Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer.

Formation of the pro-apoptotic death-inducing signaling complex (DISC) can be initiated in cancer cells via binding of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to its two pro-apoptotic receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2. Primary components of the DISC are trimerized TRAIL-R1/-R2, FADD, caspase 8 and caspase 10. The anti-apoptotic protein FLIP can also be recruited to the DISC to replace caspase 8 and form an inactive complex. Caspase 8/10 processing at the DISC triggers the caspase cascade, which eventually leads to apoptotic cell death. Besides TRAIL, TRAIL-R1- or TRAIL-R2-selective variants of TRAIL and agonistic antibodies have been designed. These ligands are of interest as anti-cancer agents since they selectively kill tumor cells. To increase tumor sensitivity to TRAIL death receptor-mediated apoptosis and to overcome drug resistance, TRAIL receptor ligands have already been combined with various therapies in preclinical models. In this review, we discuss factors influencing the initial steps of the TRAIL apoptosis signaling pathway, focusing on mechanisms modulating DISC assembly and caspase activation at the DISC. These insights will direct rational design of drug combinations with TRAIL receptor ligands to maximize DISC signaling.

Comparative analysis of radiation dose and low contrast detail detectability using routine paediatric chest radiography protocols.

OBJECTIVES: To compare low contrast detail (LCD) detectability and radiation dose for routine paediatric chest X-ray (CXR) imaging protocols among various hospitals. METHODS: CDRAD 2.0 phantom and medical grade polymethyl methacrylate (PMMA) slabs were used to simulate the chest region of four different paediatric age groups. Radiographic acquisitions were undertaken on 17 X-ray machines located in eight hospitals using their existing CXR protocols. LCD detectability represented by image quality figure inverse (IQFinv) was measured physically using the CDRAD analyser software. Incident air kerma (IAK) measurements were obtained using a solid-state dosimeter. RESULTS: The range of IQFinv, between and within the hospitals, was 1.40-4.44 and 1.52-2.18, respectively for neonates; 0.96-4.73 and 2.33-4.73 for a 1-year old; 0.87-1.81 and 0.98-1.46 for a 5-year old and 0.90-2.39 and 1.27-2.39 for a 10-year old. The range of IAK, between and within the hospitals, was 8.56-52.62 µGy and 21.79-52.62 µGy, respectively for neonates; 5.44-82.82 µGy and 36.78-82.82 µGy for a 1-year old; 10.97-59.22 µGy and 11.75-52.94 µGy for a 5-year old and 13.97-100.77 µGy and 35.72-100.77 µGy for a 10-year old. CONCLUSIONS: Results show considerable variation, between and within hospitals, in the LCD detectability and IAK. Further radiation dose optimisation for the four paediatric age groups, especially in hospitals /X-ray rooms with low LCD detectability and high IAK, are required.

Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S-phase arrest, in human myeloma cells.

Bisphosphonates (BPs) are widely used in the treatment of osteolytic bone disease associated with multiple myeloma, and have been demonstrated to exert antitumor effects both in vitro and in vivo. However, the precise molecular mechanisms involved in the direct antitumor effects of BPs in vitro are not known. Nitrogen-containing BPs, such as risedronate (RIS), act by inhibiting protein prenylation. A phosphonocarboxylate analogue of RIS, 3-PEHPC, has previously been shown in osteoclasts and macrophages to specifically inhibit prenylation of Rab GTPases. The aim of this study was to identify the molecular targets of RIS and 3-PEHPC in human myeloma cells and to determine the cellular effects of selective inhibition of Rab prenylation by 3-PEHPC as compared to nonspecific inhibition of protein prenylation by RIS in human myeloma cells. RIS dose-dependently inhibited prenylation of both Rap1A and Rab6, whereas 3-PEHPC only inhibited Rab6 prenylation. Both RIS and 3-PEHPC dose-dependently increased apoptosis in human myeloma cells. RIS induced an accumulation of cells in the S-phase of the cell cycle, associated with inhibition of DNA replication. In contrast, 3-PEHPC did not cause cell-cycle arrest. Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell-cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3-PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3-PEHPC. In conclusion, our studies demonstrate that selective inhibition of Rab prenylation induces apoptosis, but not S-phase arrest, thus identifying distinct molecular pathways that mediate the antimyeloma effect of nitrogen-containing BPs.