Anti-Fas/CD95 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) differentially regulate apoptosis in normal and neoplastic human basophils.

Basophilia is associated with allergic and parasitic diseases and advanced chronic myeloid leukemia. In the present study, we characterized the expression and function of the death receptors Fas/CD95 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors in basophils from healthy donors compared to neoplastic basophils. Peripheral blood basophils obtained from healthy donors (HD-PBB) and from patients with chronic myeloid leukemia (CML-PBB) were found to express high levels of Fas/CD95 and low levels of TRAIL-R2, whereas the basophil-like chronic myeloid leukemia cell line KU-812 expressed significant levels of TRAIL-R1 and TRAIL-R2. HD-PBB underwent apoptosis in response to anti-Fas/CD95, but showed resistance to TRAIL, unless they were co-treated with actinomycin D. Interestingly, CML-PBB and KU-812 cells exhibited the opposite response pattern with resistance to anti-Fas/CD95, but significant susceptibility to TRAIL-induced apoptosis. Our data show that anti-Fas/CD95 and TRAIL differentially regulate apoptosis of normal and neoplastic human basophils, which may direct the development of novel therapeutic strategies.

From biochemical principles of apoptosis induction by TRAIL to application in tumour therapy.

The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily which has been shown to selectively kill tumour cells, while sparing normal tissue. This attribute makes TRAIL an attractive drug candidate for cancer therapy. Although most primary tumour cells turned out to be primarily TRAIL-resistant, recent studies evidenced that a variety of cancers can be sensitised to TRAIL-induced apoptosis upon pre-treatment with chemotherapeutic agents or irradiation, while normal cells remain TRAIL-resistant. However, biomarkers that reliably predict which patients may benefit from such combinatorial therapies are required. Thus, it is essential to better understand the mechanisms underlying TRAIL resistance versus sensitivity. In this chapter, we introduce the signalling events which take place during TRAIL-induced apoptosis, describe the physiological function of TRAIL and summarise pre-clinical and clinical results obtained so far with TRAIL-receptor agonists.

Death receptors as targets for anti-cancer therapy.

Human tumour cells are characterized by their ability to avoid the normal regulatory mechanisms of cell growth, division and death. The classical chemotherapy aims to kill tumour cells by causing DNA damage-induced apoptosis. However, as many tumour cells possess mutations in intracellular apoptosis-sensing molecules like p53, they are not capable of inducing apoptosis on their own and are therefore resistant to chemotherapy. With the discovery of the death receptors the opportunity arose to directly trigger apoptosis from the outside of tumour cells, thereby circumventing chemotherapeutic resistance. Death receptors belong to the tumour necrosis factor receptor superfamily, with tumour necrosis factor (TNF) receptor-1, CD95 and TNF-related apoptosis-inducing ligand-R1 and -R2 being the most prominent members. This review covers the current knowledge about these four death receptors, summarizes pre-clinical approaches engaging these death receptors in anti-cancer therapy and also gives an overview about their application in clinical trials conducted to date.