Antisense inhibition of survivin expression as a cancer therapeutic

Rosa A. Carrasco, Nancy B. Stamm, Eric Marcusson, George Sandusky, Philip Iversen, Bharvin K R Patel

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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 G2-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.

Original languageEnglish (US)
Pages (from-to)221-232
Number of pages12
JournalMolecular Cancer Therapeutics
Volume10
Issue number2
DOIs
StatePublished - Feb 2011
Externally publishedYes

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docetaxel
Neoplasms
Antisense Oligonucleotides
Therapeutics
Apoptosis
gemcitabine
Heterografts
Cell Division
Inhibitor of Apoptosis Proteins
Spindle Apparatus
Inhibition (Psychology)
G2 Phase
Paclitaxel
Cell Cycle Checkpoints
Immunoblotting
Mitosis
Cervix Uteri
Oligonucleotides
Caspase 3
Prostate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Carrasco, R. A., Stamm, N. B., Marcusson, E., Sandusky, G., Iversen, P., & Patel, B. K. R. (2011). Antisense inhibition of survivin expression as a cancer therapeutic. Molecular Cancer Therapeutics, 10(2), 221-232. https://doi.org/10.1158/1535-7163.MCT-10-0756

Antisense inhibition of survivin expression as a cancer therapeutic. / Carrasco, Rosa A.; Stamm, Nancy B.; Marcusson, Eric; Sandusky, George; Iversen, Philip; Patel, Bharvin K R.

In: Molecular Cancer Therapeutics, Vol. 10, No. 2, 02.2011, p. 221-232.

Research output: Contribution to journalArticle

Carrasco, RA, Stamm, NB, Marcusson, E, Sandusky, G, Iversen, P & Patel, BKR 2011, 'Antisense inhibition of survivin expression as a cancer therapeutic', Molecular Cancer Therapeutics, vol. 10, no. 2, pp. 221-232. https://doi.org/10.1158/1535-7163.MCT-10-0756
Carrasco, Rosa A. ; Stamm, Nancy B. ; Marcusson, Eric ; Sandusky, George ; Iversen, Philip ; Patel, Bharvin K R. / Antisense inhibition of survivin expression as a cancer therapeutic. In: Molecular Cancer Therapeutics. 2011 ; Vol. 10, No. 2. pp. 221-232.
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