Quinidine impairs proliferation of neurofibromatosis type 2-deficient human malignant mesothelioma cells.
BACKGROUND
Human malignant mesotheliomas (HMMs) are aggressive tumors that arise from the mesothelium. They respond poorly to conventional tumor treatment and outcome is often fatal. Inactivating mutations of the neurofibromatosis type 2 (NF2) tumor suppressor gene merlin have been described in nearly 60% of primary malignant mesothelioma and in approximately 20% of the mesothelioma cell lines. Studies regarding human NF2 schwannoma cells revealed a higher proliferation and a larger noninactivating K(+) outward current compared with controls. The enhanced proliferation of merlin-deficient NF2 schwannoma cells could be reduced in the presence of quinidine, a K(+) channel blocker, whereas the proliferation of normal Schwann cells is not affected. The current study was undertaken to evaluate the effect of quinidine on the proliferation of HMM cell lines in relation to their NF2 status.


METHODS
Proliferation analyses using bromodeoxyuridine incorporation was performed by immunocytochemical staining and fluorescence assisted cell sorting. The patch-clamp technique was applied for electrophysiologic characterization of the HMM cell lines. The cytochrome P450 2D6 locus, known to be mutated at high frequencies in NF2 patients and to be specifically inhibited by quinidine, was screened for mutations by cycle sequencing.


RESULTS
Quinidine selectively reduces the proliferation of merlin-deficient HMM cell lines by causing a G(0)/G(1) arrest, whereas the proliferation rates of merlin-expressing HMM cell lines remain unchanged. The effect of quinidine on the proliferation of HMM cell lines appears to be correlated with the NF2 gene status but not with the K(+) outward current. No relation to cytochrome P450 2D6 mutations was detected.


CONCLUSIONS
Quinidine or quinidine analogs are of potential therapeutic interest for the subset of merlin-deficient mesothelioma tumors.
Utermark
Tamara
T
Department of Neurology, University of Ulm, Ulm, Germany.
Alekov
Alexi
A
Lerche
Holger
H
Abramowski
Vincent
V
Giovannini
Marco
M
Hanemann
Clemens Oliver
CO
D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D017931:DNA Primers / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology*; D018301:Neoplasms, Mesothelial / Q000378:metabolism / Q000473:pathology*; D016518:Neurofibromatosis 2 / Q000378:metabolism*; D025581:Neurofibromin 2 / Q000172:deficiency*; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D011802:Quinidine / Q000494:pharmacology*; D012583:Schwann Cells / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D017931:DNA Primers; D004791:Enzyme Inhibitors; D025581:Neurofibromin 2; D019389:Cytochrome P-450 CYP2D6; D001973:Bromodeoxyuridine; D011802:Quinidine