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Many tumor cells exhibit a disturbed intracellular redox state resulting in higher levels of reactive oxygen species (ROS). As these contribute to tumor initiation and sustenance, catalytic redox agents combining significant activity with substrate specificity promise high activity and selectivity against oxidatively stressed malignant cells. We describe here the design and synthesis of novel organochalcogen based redox sensor/effector catalysts. Their selective anticancer activity at submicromolar and low micromolar concentrations was established here in a range of tumor entities in various biological systems including cell lines, primary tumor cell cultures, and animal models. In the B-cell derived chronic lymphocytic leukemia (CLL), for instance, such compounds preferentially induce apoptosis in the cancer cells while peripheral blood mononuclear cells (PBMC) from healthy donors and the subset of normal B-cells remain largely unaffected. In support of the concept of sensor/effector based ROS amplification, we are able to demonstrate that underlying this selective activity against CLL cells are pre-existing elevated ROS levels in the leukemic cells compared to their nonmalignant counterparts. Furthermore, the catalysts act in concert with certain chemotherapeutic drugs in several carcinoma cell lines to decrease cell proliferation while showing no such interactions in normal cells. Overall, the high efficacy and selectivity of (redox) catalytic sensor/effector compounds warrant further, extensive testing toward transfer into the clinical arena.
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Garlic-derived organo sulphur compounds such as diallylsulfides provide a significant protection against carcinogenesis. Chemically synthesized, and highly pure diallylsulfides with a chain of 1-4 sulphur atoms, as well as a range of control compounds, were employed to investigate the influence of these agents on cell viability, cell cycle arrest and induction of apoptosis in HCT116 human colon cancer cells. Diallyltrisulfide, and even more efficiently diallyltetrasulfide treatment of HCT116 cells led to a reduced cell viability, cell cycle arrest and apoptosis. A similar activity was found for the propyl-analogues, while mono- and disulfides were considerably less active. Initial calculations point toward the ability of tri- and tetrasulfides to form reactive oxygen species (ROS). Here, we found that the induction of apoptosis was indeed dependent on the redox-state of the cell, with anti-oxidants being able to prevent sulfide-induced apoptosis. Furthermore, using HCT116 cells which were either positive or negative for p53 revealed that p53 is clearly dispensable for induction of apoptosis. Growth arrest and induction of apoptosis is associated with a considerable reduction of the level of cdc25C. These results support the therapeutic potential of polysulfides and allow insight into the mechanisms based on the polysulfide biochemistry.