Transient protection of cultured human cells against antitumor agents by 12-O-tetradecanoylphorbol-13-acetate.
The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown in cell cultures to enhance the frequency of resistance to methotrexate. However, we found that TPA could also partially protect human KB cells over a short time (72 h) from the cytotoxicity of several antitumor agents, including 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene)-beta-D-glucopyranoside (VP-16), vincristine, mitoxantrone, and methotrexate, but not 1-beta-D-arabinofuranosylcytosine or 5-fluorouracil. The modes of protection were different for methotrexate and VP-16. Protection by TPA was concentration dependent up to 40 nM and could be accomplished by a 2-h incubation of cells with TPA alone prior to drug treatment. This protection disappeared after a 24-h drug-free incubation. TPA-induced protection could not be mimicked by treatment of cells with 1-oleoyl-2-acetyl-glycerol (a stimulator of protein kinase C) or phospholipase C, which increased the cellular content of diacylglycerols. Thus the action of TPA on protein kinase C may not be sufficient to exert protection. Verapamil, a calcium-channel blocker which has been found to circumvent resistance of multiple drug-resistant cells, also circumvented the protective effect of TPA when used with VP-16. The presence of TPA during a 24-h exposure to radiolabeled VP-16 reduced the cellular drug content by about 30%, whereas verapamil enhanced drug content by at least 50% in TPA-treated and untreated cultures. Since substances with some TPA-like activity have been found in foods and in human circulation, the observation of clinical resistance to some compounds may partly be due to a related mechanism.
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004075:Diglycerides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000037:antagonists & inhibitors; D006801:Humans; D008727:Methotrexate / Q000037:antagonists & inhibitors; D008942:Mitoxantrone / Q000037:antagonists & inhibitors; D009303:Nasopharyngeal Neoplasms / Q000473:pathology / Q000503:physiopathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D004075:Diglycerides; D014750:Vincristine; D005047:Etoposide; D008942:Mitoxantrone; D014700:Verapamil; D010738:Type C Phospholipases; D013755:Tetradecanoylphorbol Acetate; D008727:Methotrexate