Death Receptors: New Opportunities in Cancer Therapy

Abstract

This article offers a detailed review of the current approaches to anticancer therapy that target the death receptors of malignant cells. Here, we provide a comprehensive overview of the structure and function of death receptors and their ligands, describe the current and latest trends in the development of death receptor agonists, and perform their comparative analysis. In addition, we discuss the DR4 and DR5 agonistic antibodies that are being evaluated at various stages of clinical trials. Finally, we conclude by stating that death receptor agonists may be improved through increasing their stability, solubility, and elimination half-life, as well as by overcoming the resistance of tumor cells. What’s more, effective application of these antibodies requires a more detailed study of their use in combination with other anticancer agents.

Identification of New DR5 Agonistic Nanobodies and Generation of Multivalent Nanobody Constructs for Cancer Treatment

“…Among DRs, death receptor 5 (DR5), also known as TRAIL-R2 or KILLER receptor, is the most promising candidate to develop a targeted therapy against cancer, since its expression level is significantly higher in cancer cells compared to that of healthy cells. Therefore, its triggering may potentially mediate selective activation of apoptosis in cancer cells and thus their killing [4].…”

“…Consequently, better alternatives are required, such as DR5 agonistic antibodies capable of interacting only with death receptors. Such antibodies are easy to produce, relatively safe to use, exhibiting improved pharmacokinetic properties compared to recombinant TRAIL, and are highly specific for only one single type of receptor [4].…”

Evaluating the Remote Control of Programmed Cell Death, with or without a Compensatory Cell Proliferation

“…Because stressors are variegated, SICD has numerous circumstances and thus multitudinous ad hoc modes 6 . A stressor, no matter whether it is an external one like a chemotherapeutic agent or an internal one like a change in the cellular pH, may trigger SICD via one of four basic pathways (Fig 3 ), as summarized from a rich vein of the literature that is actually overbearing 203 - 211 , 219 - 223 : 1) The stressor may bind to a death receptor on the cell membrane, in turn activating caspase-8 and then the so-called “extrinsic apoptosis pathway”, which does not involve mitochondria 209 , 224 - 231 and, in our opinion, should be renamed as “mitochondria-independent SICD” as it is not apoptosis at all. 2) The stressor may occur within, or directly act on, the mitochondria, resulting in its leakage of cytochrome c and other proteins to the cytoplasm and then the activation of the so-called “caspase-dependent apoptosis” or “caspase-independent apoptosis” 204 , 207 , 224 , 232 , 233 , which in our opinion should be redefined as “caspase-dependent or -independent SICD”.…”

In vivo acute toxicity evaluation and in vitro molecular mechanism study of antiproliferative activity of a novel indole Schiff base β-diiminato manganeseIII complex in hormone-dependent and triple negative breast cancer cells

“…Furthermore, death receptors and their ligands have critical role in the extrinsic pathway of apoptosis. Several abnormalities such as down-regulation of the receptor, deficiency of receptor function, and reduced level in the death signals have been reported in impaired death signaling resulting in reduced apoptosis (Ukrainskaya et al, 2017). Besides, BCL-2 family as key regulators of intrinsic apoptosis pathway consist of the anti-apoptotic (e.g., BCL-2, BCL-XL) and the pro-apoptotic (eg, BAX, BIM) proteins which highly regulate mitochondrial outer membrane permeabilization (MOMP) and integrity.…”