Drug Resistance Updates 9 (2006) 40–50 Tumor-specific nuclear targeting: Promises for anti-cancer therapy? Gualtiero Alvisi a , Ivan K.H. Poon a , David A. Jans a,b,∗ a Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Australia b ARC Centre of Excellence for Biotechnology and Development, Australia Received 13 January 2006; received in revised form 20 February 2006; accepted 20 February 2006 Abstract Recent developments in anti-cancer gene therapy suggest that the idea of a magic bullet for cancer may not be a pipe dream. Viral-based anti-cancer vectors for gene therapy have been used preferentially in this regard, but recent results from clinical trials have raised serious concerns as to their safety. For this reason, the development of non-viral vectors able to deliver drugs or suicide genes specifically to cancer cells is of paramount importance. In this context, great interest has been raised by recent reports that several proteins, including viral protein 3 (VP3 or Apoptin) from Chicken Anemia Virus, are capable of selectively killing tumor cells. Intriguingly, VP3’s anti-cancer activity is strongly linked to its ability to localize more efficiently in the nucleus of cancer and transformed cells than that of normal, non-transformed cells with a tumor cell-specific nuclear targeting signal (tNTS) located at the C-terminus of the protein. Clearly, the VP3 tNTS is an exciting prospect to enhance non-viral-mediated cancer cell killing. This review will discuss recent advances in the understanding of the mechanism responsible for VP3 tumor-specific nuclear localization, including its specific phosphorylation, and the implications for the enhancement of anti-cancer therapy. It also proposes alternative strategies to develop tNTSs for anti-cancer therapies. © 2006 Elsevier Ltd. All rights reserved. Keywords: Nuclear targeting; Apoptin; Cancer; Nuclear targeting signal; Apoptosis; Vehicle; Modular transporters; Therapy; Gene therapy; Drug delivery; VP3; Anti-cancer; Photosensitizers 1. Introduction Cancer can be regarded as a heterogeneous group of pro- liferative diseases, resulting from the accumulation of genetic lesions. Despite considerable advances in our understanding of the molecular mechanisms of carcinogenesis and cancer progression, cancer remains the second major cause of death due to medical causes in the United States of America as well as in much of the developed world (Weir et al., 2003). Clearly, there is an urgent need for new, efficacious and specific anti-cancer approaches (Guillemard and Saragovi, 2004). Virus-based anti-cancer gene therapies, based on the ability of adenoviral or retroviral vectors to deliver suicide genes to cancer cells (Rainov and Ren, 2003), or to kill tumor cells directly (“virolytic therapy”; Everts and van der Poel, ∗ Corresponding author at: Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton Vic. 3168, Australia. E-mail address: David.Jans@med.monash.edu.au (D.A. Jans). 2005; Mathis et al., 2005), are being tested in various clini- cal trials (www4.od.nih.gov/oba/rac/protocol.pdf). However, although one viral-based vector has been recently approved for the treatment of head and neck cancer, the outcome of several viral-based clinical trials has raised serious concerns regarding the efficacy and safety of such approaches, high- lighting the need to develop alternative strategies (Hacein- Bey-Abina et al., 2003a,b; Raper et al., 2003; Williams and Baum, 2003; Glover et al., 2005; Young et al., 2006). Here we discuss the possibility of using recently identified tumor cell-specific nuclear targeting sequences (tNTSs) as tools for enhancing non-viral drug or suicide gene delivery to the nucleus of cancer cells. 2. Nuclear delivery mechanisms A useful strategy in anti-cancer therapy is the specific delivery of high levels of either a suicide gene or a drug (see Box 1) to malignant cells, without affecting healthy 1368-7646/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.drup.2006.02.003