Mutations enhancing selectivity of antitumor cytokine TRAIL to DR5 receptor increase its cytotoxicity against tumor cells

Abstract

Tumor necrosis factor superfamily cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces apoptosis in tumor cells by binding to death receptors DR4 and DR5 without affecting normal cells. However, the therapeutic use of TRAIL is limited, because many tumor cells are resistant to it. The resistance is partially related to interaction of TRAIL with the decoy receptors DcR1 and DcR2, which do not trigger the apoptotic signal and inhibit signaling of death receptors. Previously, we designed a unique DR5-specific TRAIL mutant variant DR5-B, which binds to DR5 receptor as effectively as the original cytokine, but has practically no interaction with DR4 and DcR1 receptors, and its affinity for DcR2 is reduced 400-fold. In the present work, the cytotoxity of TRAIL and DR5-B was analyzed on 12 different tumor cell lines and two types of normal cells. In nine of 12 tumor cell lines, DR5-B killed 1.5-5.0 times more tumor cells than TRAIL, and it did not exhibit toxicity towards normal cells. Chemotherapeutic drugs such as doxorubicin, paclitaxel, and bortezomib augmented the effect of both TRAIL variants, and the enhancing effect was more pronounced for DR5-B. Half-maximal effective concentrations (EC50) for DR5-B in combination with chemotherapeutic agents were 1.5-10.0 times lower than for wild-type TRAIL. Thus, DR5-B is a promising candidate both for monotherapy and in combination with chemotherapy for treatment of TRAIL-resistant tumors.

GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells

“…Upregulation of TRAIL receptors has been reported as a mechanism to increased TRAIL cytotoxicity in some studies [31] but not all [32]. In our study, Caspase-8 inhibitors can eliminate GSK-3 inhibitors-induced sensitization to TRAIL-induced caspase-8 activation and apoptosis, which was compatible to previous reports [33].…”

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma

“…Previously, we obtained receptor-selective TRAIL variant DR5-B specifically binding to the death receptor 5 (DR5) [ 22 ]. TRAIL variant DR5-B does not bind to decoy receptors, thus overcoming the potential receptor-dependent resistance of tumor cells to TRAIL [ 23 ]. However, this can be insufficient for the treatment of highly aggressive hard-to-treat types of solid tumors, such as glioblastoma.…”

Recent Advances in the Development of Nanodelivery Systems Targeting the TRAIL Death Receptor Pathway

“…To obtain the multifunctional liposomal delivery system, PTX was loaded inside the liposomes, positively charged TRAIL was attached electrostatically to the negatively charged liposome surface, and finally, a stearyl chain (C18) fused with histidine-rich cell-penetrating peptide (CPP) named TR was attached to the surface of the liposomes by electrostatic and hydrophobic interactions. Despite PTX having been shown earlier to synergize with TRAIL in some other types of cancer [ 58 ], it has poor solubility in aqueous solutions and a low therapeutic index. The TR peptide not only selectively recognized cancer cells expressing integrin αvβ3 but also displayed pH-triggered cell penetration activity in the tumor microenvironment through charge conversion and consequent structure shift, which could be followed by pH-triggered cargo release from the liposomes with attached TR.…”