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char = i;code = 105
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char = t;code = 116
char = o;code = 111
char = r;code = 114
char = .;code = 46
result sql = Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor.
Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor.
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char = ;code = 32
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char = n;code = 110
char = n;code = 110
char = e;code = 101
char = r;code = 114
char = .;code = 46
char = ;code = 32
char = F;code = 70
char = l;code = 108
char = o;code = 111
char = w;code = 119
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = c;code = 99
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char = a;code = 97
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = y;code = 121
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = d;code = 100
char = y;code = 121
char = l;code = 108
char = s;code = 115
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = i;code = 105
char = z;code = 122
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = a;code = 97
char = l;code = 108
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = s;code = 115
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char = a;code = 97
char = u;code = 117
char = g;code = 103
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = v;code = 118
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char = a;code = 97
char = b;code = 98
char = i;code = 105
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = y;code = 121
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char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = e;code = 101
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char = t;code = 116
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = r;code = 114
char = k;code = 107
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = e;code = 101
char = n;code = 110
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = a;code = 97
char = m;code = 109
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = -;code = 45
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = p;code = 112
char = o;code = 111
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = O;code = 79
char = S;code = 83
char = U;code = 85
char = -;code = 45
char = 0;code = 48
char = 3;code = 51
char = 0;code = 48
char = 1;code = 49
char = 2;code = 50
char = .;code = 46
char = ;code = 32
char = M;code = 77
char = e;code = 101
char = c;code = 99
char = h;code = 104
char = a;code = 97
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = O;code = 79
char = S;code = 83
char = U;code = 85
char = -;code = 45
char = 0;code = 48
char = 3;code = 51
char = 0;code = 48
char = 1;code = 49
char = 2;code = 50
char = -;code = 45
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = z;code = 122
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = s;code = 115
char = o;code = 111
char = c;code = 99
char = i;code = 105
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = a;code = 97
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char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = e;code = 101
char = n;code = 110
char = t;code = 116
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char = t;code = 116
char = a;code = 97
char = m;code = 109
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = f;code = 102
char = e;code = 101
char = n;code = 110
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char = i;code = 105
char = n;code = 110
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = A;code = 65
char = k;code = 107
char = t;code = 116
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = e;code = 101
char = n;code = 110
char = h;code = 104
char = a;code = 97
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char = c;code = 99
char = e;code = 101
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char = d;code = 100
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = o;code = 111
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char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
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char = i;code = 105
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char = a;code = 97
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char = ;code = 32
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = u;code = 117
char = s;code = 115
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
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char = l;code = 108
char = t;code = 116
char = i;code = 105
char = p;code = 112
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char = e;code = 101
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char = A;code = 65
char = k;code = 107
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char = d;code = 100
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char = n;code = 110
char = s;code = 115
char = t;code = 116
char = r;code = 114
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char = a;code = 97
char = m;code = 109
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
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char = o;code = 111
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char = s;code = 115
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char = ;code = 32
char = i;code = 105
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char = c;code = 99
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char = u;code = 117
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = F;code = 70
char = O;code = 79
char = X;code = 88
char = O;code = 79
char = 3;code = 51
char = a;code = 97
char = ,;code = 44
char = ;code = 32
char = G;code = 71
char = S;code = 83
char = K;code = 75
char = 3;code = 51
char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = /;code = 47
char = b;code = 98
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = p;code = 112
char = 2;code = 50
char = 7;code = 55
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
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char = g;code = 103
char = r;code = 114
char = o;code = 111
char = w;code = 119
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = e;code = 101
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char = t;code = 116
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = i;code = 105
char = s;code = 115
char = h;code = 104
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = M;code = 77
char = D;code = 68
char = A;code = 65
char = -;code = 45
char = M;code = 77
char = B;code = 66
char = -;code = 45
char = 2;code = 50
char = 3;code = 51
char = 1;code = 49
char = ;code = 32
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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char = x;code = 120
char = e;code = 101
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char = o;code = 111
char = g;code = 103
char = r;code = 114
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = 5;code = 53
char = 0;code = 48
char = %;code = 37
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
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char = o;code = 111
char = r;code = 114
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
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char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = b;code = 98
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = a;code = 97
char = m;code = 109
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = 6;code = 54
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = /;code = 47
char = k;code = 107
char = g;code = 103
char = );code = 41
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = O;code = 79
char = S;code = 83
char = U;code = 85
char = -;code = 45
char = 0;code = 48
char = 3;code = 51
char = 0;code = 48
char = 1;code = 49
char = 2;code = 50
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char = (;code = 40
char = 1;code = 49
char = 0;code = 48
char = 0;code = 48
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char = g;code = 103
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char = k;code = 107
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char = ,;code = 44
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char = w;code = 119
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = O;code = 79
char = S;code = 83
char = U;code = 85
char = -;code = 45
char = 0;code = 48
char = 3;code = 51
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char = 1;code = 49
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char = o;code = 111
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char = p;code = 112
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char = s;code = 115
char = s;code = 115
char = e;code = 101
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char = r;code = 114
char = o;code = 111
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char = t;code = 116
char = h;code = 104
char = ;code = 32
char = b;code = 98
char = y;code = 121
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char = %;code = 37
char = ;code = 32
char = a;code = 97
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char = %;code = 37
char = ,;code = 44
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char = s;code = 115
char = p;code = 112
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = e;code = 101
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char = f;code = 102
char = i;code = 105
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char = a;code = 97
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char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = P;code = 80
char = D;code = 68
char = K;code = 75
char = -;code = 45
char = 1;code = 49
char = /;code = 47
char = A;code = 65
char = k;code = 107
char = t;code = 116
char = ;code = 32
char = s;code = 115
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char = g;code = 103
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char = a;code = 97
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char = i;code = 105
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char = t;code = 116
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char = i;code = 105
char = t;code = 116
char = i;code = 105
char = z;code = 122
char = e;code = 101
char = ;code = 32
char = E;code = 69
char = R;code = 82
char = -;code = 45
char = n;code = 110
char = e;code = 101
char = g;code = 103
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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char = b;code = 98
char = r;code = 114
char = e;code = 101
char = a;code = 97
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char = t;code = 116
char = ;code = 32
char = c;code = 99
char = a;code = 97
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char = e;code = 101
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char = l;code = 108
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char = t;code = 116
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = E;code = 69
char = R;code = 82
char = -;code = 45
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = p;code = 112
char = e;code = 101
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char = t;code = 116
char = ;code = 32
char = a;code = 97
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char = i;code = 105
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
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char = a;code = 97
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char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = e;code = 101
char = s;code = 115
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = a;code = 97
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char = o;code = 111
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char = i;code = 105
char = f;code = 102
char = e;code = 101
char = n;code = 110
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result sql = Tamoxifen is a mainstay in the treatment of estrogen receptor (ER)-positive breast cancer patients. Although the efficacy of tamoxifen has been attributed to induction of tumor cell growth arrest and apoptosis by inhibition of ER signaling, recent evidence indicates that tamoxifen possesses ER-independent antitumor activities. Here, we use OSU-03012, a small-molecule inhibitor of phosphoinositide-dependent protein kinase-1 (PDK-1) to address the hypothesis that PDK-1/Akt signaling represents a therapeutically relevant target to sensitize ER-negative breast cancer to tamoxifen. OSU-03012 sensitized both ER-positive MCF-7 and ER-negative MDA-MB-231 cells to the antiproliferative effects of tamoxifen in an ER-independent manner. Flow cytometric analysis of phosphatidylserine externalization revealed that this augmented suppression of cell viability was attributable to a marked enhancement of tamoxifen-induced apoptosis by OSU-03012. Mechanistically, this OSU-03012-mediated sensitization was associated with suppression of a transient tamoxifen-induced elevation of Akt phosphorylation and enhanced modulation of the functional status of multiple Akt downstream effectors, including FOXO3a, GSK3alpha/beta, and p27. The growth of established MDA-MB-231 tumor xenografts was suppressed by 50% after oral treatment with the combination of tamoxifen (60 mg/kg) and OSU-03012 (100 mg/kg), whereas OSU-03012 and tamoxifen alone suppressed growth by 30% and 0%, respectively. These findings indicate that the inhibition of PDK-1/Akt signaling to sensitize ER-negative breast cancer cells to the ER-independent antitumor activities of tamoxifen represents a feasible approach to extending the use of tamoxifen to a broader population of breast cancer patients. Considering the urgent need for novel therapeutic strategies for ER-negative breast cancer patients, this combinatorial approach is worthy of continued investigation.

Publication: Mol. Cancer Ther. 2008 Apr ;7(4)::800-8. :doi: 10.1158/1535-7163.MCT-07-0434.
Publication Date: 2008 Apr
Study Author(s): Weng, Shu-Chuan;Kashida, Yoko;Kulp, Samuel K;Wang, Dasheng;Brueggemeier, Robert W;Shapiro, Charles L;Chen, Ching-Shih;
Institution: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 336 L.M. Parks Hall, 500 West 12th Avenue, Columbus, OH 43210, USA.
Shortcut link to this study:
Tamoxifen is a mainstay in the treatment of estrogen receptor (ER)-positive breast cancer patients. Although the efficacy of tamoxifen has been attributed to induction of tumor cell growth arrest and apoptosis by inhibition of ER signaling, recent evidence indicates that tamoxifen possesses ER-independent antitumor activities. Here, we use OSU-03012, a small-molecule inhibitor of phosphoinositide-dependent protein kinase-1 (PDK-1) to address the hypothesis that PDK-1/Akt signaling represents a therapeutically relevant target to sensitize ER-negative breast cancer to tamoxifen. OSU-03012 sensitized both ER-positive MCF-7 and ER-negative MDA-MB-231 cells to the antiproliferative effects of tamoxifen in an ER-independent manner. Flow cytometric analysis of phosphatidylserine externalization revealed that this augmented suppression of cell viability was attributable to a marked enhancement of tamoxifen-induced apoptosis by OSU-03012. Mechanistically, this OSU-03012-mediated sensitization was associated with suppression of a transient tamoxifen-induced elevation of Akt phosphorylation and enhanced modulation of the functional status of multiple Akt downstream effectors, including FOXO3a, GSK3alpha/beta, and p27. The growth of established MDA-MB-231 tumor xenografts was suppressed by 50% after oral treatment with the combination of tamoxifen (60 mg/kg) and OSU-03012 (100 mg/kg), whereas OSU-03012 and tamoxifen alone suppressed growth by 30% and 0%, respectively. These findings indicate that the inhibition of PDK-1/Akt signaling to sensitize ER-negative breast cancer cells to the ER-independent antitumor activities of tamoxifen represents a feasible approach to extending the use of tamoxifen to a broader population of breast cancer patients. Considering the urgent need for novel therapeutic strategies for ER-negative breast cancer patients, this combinatorial approach is worthy of continued investigation.
PMID: 18413793

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