Targeting death-inducing receptors in cancer therapy

Abstract

Deregulated cell death pathways may lead to the development of cancer, and induction of tumor cell apoptosis is the basis of many cancer therapies. Knowledge accumulated concerning the molecular mechanisms of apoptotic cell death has aided the development of new therapeutic strategies to treat cancer. Signals through death receptors of the tumor necrosis factor (TNF) superfamily have been well elucidated, and death receptors are now one of the most attractive therapeutic targets in cancer. In particular, DR5 and DR4, death receptors of TNF-related apoptosis-inducing ligand (TRAIL or Apo2L), are interesting targets of antibody-based therapy, since TRAIL may also bind decoy receptors that may prevent TRAIL-mediated apoptosis, whereas TRAIL ligand itself selectively induces apoptosis in cancer cells. Here, we review the potential therapeutic utility of agonistic antibodies against DR5 and DR4 and discuss the possible extension of this single-antibody-based strategy when combined with additional modalities that either synergizes to cause enhanced apoptosis or further engage the cellular immune response. Rational design of antibody-based therapies combining the induction of tumor cell apoptosis and activation of tumor-specific adaptive immunity enables promotion of distinct steps of the antitumor immune response, thereby enhancing tumorspecific lymphocytes that can eradicate TRAIL/DR5-resistant mutating, large established and heterogeneous tumors in a manner that does not require the definition of individual tumor-specific antigens.

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

“…Members of the tumor necrosis factor super family have a central role in normal and pathological conditions (Takeda et al, 2007). Among them, CD95 (Fas/Apo-1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors are potent activators of the apoptotic pathway in response to their specific ligand.…”

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

“…4A), showing the extrinsic pathway triggered by AY4 binding to DR4 connected with the intrinsic pathway through Bid activation (1, 2, 4). As stated earlier, activated Bid exerts its proapoptotic function in mitochondria through its conformational activation of Bax and/or Bak (2,4). Bax is required rather than Bak for TRAIL-mediated apoptotic cell death (38).…”

“…[1][2][3][4]. Activated caspase-8 by the DISC formation triggers the extrinsic pathway by directly activating the downstream effector caspases, such as caspase-3, caspase-6, and caspase-7, which in turn cleave many cellular substrates to exert apoptosis (1)(2)(3)(4)(5).…”

“…[1][2][3][4]. Activated caspase-8 by the DISC formation triggers the extrinsic pathway by directly activating the downstream effector caspases, such as caspase-3, caspase-6, and caspase-7, which in turn cleave many cellular substrates to exert apoptosis (1)(2)(3)(4)(5). The extrinsic pathway can be amplified by cross-talk with the intrinsic pathway, the link of which is Bid cleavage by activated caspase-8 (1)(2)(3)(4)(5).…”

“…Activated caspase-8 by the DISC formation triggers the extrinsic pathway by directly activating the downstream effector caspases, such as caspase-3, caspase-6, and caspase-7, which in turn cleave many cellular substrates to exert apoptosis (1)(2)(3)(4)(5). The extrinsic pathway can be amplified by cross-talk with the intrinsic pathway, the link of which is Bid cleavage by activated caspase-8 (1)(2)(3)(4)(5). Cleaved Bid (tBid) induces oligomerization of proapoptotic Bax and/or Bak, leading to the release of cytochrome c and Smac/ Diablo from mitochondria into cytoplasm and activation of caspase-9 (1-5).…”