Survivin, a family member of the
inhibitor of apoptosis proteins that is expressed during mitosis in a cell cycle-dependent manner and localized to different components of the mitotic apparatus, plays an important role in both cell division and inhibition of apoptosis.
Survivin is expressed in a vast majority of human
cancers, but not in normal adult tissues.
Survivin expression is often correlated with poor prognosis in a wide variety of
cancer patients. These features make
survivin an attractive target against which
cancer therapeutics could be developed. We have identified a
survivin antisense oligonucleotide (ASO) that potently downregulated
survivin expression in human
cancer cells derived from lung, colon, pancreas, liver, breast, prostate, ovary, cervix, skin, and brain as measured by quantitative RT-PCR and immunoblotting analysis. Specific inhibition of
survivin expression in multiple
cancer cell lines by this ASO (
LY2181308) induced caspase-3-dependent apoptosis, cell cycle arrest in the G(2)-M phase, and multinucleated cells. We also showed that inhibition of
survivin expression by
LY2181308 sensitized
tumor cells to chemotherapeutic-induced apoptosis. Most importantly, in an in vivo human xenograft
tumor model,
LY2181308 produced significant antitumor activity as compared with saline or its sequence-specific control
oligonucleotide and sensitized to
gemcitabine,
paclitaxel, and
docetaxel. Furthermore, we showed that this antitumor activity was associated with significant inhibition of
survivin expression in these xenograft
tumors. On the basis of these,
LY2181308 is being evaluated in a clinical setting (Phase II) in combination with
docetaxel for the treatment of
prostate cancer.