SPC3042: a proapoptotic survivin inhibitor.

Abstract

The ability to regulate the cellular homeostasis of a higher organism through tight control of apoptosis and cell division is crucial for life. Dysregulation of these mechanisms is often associated with cancerous phenotypes in cells. Optimal cancer therapy is a fine balance between effective cancer cell killing and at the same time minimizing, or avoiding, damage to the surrounding healthy tissue. To obtain this, it is necessary to identify and inhibit molecular targets on which the cancer cells are strongly dependent. Survivin represents such a target, and it has been published previously that peptide vaccines, the small-molecule YM155, and the antisense molecule LY2181308/ISIS23722, via different mechanisms, have been used as survivin inhibitors. In this article, a new potent antisense inhibitor of survivin, SPC3042, is presented, and the properties of SPC3042 are compared with the previously published antisense drug, LY2181308/ISIS23722. SPC3042 is a 16-mer locked nucleic acid (LNA) oligonucleotide and designed as a fully phosphorothiolated gapmer containing 7 LNA nucleotides in the flanks. The LNA nucleotides in SPC3042 provide nuclease stability and higher potency for survivin mRNA inhibition compared with earlier generations of antisense reagents. It is shown that the down-regulation of survivin with SPC3042 leads to cell cycle arrest, pronounced cellular apoptosis, and down-regulation of Bcl-2. It is also shown that SPC3042 is a sensitizer of prostate cancer cells to Taxol treatment in vitro and in vivo.

• Authors: Jens Bo Hansen, Niels Fisker, Majken Westergaard, Lene Sønderby Kjaerulff, Henrik Frydenlund Hansen, Charlotte Albaek Thrue, Christoph Rosenbohm, Margit Wissenbach, Henrik Orum, Troels Koch
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 9 Pg. 2736-45 (Sep 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18790754 (Publication Type: Journal Article)

Chemical References

• Apoptosis Regulatory Proteins
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Oligodeoxyribonucleotides
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• SPC 3042
• Survivin
• Deoxyribonucleases
• Caspases
• Paclitaxel

Topics

• Animals
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (antagonists & inhibitors)
• Base Sequence
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Deoxyribonucleases (metabolism)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inhibitor of Apoptosis Proteins
• Male
• Mice
• Microtubule-Associated Proteins (antagonists & inhibitors, genetics, metabolism)
• Molecular Sequence Data
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Nucleic Acid Denaturation (drug effects)
• Oligodeoxyribonucleotides (pharmacology)
• Paclitaxel (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Survivin
• Temperature
• Xenograft Model Antitumor Assays