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Molecular Cancer Therapeutics
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Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Peiying Yang, David G. Menter, Carrie Cartwright, Diana Chan, Susan Dixon, Milind Suraokar, Gabriela Mendoza, Norma Llansa and Robert A. Newman
Peiying Yang
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David G. Menter
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Carrie Cartwright
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Diana Chan
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Susan Dixon
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Milind Suraokar
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Gabriela Mendoza
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Norma Llansa
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Robert A. Newman
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DOI: 10.1158/1535-7163.MCT-08-1085 Published August 2009
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    Figure 1.

    Oleandrin-mediated inhibition of cell proliferation association with Na+,K+-ATPase expression patterns. A, human and murine pancreatic cancer cell lines were exposed to oleandrin (72 h) followed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis. B, Western blot analysis of total cell lysates for α3 and α1 isoform expression patterns as well as the ratio of α3 to α1 isoforms. C, cumulative expression pattern in a series of 19 human pancreatic, colon, breast, oral, and ovarian tumor cell lines represented as a ratio of α3 to α1 isoforms as a function of oleandrin sensitivity. Points, mean ± SD of the relative α3 to α1 ratio as a function of the cellular sensitivity to oleandrin (IC50 value).

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    Figure 2.

    Expression of α3 isoform in BxPC3 and Panc-1 human pancreatic cancer cell lines. Cell lines were exposed to diluent (Control) or oleandrin (50 nmol/L) and MitoTracker Orange CM-H2XRos (red-orange) to detect the presence and location of mitochondria for 2 h prior to fixation. After processing for α3 immunostaining, cells were counterstained with DAPI to detect nuclei (blue). BxPC3 cells contain low α3 levels whereas Panc-1 cells exhibit high α3 content. Also shown is a change in cell morphology to a more differentiated morphology upon exposure of Panc-1 cells to oleandrin. Insets, higher magnification of representative cells. B, exposure of Panc-1 cells to oleandrin did not affect the expression of α3 protein for at least 48 h at concentrations up to 50 nmol/L.

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    Figure 3.

    Uptake of fluorescent oleandrin analogue (BODIPY-oleandrin) by living cells. A, concentration-dependent uptake of oleandrin within BxPC-3 human pancreatic cells was observed at concentrations as high as 50 nmol/L over the 24 h observation period. In contrast, drug uptake was easily noted within Panc-1 cells with concentrations as low as 5 nmol/L. B, time-dependent uptake of oleandrin was evident in Panc-1 cells as early as 2 h, whereas at 24 h, nearly all cells contained marked concentrations of the drug. In contrast, no drug is observed in BxPC3 cells. Living cells were counterstained with MitoTracker orange CM-H2XRos (red) to detect viable mitochondria and DAPI, which is excluded from viable cells with intact plasma membranes. More yellow signals indicate where mitochondria and BODIPY-oleandrin colocalize. DAPI uptake was minimal over this 2-h timeframe. Insets, a higher magnification of representative cells.

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    Figure 4.

    Decreasing the expression of α3 protein in Panc-1 cells affects cell sensitivity to oleandrin. A, cells were transfected for 24 h with either control siRNA or α3 siRNA. As shown, this resulted in an approximately 50% reduction of α3 protein. The extent of the reduction was dependent on the concentration of the α3 siRNA agent. 1, nontransfected control; 2, cells transfected with transfection agent alone; 3, control siRNA–transfected cells; 4, α3 siRNA–transfected cells. B, oleandrin uptake or association with Panc-1 cells is clearly evident in the nontransfected cells (1) yet significantly reduced in the siRNA-treated cells (2). C, the cells exhibiting knockdown of α3 protein were less sensitive to oleandrin implying that the α3 target is necessary to retain sensitivity to this cardiac glycoside.

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    Figure 5.

    The antiproliferative activity of oleandrin was reduced in Panc-1 cells transfected with α1 subunits. By transfecting Na,K-ATPase α1 subunit to Panc-1 cells (which normally lack α1 expression), the relative expression of α3 to α1 was reduced in the transfected Panc-1 cells. As a result, the sensitivity of these cells to oleandrin treatment was reduced as evidenced by the shift of IC50 value of oleandrin from 4.7 nmol/L of nontransfected Panc-1 cells to >50 nmol/L in α1-transfected cells.

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  • Table 1.

    Description of human cancer cell phenotype and cell culture medium

    Name of cellsPhenotype descriptionCell culture medium
    PANC-1Human pancreatic carcinomaDMEM/10% FBS
    BXPC3Human pancreatic adenocarcinomaRPMI 1640/10% FBS/NaP
    MiaPacaHuman pancreatic adenocarcinomaDMEM/10% FBS/2% equine serum
    MDA 231Breast cancerDMEM/10% FBS
    SUM 149Breast cancerF12/5% FBS/HEPES/insulin/hydrocortisone
    CaCO2Colon carcinomaRPMI 1640/10% FBS
    DOD-1Colon carcinomaRPMI 1640/10% FBS
    HCT 116Colon carcinomaRPMI 1640/10% FBS
    HT 29Colon carcinomaRPMI 1640/10% FBS
    LIS-174tColon carcinomaMEM/10% FBS/NaP/NEAA
    BROHuman melanomaMEM/10% FBS/NaP
    SCC-9Oral squamous cell carcinomaDMEM/10% FBS
    CAL27Oral squamous cell carcinomaDMEM/10% FBS
    MCF-7Breast cancerMEM/10% FBS/insulin/hydrocortisone/EGF

    Abbreviations: NaP, sodium pyruvate; FBS, fetal bovine serum; NEAA, nonessential amino acids; EGF, epidermal growth factor.

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    • Supplementary Figures 1-3
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Molecular Cancer Therapeutics: 8 (8)
August 2009
Volume 8, Issue 8
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Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets
Peiying Yang, David G. Menter, Carrie Cartwright, Diana Chan, Susan Dixon, Milind Suraokar, Gabriela Mendoza, Norma Llansa and Robert A. Newman
Mol Cancer Ther August 1 2009 (8) (8) 2319-2328; DOI: 10.1158/1535-7163.MCT-08-1085

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Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets
Peiying Yang, David G. Menter, Carrie Cartwright, Diana Chan, Susan Dixon, Milind Suraokar, Gabriela Mendoza, Norma Llansa and Robert A. Newman
Mol Cancer Ther August 1 2009 (8) (8) 2319-2328; DOI: 10.1158/1535-7163.MCT-08-1085
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