title: Microtubule antagonists activate programmed cell death (apoptosis) in cultured rat hepatocytes.
abstract: We investigated the mechanism of lethal injury following the disruption of microtubules in cultured hepatocytes treated with vinblastine (VBL) or colchicine (COL). These agents kill hepatocytes by a process readily distinguished from two well-known pathways that lead to a loss of viability, namely, oxidative stress and inhibition of mitochondrial electron transport. Cell killing with VBL and COL was accompanied by fragmentation of DNA. Both the loss of viability and the fragmentation of DNA were prevented by the inhibition of protein synthesis within 6 hours following exposure to VBL or COL. Cell death and the fragmentation of DNA were also prevented when Ca2+ was removed from the culture medium. By contrast, the inhibition of protein kinase C prevented cell killing by VBL or COL, but did not alter the extent of DNA fragmentation. The requirements here for protein synthesis, extracellular Ca2+, and protein kinase C activity define a model of apoptosis, or programmed cell death, that seems to involve mechanisms that can be dissociated from the fragmentation of DNA.
authors.affiliation: Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799.
authors.forename: K
authors.initials: K
authors.lastname: Tsukidate
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: J W
authors.initials: JW
authors.lastname: Snyder
authors.forename: J L
authors.initials: JL
authors.lastname: Farber
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D004249:DNA Damage; D004587:Electrophoresis, Agar Gel; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008297:Male; D008870:Microtubules / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D014747:Vinblastine; D011494:Protein Kinases; D003078:Colchicine; D002118:Calcium