The compound 13-D selectively induces apoptosis in white blood cancers versus other cancer cell types.
As general cytotoxins are still the backbone of anticancer chemotherapy, the identification of selective inducers of cell death in defined cancer types and subtypes is one of the major goals of modern oncology research. Thus, compounds identified with such selectivity have utility as probes of cancer-type-specific biological pathways, and optimized versions have potential in targeted anticancer therapy. Described herein is the discovery that compound 13-D selectively induces apoptotic cell death in white blood cancer cell lines but not in other cancer cell lines. Further experiments indicate that this selectivity is not simply due to selective cell permeability. The compound localizes to both the nucleus and cytoplasm and arrests cells in the prophase/prometaphase of the cell cycle, and there is a very sharp dependence of activity on compound structure, with the trans-alpha,beta-unsaturated amide of 13-D being critical for inducing cell death. The macromolecular target of 13-D could be involved in white blood cell-specific oncogenic pathways.
Putt
Karson S
KS
Department of Biochemistry, University of Illinois, Roger Adams Laboratory, Urbana, IL 6180, USA.
Nesterenko
Vitaliy
V
Dothager
Robin S
RS
Hergenrother
Paul J
PJ
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003373:Coumaric Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003593:Cytoplasm / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003373:Coumaric Acids; C518602:N-(2-hydroxy-2-(4-hydroxyphenyl)ethyl) 3-(4-hydroxy-3-methoxyphenyl)propenamide