Studies on calcium dependence reveal multiple modes of action for triptolide.
Triptolide, a diterpene triepoxide isolated from the traditional Chinese medicinal vine Trypterygium wilfordii hook f., has been shown to induce rapid apoptosis in a myriad of cancer cell lines and inhibit NFkappaB transactivation. To understand further the general cellular mechanisms for this therapeutically relevant natural product, binding and biological activities were assessed. Studies showed that triptolide binding was saturable, reversible, and primarily localized to cell membranes. Depletion of calcium enhanced overall binding while differentially modulating biological function. Furthermore, triptolide's structural moieties demonstrated variability in the regulation of cell death versus inhibition of NFkappaB transactivation. These results implicate triptolide in the manipulation of at least two distinct cellular pathways with differing requirements for calcium and effective triptolide concentration in order to elicit each particular biological function.
Leuenroth
Stephanie J
SJ
Department of Molecular, Cell, and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA.
Crews
Craig M
CM
D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004852:Epoxy Compounds; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010616:Phenanthrenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015533:Transcriptional Activation
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D002135:Calcium-Binding Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; D016328:NF-kappa B; D010616:Phenanthrenes; C001899:triptolide; D002118:Calcium