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A protein kinase Cbeta inhibitor attenuates multidrug resistance of neuroblastoma cells.

Svensson K, Larsson C - BMC Cancer (2003)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Medicine, Lund Univeristy, Entrance 78, 3rd floor, Malmö University Hospital, SE-205 02 Malmö, Sweden. Karin.J.Svensson@astrazeneca.com

ABSTRACT

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.

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Suppression of neuroblastoma cell growth by LY379196. Neuroblastoma IMR-32 (A), SH-SY5Y (B), and SK-N-BE(2) (C) cells were grown for four (A and B) or three (C) days in regular growth medium supplemented with increasing concentrations of LY379196. Thereafter the number of viable cells was determined with an MTT assay. Data are expressed as percent of values obtained in the absence of LY379196 and are mean ± SEM (n = 9–18 from 3–6 separate experiments).
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Figure 1: Suppression of neuroblastoma cell growth by LY379196. Neuroblastoma IMR-32 (A), SH-SY5Y (B), and SK-N-BE(2) (C) cells were grown for four (A and B) or three (C) days in regular growth medium supplemented with increasing concentrations of LY379196. Thereafter the number of viable cells was determined with an MTT assay. Data are expressed as percent of values obtained in the absence of LY379196 and are mean ± SEM (n = 9–18 from 3–6 separate experiments).

Mentions: In a previous study we found that inhibition of PKCβ with LY379196 suppresses the proliferation and growth of SK-N-BE(2) cells [5]. In order to examine whether this is a cell line-specific effect, or if it is more general in terms of neuroblastoma cells, three neuroblastoma cell lines – IMR-32, SH-SY5Y, and SK-N-BE(2) – were cultured in the presence of increasing concentrations of LY379196 (Figure 1). This showed that all cell lines were sensitive to LY379196. At a concentration of 300 nM, LY379196 suppressed the number of viable cells with 16–24% for the three cell lines, which indicates that a PKCβ isoform has a positive effect on neuroblastoma cell growth.


A protein kinase Cbeta inhibitor attenuates multidrug resistance of neuroblastoma cells.

Svensson K, Larsson C - BMC Cancer (2003)

Suppression of neuroblastoma cell growth by LY379196. Neuroblastoma IMR-32 (A), SH-SY5Y (B), and SK-N-BE(2) (C) cells were grown for four (A and B) or three (C) days in regular growth medium supplemented with increasing concentrations of LY379196. Thereafter the number of viable cells was determined with an MTT assay. Data are expressed as percent of values obtained in the absence of LY379196 and are mean ± SEM (n = 9–18 from 3–6 separate experiments).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC153510&req=5

Figure 1: Suppression of neuroblastoma cell growth by LY379196. Neuroblastoma IMR-32 (A), SH-SY5Y (B), and SK-N-BE(2) (C) cells were grown for four (A and B) or three (C) days in regular growth medium supplemented with increasing concentrations of LY379196. Thereafter the number of viable cells was determined with an MTT assay. Data are expressed as percent of values obtained in the absence of LY379196 and are mean ± SEM (n = 9–18 from 3–6 separate experiments).
Mentions: In a previous study we found that inhibition of PKCβ with LY379196 suppresses the proliferation and growth of SK-N-BE(2) cells [5]. In order to examine whether this is a cell line-specific effect, or if it is more general in terms of neuroblastoma cells, three neuroblastoma cell lines – IMR-32, SH-SY5Y, and SK-N-BE(2) – were cultured in the presence of increasing concentrations of LY379196 (Figure 1). This showed that all cell lines were sensitive to LY379196. At a concentration of 300 nM, LY379196 suppressed the number of viable cells with 16–24% for the three cell lines, which indicates that a PKCβ isoform has a positive effect on neuroblastoma cell growth.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Medicine, Lund Univeristy, Entrance 78, 3rd floor, Malmö University Hospital, SE-205 02 Malmö, Sweden. Karin.J.Svensson@astrazeneca.com

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus