title: Investigations on the mechanism of action of the antiproliferant and ion channel antagonist flufenamic acid.
abstract: The compound flufenamic acid has been previously described as an inhibitor of chloride- and non-selective cation channels. Moreover, this compound showed antiproliferative effects in the mouse fibroblast cell line LM(TK-). In this study, we investigated the effects of this compound on cell proliferation and membrane currents induced by mitogens (such as fetal calf serum, FCS) or platelet-derived growth factor (PDGF) in LM(TK-) cells. After a brief application of FCS or PDGF (5-15 s), the electrical response of the cells was biphasic: First, a transient potassium conductance was activated, which appeared 8.3 +/- 0.7 s after the onset of stimulation and lasted for 30.1 +/- 2.9 s. The corresponding single channel currents in cell-attached patches had an amplitude of 3-4 pA (at a holding potential of +60 mV). The second effect of serum or PDGF was the occurrence of a cation conductance for monovalent ions (sodium, potassium and cesium) and calcium. In contrast to the potassium current, this conductance activated later (11.8 +/- 1.6 s after onset of fetal calf serum stimulation) and remained activated for minutes. Flufenamic acid inhibited the proliferation of LM(TK-) cells reversibly and in a concentration-dependent manner. This effect can be correlated with the inhibitory effects of flufenamic acid on mitogen-induced membrane currents: The compound inhibited the non-selective cation current with an IC50 of 38 microM, whereas 135 microM were necessary for halfmaximal inhibition of the potassium current; this is very close to the concentration for halfmaximal inhibition of cell proliferation (120 microM). Hence, on the grounds of this comparison the blockade of the non-selective cation current appears to be of only minor importance for the blockade of cell proliferation.
authors.affiliation: Boehringer Ingelheim KG, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Weiser
authors.forename: M
authors.initials: M
authors.lastname: Wienrich
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002586:Cesium / Q000494:pharmacology; D004594:Electrophysiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005439:Flufenamic Acid / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007473:Ion Channels; D010982:Platelet-Derived Growth Factor; D015221:Potassium Channels; D002586:Cesium; D005439:Flufenamic Acid