthesis, RNA-synthesis, protein-synthesis, metabolic activity, p53 response or the induction of replicative-senescence. Our results suggest that these cell lines are equally sensitive to the direct effects of ACT-D but these DROSHA-null cells are more sensitive to apoptosis induced by a subset of drugs exemplified by ACT-D.