Survivin, a family member of the inhibitor of apoptosis proteins (IAP) 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 to develop cancer therapeutics. We have identified a survivin antisense oligonucleotide (ASO) that potently down regulated 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 G2/M phase, and multinucleated cells. We also demonstrated that inhibition of survivin expression by LY2181308 sensitized tumor cells to chemotherapeutics induced apoptosis. Most importantly, in an in-vivo human xenograft tumor model, LY2181308 produced significant antitumor activity as compared to saline or its sequence-specific control oligonucleotide, and sensitized to gemcitabine, paclitaxel, and docetaxel. Furthermore, we demonstrated that this antitumor activity was associated with significant inhibition of survivin expression in these xenograft tumors. Based on these LY2181308 is being evaluated in a clinical setting (Phase II) in combination with docetaxel for the treatment of prostate cancer.
- Received September 1, 2010.
- Revision received November 11, 2010.
- Accepted December 4, 2010.
- Copyright © 2011, American Association for Cancer Research.