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RNA Interference Therapeutics for Cancer: Challenges and Opportunities (Review)

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RNA Interference Therapeutics for Cancer: Challenges and Opportunities (Review) MOLECULAR MEDICINE REPORTS 6: 9-15, 2012 RNA interference therapeutics for cancer: Challenges and opportunities (Review) ROOP SINGH BORA1,3, DIKSHI GUPTA1,4, TRILOCHAN KANWALJIT SINGH MUKKUR2 and KULVINDER SINGH SAINI1,5 1Department of Biotechnology, Ranbaxy Laboratories Limited, Gurgaon-122 015, Haryana, India; 2School of Biomedical Sciences, Curtin Health Innovation Research Institute, Western Australian Biomedical Research Institute, Curtin University, Bentley Campus, Perth, Western Australia 6102, Australia Received December 20, 2011; Accepted March 20, 2012 DOI: 10.3892/mmr.2012.871 Abstract. RNA interference (RNAi) is a sequence-specific, Contents post-transcriptional gene silencing mechanism in animals and plants, which is mediated by double-stranded RNA (dsRNA). 1. Introduction There has recently been an increasing interest in harnessing 2. RNA interference therapeutics for cancer treatment the gene silencing activity of dsRNA to develop novel drugs 3. Strategies for improving the pharmacokinetics of therapeutic for the treatment of various diseases, such as cancer, neuro- small interfering RNA logical disorders, age-related macular degeneration and viral 4. Target specificity infections. Small interfering RNA (siRNA)-based drugs 5. Safety issues have distinct advantages over conventional small molecule 6. Conclusions or protein-based drugs, including high specificity, higher potency and reduced toxicity. However, there are several technical obstacles to overcome before siRNA-based drugs 1. Introduction reach the clinic. Delivery of siRNA to the target tissues and stability in the serum remain a major challenge and are the RNA interference (RNAi) is an evolutionarily conserved main focus of current research and development efforts. This process of sequence-specific, post-transcriptional gene review focused primarily on the progress made in developing silencing in animals and plants, mediated by double-stranded RNAi as therapeutics for cancer and the challenges associ- RNA (dsRNA), which is homologous in sequence to the target ated with its clinical development. Use of ligands recognizing gene. Gene silencing by dsRNA was first observed in the early cell-specific receptors to achieve tumor-specific delivery of 1990s in plants (1). However, the phenomenon of RNAi was first siRNA, methods for enhanced siRNA delivery, improving the discovered by Fire et al in 1998, who reported that injection of bioavailability and pharmacokinetic properties of siRNA and dsRNA into Caenorhabditis elegans resulted in the silencing reducing the off-target effects and non-specific gene silencing of the complementary messenger RNA (mRNA) sequence (2). are discussed in the light of current evidence. Since the introduced dsRNA molecules blocked the function of the targeted gene, the process was termed ‘RNA interference’. It was also observed that dsRNAs, which are several hundred bases in length, not only caused significant gene silencing in Caenorhabditis elegans, but were also more potent and active Correspondence to: Dr Roop Singh Bora, 3Present address: than the corresponding single-stranded antisense molecules (2). Ranbaxy Biologics Division, Ranbaxy Laboratories Limited, Sy. However, subsequent studies established that it was not easy to No. 16, Ekarajapura, Hasigala Post, Siddlaghatta Road, Hoskote, detect potent and specific RNAi in commonly used mammalian Bangalore-562114, Karnataka, India cell lines using large size dsRNA (3-5). The findings of these E-mail: [email protected] studies showed that long dsRNA was responsible for inducing 4 interferon response in the mammalian cells by activating Present address: Centre for Biomedical Engineering, Indian the protein kinase PKR and 2', 5'-oligoadenylate synthetase. Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India Activated protein kinase, PKR, inhibited protein translation Present address: 5Research and Development office, Eternal by phosphorylation of the translation initiation factors elF2. University, Baru Sahib 173101, Himachal Pradesh, India Moreover, activated 2', 5'-oligoadenylate synthetase resulted in non-specific mRNA degradation by activated ribonuclease L. Key words: RNA interference, short interfering RNA, gene silencing, The global shutdown due to non-specific mRNA degradation cancer, short interfering RNA delivery, target specificity and inhibition of protein synthesis eventually resulted in cell death (6-8). In their study, Elbashir et al (3) provided the first evidence that 21-23 nucleotide (nt) double-stranded siRNA 10 BORA et al: RNAi THERAPEUTICS FOR CANCER mediates sequence-specific gene silencing in mammalian other genes contributing to tumor progression are potentially cells without activating the interferon response. Subsequently, important targets for gene silencing by RNAi. Due to the this technology was improvised and successfully applied to precise mechanism of action, high specificity and potency of perform target-specific gene silencing in adult mouse models RNAi-mediated gene silencing, there are reduced chances of (9-11). Short (21-23 nt) siRNAs are usually considered optimal side-effects that are often associated with chemotherapy drugs. for gene silencing, however, a 27-mer siRNA was able to The major advantage of RNAi therapeutics in cancer would achieve a 100-fold stronger and more potent gene silencing, be the simultaneous targeting of multiple genes, belonging to compared to a corresponding 21-23 nt sequence (12). different cellular pathways that are involved in tumor progres- RNAi is initiated by dsRNAs that undergo processing by sion. The concurrent inhibition of several genes is potentially a an endonuclease enzyme known as Dicer. The long fragment of more potent and effective way to treat cancer and it would also dsRNA is cleaved by Dicer into duplexes with 19 paired nucleo- minimize the probability of multiple drug resistance normally tides and two nucleotide overhangs at the two 3'-ends (13,14). encountered with small molecule-based cancer therapies. These duplexes, referred to as short interfering RNAs (siRNAs), Another advantage of RNAi-based therapeutics involves the associate with the RNA-induced silencing complex (RISC), development of personalized anticancer drugs suitable for a a large protein complex (~160 kDa) comprising of Argonaute particular patient. Such personalized medicine is likely to be (Ago) proteins (15,16). In humans, there are eight members more effective in controlling the cancer, thereby improving the of the Ago family, however, only Ago2 possesses an active success rate of cancer drugs. catalytic domain for cleavage activity (17,18). Within the RISC, Several potential siRNA targets in cancer have been siRNA unwinds and the sense strand is removed and degraded described in the literature, although proof-of-concept studies by nucleases. The antisense strand of the siRNA directs RISC in animal models are just beginning to emerge. Judge et al (27) to the target mRNA. The cleavage site, which is ~10 nucleotides showed that administration of siRNA targeting the essential from the 5'-end of the siRNA, on the target mRNA, is aligned cell-cycle proteins, such as kinesin spindle protein (KSP) and with the Ago2 PIWI endonuclease domain. Ago2 cleaves the polo-like kinase 1 (PLK1), exhibited potent antitumor activity phosphodiester bond on the mRNA and releases the cleaved in both hepatic and subcutaneous tumor models. KSP is a mRNA fragments that are finally degraded resulting in the mitotic spindle motor protein that is involved in chromosome gene silencing (19,20). The siRNA-loaded RISC can be recycled segregation during mitosis. Inhibition of KSP prevents the for several rounds of the gene silencing process, which makes formation of bipolar mitotic spindles resulting in cell-cycle siRNA extremely attractive for therapeutic interventions (21). arrest and induction of apoptosis (32). Similarly, PLK1 is Recently, RNAi has rapidly progressed from bench to important in mitosis and cytokinesis. Overexpression of PLK1 bedside with several RNAi-based drugs undergoing clinical is observed in several human types of cancer and inhibition of trials. Several in vitro and in vivo proof-of-concept studies PLK1 activity induces tumor cell apoptosis (33). These studies have shown that almost every human disease with a gain-of- clearly suggest that siRNA specifically targeting KSP and function genetic lesion or overexpression of disease causing PLK1 can be developed as a therapy for cancer. Among other gene(s) is a potential target for RNAi-based therapeutics cancer-directed approaches is the targeting of pleiotrophin, (22). RNAi has shown potential for the treatment of various which effectively reduced tumor growth in mouse xenograft diseases which are not amenable to small molecule (chemical) models of glioblastoma multiforme (34). drugs or protein-based therapeutics. Several in vivo studies Protein kinase N3 (PKN3) has been validated as a thera- in animal models have shown that RNAi-based drugs can be peutic target in cancer, as inhibition of this kinase resulted in effective in the treatment of various diseases, such as hyper- the reduction of lymph node metastases in orthotopic prostate cholesterolemia (23), viral hepatitis (24), Huntington's disease cancer models (35). In their study, Aleku et al (36) showed that (25,26) and cancer (27-29). Initially, RNAi-based clinical systemic administration of Atu027, a siRNA-lipoplex targeted trials focused on the direct localized delivery of siRNA and against PKN3 in mice,
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