siRNA-based approaches in cancer therapy

Abstract

The availability of the human genome sequence has revolutionized the strategy of employing nucleic acids with sequences complementary to specific target genes to improve drug discovery and target validation. Development of sequence-specific DNA or RNA analogs that can block the activity of selected single-stranded genetic sequences offers the possibility of rational design with high specificity, lacking in many current drug treatments for various diseases including cancer, at relatively inexpensive costs. Antisense technology is one such example that has shown promising results and boasts of yielding the only approved drug to date in the genomics field. However, in vivo delivery issues have yet to be completely overcome for widespread clinical applications. In contrast to antisense oligonucleotides, the mechanism of silencing an endogenous gene by the introduction of a homologous double-stranded RNA (dsRNA), transgene or virus is called post-transcriptional gene silencing (PTGS) or RNA interference. PTGS is a natural mechanism whereby metazoan cells suppress expansion of genes when they come across dsRNA molecules with the same sequence. Short interfering RNA is currently the fastest growing sector of this antigene field for target validation and therapeutic applications. Although, in theory, the development of genomics-based agents to inhibit gene expression is simple and straightforward, the fundamental concern relies upon the capacity of the oligonucleotide to gain access to the target RNA. This paper summarizes the advances in the last decade in the field of PTGS using RNA interference approaches and provides relevant comparisons with other oligonucleotide-based approaches with a specific focus on oncology applications. Cancer Gene Therapy (2006) Genomic-based strategiesThe American Cancer Society estimates that, in 2005, a total of 1 372 910 new cancer cases and 570 280 deaths are expected in the United States. 1 These morbid statistics demonstrate the necessity of newer therapeutic modalities for achieving successful cancer treatment and cure. Downregulation of genes that contribute to cancer progression has been the goal of targeted genomics-based strategies, with the expectation that such an approach may lead to selective and specific inhibition of tumor growth with minimal untoward side effects on normal cells. Identification of target genes involved in neoplastic transformation and tumor progression has triggered the idea that nucleotide sequences of cancer-relevant genes could lead to the development of tailored anticancer agents that lack many of the toxic side effects of traditional cytotoxic drugs. This has led to a recent acceleration in the development and optimization of genomic-based strategies for cancer therapy. This idea dates back to the 1960s when RNA sequences were shown to serve as endogenous inhibitors of gene expression in procaryotes. The antigene approaches include the following:(1) Ribozymes: 2,3 These were discovered in the 1970s, and the elucidation of the transactivating hammerh...

siRNA-mediated Silencing of Survivin Inhibits Proliferation and Enhances Etoposide Chemosensitivity in Acute Myeloid Leukemia Cells

“…Once it introduces to the target cells, it combines specifically with complementary mRNA and inhibits its translation to the corresponding protein. Owing to its benefits such as specificity, low cytotoxicity and high efficacy, siRNA is widely used in gene therapy investigations (Devi, 2006;Yang and Mattes, 2008;Shan, 2010). Moreover, because of the advantages of siRNA such as the greater resistance to nucleases degradation, it is preferred to the ASO and ribozyme approaches (Brantl, 2002;Aoki et al, 2003).…”

“…Moreover, because of the advantages of siRNA such as the greater resistance to nucleases degradation, it is preferred to the ASO and ribozyme approaches (Brantl, 2002;Aoki et al, 2003). On the contrary, transient essence of double-stranded siRNA is one of the main drawbacks of long term siRNAbased therapeutics which can be remedy by use of the constitutive vector-based systems (Devi, 2006;Yang and Mattes, 2008;Shan, 2010).…”

Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression

“…Specific inhibition of XIAP mRNA using an siRNA strategy (43) in the absence of trastuzumab treatment decreased XIAP protein expression; however, this did not lead to a significant change in viability or apoptosis. This is not surprising as previous reports from our laboratory and others have shown that in many cell lines, inhibiting XIAP by itself does not increase spontaneous apoptosis (31,44); however, there is a need for an initial insult or stress to the cells like treatment with therapeutic agents.…”

Efficient in vivo microRNA targeting of liver metastasis

“…MicroRNA-based cancer gene therapy (reviewed by Tong andNemunaitis, 2008 andWeinberg, 2009a) offers the possibility of targeting multiple gene networks controlled by an individual miRNA (Valastyan and Weinberg, 2009b). The efficacy of localized small interfering RNA-based therapeutics (Devi, 2006;de Fougerolles et al, 2007;Davis et al, 2010) against various tumors is currently being assessed in a number of ongoing clinical trials (Tolcher et al, 2002;Chi et al, 2008;Hau et al, 2009). Similarly, miRNAs can be inhibited in vitro with specific cholesterol conjugated (Krutzfeldt et al, 2005), 2 0 -Omethyl oligonucleotide antagonists (AMOs) or 'antagomirs', when delivered as liposomal complexes, or nonconjugated (Esau et al, 2006) into mice, rats and nonhuman primates (Elmen et al, 2008).…”