Resistance to HSP90 inhibition involving loss of MCL1 addiction

YesInhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality

Applications of CYP-450 expression for biomonitoring in environmental health

Cytochrome P450s (CYPs) are one of the first steps in the metabolism of xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs), which are bioactivated into carcinogens. As such, changes in CYP expression are potential biomarkers in human biomonitoring applications. For the proper biomonitoring of environmental toxicants, it is important to understand the biological relevance of each biomarker and the associations among the biomarkers for uses as exposure, effects, and susceptibility biomarkers. Here, we have reviewed various aspects of CYPs for biomonitoring environmental health in terms of the CYP substrates, such as PAHs, aromatic amines, benzene/toluene, and tobacco smoking-related nitrosamines. This review also includes association studies between CYP phenotypical alterations and other exposure, susceptibility, and effect biomarkers. The association studies were mainly performed in CYP gene-transfected cells and noninvasive human biospecies, such as urine and peripheral blood. In conclusion, we suggest that phenotypical alterations in CYPs with exposure to environmental toxicants are useful as susceptibility or effect biomarkers, particularly when the phenotype-related genotypes are unknown

Additive effects of gastric volumes and macronutrient composition on the sensation of postprandial fullness in humans

Background/Objectives: Intake of food or fluid distends the stomach and triggers mechanoreceptors and vagal afferents. Wall stretch and tension produces a feeling of fullness. Duodenal infusion studies assessing gastric sensitivity by barostat have shown that the products of fat digestion have a greater effect on the sensation of fullness and also dyspeptic symptoms than carbohydrates. We tested here the hypothesis that fat and carbohydrate have different effects on gastric sensation under physiological conditions using non-invasive magnetic resonance imaging (MRI) to measure gastric volumes. Subjects/Methods: Thirteen healthy subjects received a rice pudding test meal with added fat or added carbohydrate on two separate occasions and underwent serial postprandial MRI scans for 4.5 h. Fullness was assessed on a 100-mm visual analogue scale. Results: Gastric half emptying time was significantly slower for the high-carbohydrate meal than for the high-fat meal, P=0.0327. Fullness significantly correlated with gastric volumes for both meals; however, the change from baseline in fullness scores was higher for the high-fat meal for any given change in stomach volume (P=0.0147), despite the lower energy content and faster gastric emptying of the high-fat meal. Conclusions: Total gastric volume correlates positively and linearly with postprandial fullness and ingestion of a high-fat meal increases this sensation compared with high-carbohydrate meal. These findings can be of clinical interest in patients presenting with postprandial dyspepsia whereby manipulating gastric sensitivity by dietary intervention may help to control digestive sensations

Sequence-specific DNA damage by reactive oxygen species: Implications for carcinogenesis and aging

Reactive oxygen species (ROS) generated by environmental chemicals can cause sequence-specific DNA damage, which may lead to carcinogenesis and aging. We investigated the mechanism of DNA damage by environmental chemicals (catechol, propyl gallate and bisphenol-A), homocysteine and UVA radiation using human cultured cell lines and32P-labeled DNA fragments. Carcinogenic catechol induced piperidine-labile sites frequently at thymine residues in the presence of Cu(II) and NADH. Furthermore, catechol increased the formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, but not in HP100, a hydrogen peroxide (H2O2)-resistant cell line derived from HL-60. Thus, it is concluded that oxidative DNA damage through generation of H2O2 plays an important role in the carcinogenic process of catechol. In addition, an environmental factor, bisphenol-A, and a dietary factor, propyl, gallate, also induced sequence-specific DNA damage via ROS generation