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Download 2579-2588 March 15, 2007
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Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress by Crescent R. Isham, Jennifer D. Tibodeau, Wendy Jin, Ruifang Xu, Michael M. Timm, and Keith C. Bible Blood Volume 109(6):2579-2588 March 15, 2007 ©2007 by American Society of Hematology Chaetocin bears chemical structural similarity to the acetylated histone lysine moiety mimicked by many histone deacetylase inhibitors (HDACIs) and has antimyeloma activity in vitro yet does not appreciably alter levels of acetylated histone H3 in myeloma c... Crescent R. Isham et al. Blood 2007;109:2579-2588 ©2007 by American Society of Hematology Chaetocin kills myeloma cells in vitro via induction of morphologic apoptosis accompanied by loss of mitochondrial membrane potential, PARP cleavage, and DNA ladder formation. Crescent R. Isham et al. Blood 2007;109:2579-2588 ©2007 by American Society of Hematology Chaetocin kills freshly collected sorted patient CD138+ myeloma cells while sparing matched normal CD138− bone marrow leukocytes, normal B cells, and neoplastic B-CLL (chronic lymphocytic leukemia) cells. Crescent R. Isham et al. Blood 2007;109:2579-2588 ©2007 by American Society of Hematology Patient myeloma cells treated in whole bone marrow cell–mixed culture are selectively killed by chaetocin in comparison to other bone marrow leukocytes, and chaetocin has in vivo antimyeloma activity. Crescent R. Isham et al. Blood 2007;109:2579-2588 ©2007 by American Society of Hematology Chaetocin is rapidly and dramatically accumulated in cancer cells by means that require intact/unreduced chaetocin disulfide bonds. Crescent R. Isham et al. Blood 2007;109:2579-2588 ©2007 by American Society of Hematology Unlike HDAC inhibitors, chaetocin-induced reductions in A549 cell-colony formation are attenuated by cotreatment with glutathione or NAC. (A) Glutathione or NAC, but not inhibitors of DNA (aphidicolin), RNA (DRB), or protein (cycloheximide) synthesis, atten... Crescent R. Isham et al. Blood 2007;109:2579-2588 ©2007 by American Society of Hematology Chaetocin induces oxidative stress in A549 cells without substantial depletion of intracellular reduced glutathione levels, whereas the selective cytotoxicity of chaetocin in freshly collected myeloma cells appears to be attributable to their increased sens... Crescent R. Isham et al. Blood 2007;109:2579-2588 ©2007 by American Society of Hematology
