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. [Mol Cancer Ther 2008;7(9):2736 -45]

Reduced Expression of the Androgen Receptor by Third Generation of Antisense Shows Antitumor Activity in Models of Prostate Cancer

“…Such LNA oligonucleotides have low single-digit nanomolar or high picomolar IC 50 values for mRNA downmodulation that have been achieved in cell culture for LNA-ASOs against AR as well as HIF-1a (13) and survivin (14,23) when used with transfection reagents. Thus, LNA-ASOs have potencies similar to those of siRNAs but without the inherent instability of siRNAs.…”

The Central Role of Survivin in Proliferation and Apoptosis of Malignant Pleural Mesothelioma

“…Low molecular weight chemical inhibitors, such as YM155 (Nakahara et al, 2007), and immunogenic peptides, such as survivin-2B80-88 (Tsuruma et al, 2004) are being tested in the preclinical and early-phase clinical setting for breast, lung and colorectal cancer. Promising results of such antisurvivin therapies, applied to other cancer types (Hansen et al, 2008;Olie et al, 2000;Tsuruma et al, 2008), further confirm the feasibility and effectiveness of antisurvivin therapeutic approaches for the treatment of malignant pleural mesothelioma patients.…”

We Should Continue the Half-Century History of Applications of Antisense Oligonucleotides in Medicine, Agriculture and Forestry: A Mini-Review

“…Each LNA residue introduced into a duplex comprising DNA or RNA strands increases its melting temperature by several degrees, which, along with the rigid conformation of the LNA residues, contributes to the stability of the duplex [55,56]. In the presence of transfection reagents in cell culture, LNA oligonucleotides have low single-digit nanomolar or high picomolar IC50 values for mRNA down-modulation [57,58]. In general, LNAs i) lack the unspecific toxicity of phosphorothioates;…”