DNA origami as a potential anti-cancer drug

In this article published in ACS NANO, a DNA origami structure is shown capable of clustering DR5. When this cluster inducing origami is added to cancer cells, it is shown to cause apoptosis and cell death. As much as 80% of some cell types went into apoptosis with one version of this DNA origami structure.

Despite the many advances in oncology, cancer still remains one of the leading causes of death in many countries in the 21^st century. In particular, breast cancer is accounting for a big part of cancer-related deaths in women. While developments in primary tumor removal have been made in recent years, metastasis is still most often incurable, making research in this field particularly important. One very interesting target for battling metastases is Death Receptor 5 (DR5), which is known to have a specific effect on tumor cells if activated by Tumor Necrosis Factor Apoptosis Inducing Ligand (TRAIL) (Ashkenazi et al., 1999; Walczak et al., 1999). Specifically, it is effective against metastatic cells in breast cancer (Rahman et al., 2009). Unfortunately, when TRAIL (Tumor Necrosis Factor Related Apoptosis Inducing Ligand) is used by itself as a drug, it loses its effectiveness (Duiker et al., 2006). It was shown later that this had to do with the receptor itself, which had to cluster in a hexagon-like shape before it could be activated by TRAIL (Valley et al., 2012). It seemed like clustering this receptor while activating it could be the key to its anti-tumor effect. Now for patterning and clustering, DNA origami could provide an answer, which is exactly what was shown in this study.

In our article “Clustering of Death Receptor for Apoptosis Using Nanoscale Patterns of Peptides“, a DNA origami structure is shown capable of clustering DR5. When this cluster inducing origami is added to cancer cells, it is shown to cause apoptosis and cell death. As much as 80% of some cell types went into apoptosis with one version of this DNA origami structure.We further show that the type of structure, as well as the distance between DR5 ligands is important for this effect. Floppy structures or large distances between ligands do not induce apoptosis as effective as rigid structures and shorter distances. In this study, approximately 6nm between ligands on a square lattice structure was shown to be most effective.

In summary, we show a structure that can induce apoptosis in cancer cells by clustering Death Receptor 5 (DR5). Providing a potential avenue for future drug development.

References:

Ashkenazi, A., Pai, R.C., Fong, S., Leung, S., Lawrence, D.A., Marsters, S.A., Blackie, C., Chang, L., McMurtrey, A.E., Hebert, A., et al. (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155–162.

Duiker, E.W., Mom, C.H., de Jong, S., Willemse, P.H.B., Gietema, J.A., van der Zee, A.G.J., and de Vries, E.G.E. (2006). The clinical trail of TRAIL. Eur. J. Cancer 42, 2233–2240.

Valley, C.C., Lewis, A.K., Mudaliar, D.J., Perlmutter, J.D., Braun, A.R., Karim, C.B., Thomas, D.D., Brody, J.R., and Sachs, J.N. (2012). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces Death Receptor 5 networks that are highly organized. J. Biol. Chem. jbc.M111.306480.

Walczak, H., Miller, R.E., Ariail, K., Gliniak, B., Griffith, T.S., Kubin, M., Chin, W., Jones, J., Woodward, A., Le, T., et al. (1999). Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivo. Nat. Med. 5, 157.