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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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The effect of the combination of LY379196 and anticancer drugs on neuroblastoma cell growth. IMR-32, SH-SY5Y, and SK-N-BE(2) cells were grown in medium supplemented with increasing concentrations of doxorubicin, etoposide, paclitaxel, vincristine, and carboplatin. Different amounts of LY379196 were also included in the medium yielding final concentrations of 0 (■, black), 20 (●, red), 100 (▲, green) or 500 (▼, blue) nM. After three (SK-N-BE(2)) or four (IMR-32 and SH-SY5Y) days in culture the amount of viable cells was analyzed with an MTT assay. The concentrations of the anticancer drugs are indicated on the x-axes as lg([drug]/1M). Data are expressed as percent of values obtained in the absence of drugs and are mean ± SEM (n = 8–9).
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Figure 2: The effect of the combination of LY379196 and anticancer drugs on neuroblastoma cell growth. IMR-32, SH-SY5Y, and SK-N-BE(2) cells were grown in medium supplemented with increasing concentrations of doxorubicin, etoposide, paclitaxel, vincristine, and carboplatin. Different amounts of LY379196 were also included in the medium yielding final concentrations of 0 (■, black), 20 (●, red), 100 (▲, green) or 500 (▼, blue) nM. After three (SK-N-BE(2)) or four (IMR-32 and SH-SY5Y) days in culture the amount of viable cells was analyzed with an MTT assay. The concentrations of the anticancer drugs are indicated on the x-axes as lg([drug]/1M). Data are expressed as percent of values obtained in the absence of drugs and are mean ± SEM (n = 8–9).

Mentions: To elucidate a putative synergistic effect of the PKCβ inhibitor and different anticancer drugs used for neuroblastoma therapy the three cell lines were cultured in the presence of increasing concentrations of doxorubicin, etoposide, paclitaxel, vincristine, or carboplatin together with different concentrations of LY379196 (Figure 2, Table 1). The cell lines displayed different sensitivity to the anticancer drugs. IMR-32 was consistently the most sensitive to all drugs investigated. SH-SY5Y and IMR-32 were equally sensitive to the topoisomerase inhibitors doxorubicin and etoposide whereas SH-SY5Y cells were three- to four-fold less sensitive to the microtubule interacting agents paclitaxel and vincristine and to the DNA intercalator carboplatin. SK-N-BE(2) was the most resistant cell line being more than fifty-fold more resistant to doxorubicin, etoposide and carboplatin than the other cell lines. SK-N-BE(2) cells also displayed a substantially higher resistance to vincristine and paclitaxel.


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

Svensson K, Larsson C - BMC Cancer (2003)

The effect of the combination of LY379196 and anticancer drugs on neuroblastoma cell growth. IMR-32, SH-SY5Y, and SK-N-BE(2) cells were grown in medium supplemented with increasing concentrations of doxorubicin, etoposide, paclitaxel, vincristine, and carboplatin. Different amounts of LY379196 were also included in the medium yielding final concentrations of 0 (■, black), 20 (●, red), 100 (▲, green) or 500 (▼, blue) nM. After three (SK-N-BE(2)) or four (IMR-32 and SH-SY5Y) days in culture the amount of viable cells was analyzed with an MTT assay. The concentrations of the anticancer drugs are indicated on the x-axes as lg([drug]/1M). Data are expressed as percent of values obtained in the absence of drugs and are mean ± SEM (n = 8–9).
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Related In: Results  -  Collection

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Figure 2: The effect of the combination of LY379196 and anticancer drugs on neuroblastoma cell growth. IMR-32, SH-SY5Y, and SK-N-BE(2) cells were grown in medium supplemented with increasing concentrations of doxorubicin, etoposide, paclitaxel, vincristine, and carboplatin. Different amounts of LY379196 were also included in the medium yielding final concentrations of 0 (■, black), 20 (●, red), 100 (▲, green) or 500 (▼, blue) nM. After three (SK-N-BE(2)) or four (IMR-32 and SH-SY5Y) days in culture the amount of viable cells was analyzed with an MTT assay. The concentrations of the anticancer drugs are indicated on the x-axes as lg([drug]/1M). Data are expressed as percent of values obtained in the absence of drugs and are mean ± SEM (n = 8–9).
Mentions: To elucidate a putative synergistic effect of the PKCβ inhibitor and different anticancer drugs used for neuroblastoma therapy the three cell lines were cultured in the presence of increasing concentrations of doxorubicin, etoposide, paclitaxel, vincristine, or carboplatin together with different concentrations of LY379196 (Figure 2, Table 1). The cell lines displayed different sensitivity to the anticancer drugs. IMR-32 was consistently the most sensitive to all drugs investigated. SH-SY5Y and IMR-32 were equally sensitive to the topoisomerase inhibitors doxorubicin and etoposide whereas SH-SY5Y cells were three- to four-fold less sensitive to the microtubule interacting agents paclitaxel and vincristine and to the DNA intercalator carboplatin. SK-N-BE(2) was the most resistant cell line being more than fifty-fold more resistant to doxorubicin, etoposide and carboplatin than the other cell lines. SK-N-BE(2) cells also displayed a substantially higher resistance to vincristine and paclitaxel.

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