RNA interference therapeutics for cancer: Challenges and opportunities (Review)

Abstract

Abstract. RNA interference (RNAi) is a sequence-specific, post-transcriptional gene silencing mechanism in animals and plants, which is mediated by double-stranded RNA (dsRNA). There has recently been an increasing interest in harnessing the gene silencing activity of dsRNA to develop novel drugs for the treatment of various diseases, such as cancer, neurological disorders, age-related macular degeneration and viral infections. Small interfering RNA (siRNA)-based drugs have distinct advantages over conventional small molecule or protein-based drugs, including high specificity, higher potency and reduced toxicity. However, there are several technical obstacles to overcome before siRNA-based drugs reach the clinic. Delivery of siRNA to the target tissues and stability in the serum remain a major challenge and are the main focus of current research and development efforts. This review focused primarily on the progress made in developing RNAi as therapeutics for cancer and the challenges associated with its clinical development. Use of ligands recognizing cell-specific receptors to achieve tumor-specific delivery of siRNA, methods for enhanced siRNA delivery, improving the bioavailability and pharmacokinetic properties of siRNA and reducing the off-target effects and non-specific gene silencing are discussed in the light of current evidence.

Systemic tumor-specific gene delivery

“…One advantage of using siRNA which downregulates the overexpressed proteins is that non-specific delivery is often less toxic than the delivery of plasmid DNAs that encode genes such as IL-12 and TNF-alpha. However, to limit the toxicity that does exist and to increase knockdown at the tumor site, many groups have added ligands to delivery systems to increase tumor specificity [65]. …”

Cancer stem cells: a challenging paradigm for designing targeted drug therapies

“…However, the major bottleneck remains the targeted delivery of these therapeutic agents into tumors [154]. One of the promising technological advances here is the targeted delivery of a chemical drug or miRNA packaged into a minicell, which can be targeted to tumors via minicell surface-attached bispecific antibodies, which has made tremendous progress in the clinic [155][156][157].…”

Silencing of AP-4 inhibits proliferation, induces cell cycle arrest and promotes apoptosis in human lung cancer cells

“…At present, the most commonly utilized nucleic-acid-based sequence-specific gene silencing molecules are siRNAs, which consist of symmetrical duplexes of 19-21 base pairs (15). The siRNA method is able to inhibit target gene expression with specificity, potency and endurance, and has broad therapeutic potential for the treatment of various human diseases, including infections and cancer (16).…”