A protein kinase Cbeta inhibitor attenuates multidrug resistance of neuroblastoma cells.
BACKGROUND
The acquisition of drug resistance is a major reason for poor outcome of neuroblastoma. Protein kinase C (PKC) has been suggested to influence drug resistance in cancer cells. The aim of this study was to elucidate whether inhibition of PKCbeta isoforms influences drug-resistance of neuroblastoma cells.


METHODS
The effect of the PKCbeta inhibitor LY379196 on the growth-suppressing effects of different chemotherapeutics on neuroblastoma cells was analyzed with MTT assays. The effect of LY379196 on the accumulation of [3H]vincristine was also investigated


RESULTS
The PKCbeta inhibitor LY379196 suppressed the growth of three neuroblastoma cell lines. LY379196 also augmented the growth-suppressive effect of doxorubicin, etoposide, paclitaxel, and vincristine, but not of carboplatin. The effect was most marked for vincristine and for the cell-line (SK-N-BE(2)) that was least sensitive to vincristine. No effect was observed on the non-resistant IMR-32 cells. Two other PKC inhibitors, Gö6976 and GF109203X, also enhanced the vincristine effect. The PKC inhibitors caused an increased accumulation of [3H]vincristine in SK-N-BE(2) cells.


CONCLUSIONS
This indicates that inhibition of PKCbeta could attenuate multidrug resistance in neuroblastoma cells by augmenting the levels of natural product anticancer drugs in resistant cells.
Svensson
Karin
K
Molecular Medicine, Lund Univeristy, Entrance 78, 3rd floor, Malmö University Hospital, SE-205 02 Malmö, Sweden. Karin.J.Svensson@astrazeneca.com
Larsson
Christer
C
D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008698:Mesylates / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology; D010524:Peripheral Nervous System Neoplasms / Q000188:drug therapy*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; D007211:Indoles; D008301:Maleimides; D008698:Mesylates; D011758:Pyrroles; D014750:Vincristine; D004317:Doxorubicin; D016190:Carboplatin; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D017239:Paclitaxel