Nano-TRAIL: a promising path to cancer therapy

Abstract

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, also called apo-2 ligand (TRAIL/Apo-2L), is a cytokine that triggers apoptosis by binding to TRAIL-R1 (DR4) and TRAIL-R2 (DR5) death receptors. Apoptosis occurs through either the extrinsic or intrinsic pathway. The administration of recombinant human TRAIL (rhTRAIL) or TRAIL-receptor (TRAIL-R) agonists promotes apoptosis preferentially in cancerous cells over normal cells in vitro; this phenomenon has also been observed in clinical studies. The limited efficacy of rhTRAIL in clinical trials could be attributed to drug resistance, short half-life, targeted delivery issues, and off-target toxicities. Nanoparticles are excellent drug and gene delivery systems characterized by improved permeability and retention, increased stability and biocompatibility, and precision targeting. In this review, we discuss resistance mechanisms to TRAIL and methods to overcome TRAIL resistance by using nanoparticle-based formulations developed for the delivery of TRAIL peptides, TRAIL-R agonists, and TRAIL genes to cancer cells. We also discuss combinatorial approaches of chemotherapeutic drugs with TRAIL. These studies demonstrate TRAIL's potential as an anticancer agent.

Keywords: TRAIL; apoptosis; cancer cells; nanomedicine; nanoparticles.

Figure 1

Structure of TRAIL receptors. TRAIL binds to death receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) at the extracellular domains. The death domains (DD) on the cytoplasmic side lead to recruitment of other DD containing proteins that lead to apoptosis. TRAIL decoy receptors lack the cytoplasmic DD or have a truncated DD which fails to trigger apoptosis. OPG is a soluble receptor of TRAIL with low affinity.

Figure 2

TRAIL-Induced Apoptosis: Cross talk between the Extrinsic and Intrinsic Pathways. TRAIL binding to death receptors leads to its trimerization on the cell surface and formation of DISC. Caspase-8 gets activated in the DISC and triggers the extrinsic pathway of apoptosis. Activated caspase-8 also leads to activation of the mitochondrial pathway or intrinsic pathway of apoptosis resulting in activation of caspase-9 and executioner caspases-3 and -7. Several checkpoints of apoptosis, like increase in anti-apoptotic proteins (IAPs), Bcl-xLetc are also represented at various stages of apoptosis. ATP: Adenosine triphosphate; DISC: Death Inducing Signaling Complex; FADD: Fas-associated death domain; MOMP: mitochondrial outer membrane permeabilization.

Figure 3

TRAIL Receptor endocytosis. Death receptors are constitutively recycled by clathrin mediated endocytosis. Lack of death receptors leads to TRAIL resistance. After endocytosis of the receptor, clathrin and adaptor proteins (AP2) are recycled to the cell membrane to continue with more endocytosis of the receptors. Pharmacological inhibitors like PAO or chlorpromazine prevent the arrangement of clathrin and AP2 at the vesicles, hence prevent endocytosis, resulting in persistent expression of the death receptors at the surface and increased apoptosis.

Figure 4

Types of Nanoparticles. Nanoparticles are classified based on the material used to prepare the various particles, organic, inorganic or hybrid. Different kinds of these formulations are represented here. NPs: Nanoparticles.