Toxicity of phorbol esters for human epithelial cells expressing a mutant ras oncogene.
Phorbol esters and related compounds provide a promising source of potential anticancer agents. The mechanism of their toxicity, however, is unclear, and interpretation has been complicated by the conflicting responses exhibited by different transformed cell lines. Previously we showed that in primary thyroid follicular cells, expression of mutant p21ras conferred a striking sensitivity to the toxic effects of phorbol esters. We have now extended this work using a thyroid cell line with an inducible mutant ras gene to exclude the possibility that this result was a trivial consequence of the marked growth stimulation induced in these cells by mutant p21ras. Furthermore, by assessing the action of a panel of phorbol esters and a potential chemotherapeutic agent, bryostatin, we demonstrated that this phenomenon was only a function of biologically active phorbol esters. These results provide a molecular rationale for the development of phorbol ester analogues as chemotherapeutic agents.
Dawson
T
T
Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom.
Bond
J
J
Eccles
N
N
Wynford-Thomas
D
D
D000970:Antineoplastic Agents / Q000494:pharmacology; D054713:Bryostatins; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007783:Lactones / Q000633:toxicity; D018942:Macrolides; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D015240:Phorbol 12,13-Dibutyrate / Q000633:toxicity; D010703:Phorbol Esters / Q000633:toxicity*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D015032:Zinc / Q000494:pharmacology
D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D010703:Phorbol Esters; C008876:phorbol-12,13-didecanoate; D015240:Phorbol 12,13-Dibutyrate; C046785:bryostatin 1; D004247:DNA; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D015032:Zinc; D013755:Tetradecanoylphorbol Acetate