Cancer research
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Because apoptosis is deregulated in most cancers, apoptosis-modulating approaches offer an attractive opportunity for clinical therapy of many tumors, including that of the prostate. LNCaP-derived C4-2 human prostate cancer cells are quite resistant to treatment with Apo2 ligand (Apo2L) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), when using a nontagged, Zn-bound recombinant trimeric version that is devoid of any exogeneous sequences and therefore least likely to be immunogenic in human patients and that has been optimized for maximum efficacy and minimum toxicity. When combined with the topoisomerase I inhibitor CPT-11 (irinotecan), Apo2L/TRAIL exhibits enhanced apoptotic activity in C4-2 cells cultured in vitro as well as xenografted as tumors in vivo. ⋯ Down-regulation of Bax by small interference (RNA) (siRNA) in C4-2 cells significantly prevented PARP cleavage and apoptosis. Strikingly, similar experiments in cells stably expressing a dominant-negative death receptor DR5 led to complete ablation of PARP cleavage and apoptosis, indicating the essential role of both mitochondrial and receptor-mediated apoptotic pathways. Our data indicate that the combined treatment of Apo2L/TRAIL and CPT-11 achieves tumor control in prostate cancer tumors through regulation of Bcl-2 family proteins and potent activation of caspases.
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The health-related effects of interactions between reactive oxygen species (ROS) and dietary antioxidants and the consequences of dietary antioxidant supplementation on human health are by no means clear. Although ROS, normal byproducts of aerobic metabolism, are essential for various defense mechanisms in most cells, they can also cause oxidative damage to DNA, proteins, and lipids, resulting in enhanced disease risk. Dietary antioxidants (e.g., vitamin E, vitamin C, beta-carotene, and selenium), as well as endogenous antioxidant mechanisms, can help maintain an appropriate balance between the desirable and undesirable cellular effects of ROS. ⋯ Some data suggest antioxidants can ameliorate toxic side effects of therapy without affecting treatment efficacy, whereas other data suggest antioxidants interfere with radiotherapy or chemotherapy. Overall, examination of the evidence related to potential interactions between ROS and dietary antioxidants and effects on human health indicates that consuming dietary antioxidant supplements has pros and cons for any population and raises numerous questions, issues, and challenges that make this topic a fertile field for future research. Overall, current knowledge makes it premature to generalize and make specific recommendations about antioxidant usage for those at high risk for cancer or undergoing treatment.
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p53 transgenic mice carrying a dominant negative mutation were crossed with Ink4A/Arf heterozygous-deficient mice to investigate whether there is a synergy between these two germ-line mutations in promoting carcinogen-induced lung tumor progression in mice. Mice with a p53 dominant negative mutation and Ink4A/Arf heterozygous deficiency exhibited >20-fold increase in tumor volume compared with approximately 4-fold increase in Ink4A/Arf heterozygous-deficient mice and a 9-fold increase in mice with only the p53 dominant negative mutation. The effect of Ink4A/Arf heterozygous deficiency on lung tumor progression occurred late in the carcinogenesis process (>30 weeks after carcinogen treatment). ⋯ Thus, mutant mice with alterations in p53 and/or Ink4A/Arf exhibited a significant resistance to chemoprevention by budesonide. Because p53 and Ink4a/Arf mutations are the most prevalent mutations in human lung cancers, the effectiveness of chemopreventive agents on the mutant A/J mice containing alterations with p53 and Ink4a/Arf is the best preclinical estimate of their efficacy in humans. Thus, the mutant A/J mouse model should prove useful for chemoprevention studies.