char = A;code = 65
char = p;code = 112
char = l;code = 108
char = i;code = 105
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = ;code = 32
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 = s;code = 115
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 = i;code = 105
char = n;code = 110
char = ;code = 32
char = h;code = 104
char = u;code = 117
char = m;code = 109
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = s;code = 115
char = ;code = 32
char = v;code = 118
char = i;code = 105
char = a;code = 97
char = ;code = 32
char = g;code = 103
char = l;code = 108
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = p;code = 112
char = l;code = 108
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = p;code = 112
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = l;code = 108
char = ;code = 32
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 = f;code = 102
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = S;code = 83
char = r;code = 114
char = c;code = 99
char = ,;code = 44
char = ;code = 32
char = J;code = 74
char = N;code = 78
char = K;code = 75
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = 3;code = 51
char = 8;code = 56
char = ;code = 32
char = M;code = 77
char = A;code = 65
char = P;code = 80
char = K;code = 75
char = .;code = 46
result sql = Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK.
Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK.
char = W;code = 87
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = A;code = 65
char = p;code = 112
char = l;code = 108
char = i;code = 105
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = t;code = 116
char = u;code = 117
char = m;code = 109
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = i;code = 105
char = g;code = 103
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = p;code = 112
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char = e;code = 101
char = s;code = 115
char = e;code = 101
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char = t;code = 116
char = l;code = 108
char = y;code = 121
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char = u;code = 117
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char = d;code = 100
char = e;code = 101
char = r;code = 114
char = g;code = 103
char = o;code = 111
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = P;code = 80
char = h;code = 104
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = I;code = 73
char = I;code = 73
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = t;code = 116
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char = a;code = 97
char = l;code = 108
char = s;code = 115
char = ,;code = 44
char = ;code = 32
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 = g;code = 103
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char = o;code = 111
char = w;code = 119
char = t;code = 116
char = h;code = 104
char = ;code = 32
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char = r;code = 114
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = ;code = 32
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char = d;code = 100
char = ;code = 32
char = a;code = 97
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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 = i;code = 105
char = n;code = 110
char = ;code = 32
char = h;code = 104
char = u;code = 117
char = m;code = 109
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = M;code = 77
char = D;code = 68
char = A;code = 65
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char = M;code = 77
char = B;code = 66
char = -;code = 45
char = 2;code = 50
char = 3;code = 51
char = 1;code = 49
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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
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = s;code = 115
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char = a;code = 97
char = t;code = 116
char = ;code = 32
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char = a;code = 97
char = n;code = 110
char = o;code = 111
char = m;code = 109
char = o;code = 111
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
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char = n;code = 110
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char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = p;code = 112
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char = d;code = 100
char = i;code = 105
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char = i;code = 105
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char = d;code = 100
char = u;code = 117
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char = e;code = 101
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char = p;code = 112
char = e;code = 101
char = c;code = 99
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char = f;code = 102
char = i;code = 105
char = c;code = 99
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char = c;code = 99
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char = l;code = 108
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char = l;code = 108
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char = s;code = 115
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char = m;code = 109
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char = d;code = 100
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char = g;code = 103
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char = s;code = 115
char = t;code = 116
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char = i;code = 105
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char = d;code = 100
char = ;code = 32
char = a;code = 97
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char = i;code = 105
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
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char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = p;code = 112
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char = d;code = 100
char = e;code = 101
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char = m;code = 109
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = g;code = 103
char = r;code = 114
char = o;code = 111
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char = h;code = 104
char = ;code = 32
char = f;code = 102
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = o;code = 111
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char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = (;code = 40
char = E;code = 69
char = G;code = 71
char = F;code = 70
char = R;code = 82
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = n;code = 110
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char = c;code = 99
char = e;code = 101
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char = o;code = 111
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char = ;code = 32
char = p;code = 112
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char = e;code = 101
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char = n;code = 110
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char = t;code = 116
char = y;code = 121
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char = o;code = 111
char = s;code = 115
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char = n;code = 110
char = e;code = 101
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char = k;code = 107
char = i;code = 105
char = n;code = 110
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char = e;code = 101
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char = S;code = 83
char = r;code = 114
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char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = s;code = 115
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = n;code = 110
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char = /;code = 47
char = t;code = 116
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char = r;code = 114
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = n;code = 110
char = e;code = 101
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char = k;code = 107
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = J;code = 74
char = N;code = 78
char = K;code = 75
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = p;code = 112
char = 3;code = 51
char = 8;code = 56
char = ;code = 32
char = M;code = 77
char = A;code = 65
char = P;code = 80
char = K;code = 75
char = .;code = 46
char = ;code = 32
char = A;code = 65
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char = l;code = 108
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char = i;code = 105
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char = d;code = 100
char = u;code = 117
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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
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char = o;code = 111
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char = i;code = 105
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = a;code = 97
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char = ;code = 32
char = o;code = 111
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char = l;code = 108
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char = a;code = 97
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char = l;code = 108
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char = c;code = 99
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char = i;code = 105
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char = A;code = 65
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char = E;code = 69
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char = P;code = 80
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char = J;code = 74
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char = K;code = 75
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char = o;code = 111
char = r;code = 114
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char = E;code = 69
char = G;code = 71
char = F;code = 70
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char = G;code = 71
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char = R;code = 82
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char = f;code = 102
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char = i;code = 105
char = e;code = 101
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char = e;code = 101
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char = b;code = 98
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char = f;code = 102
char = i;code = 105
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char = b;code = 98
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char = a;code = 97
char = s;code = 115
char = t;code = 116
char = s;code = 115
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char = e;code = 101
char = r;code = 114
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char = a;code = 97
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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 = u;code = 117
char = p;code = 112
char = o;code = 111
char = n;code = 110
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char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
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char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
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char = m;code = 109
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char = r;code = 114
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char = s;code = 115
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char = o;code = 111
char = w;code = 119
char = l;code = 108
char = y;code = 121
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char = t;code = 116
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char = a;code = 97
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char = w;code = 119
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char = t;code = 116
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char = p;code = 112
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char = E;code = 69
char = G;code = 71
char = F;code = 70
char = R;code = 82
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char = f;code = 102
char = i;code = 105
char = b;code = 98
char = r;code = 114
char = o;code = 111
char = b;code = 98
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = t;code = 116
char = s;code = 115
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char = a;code = 97
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char = ;code = 32
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = o;code = 111
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char = s;code = 115
char = h;code = 104
char = o;code = 111
char = w;code = 119
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = a;code = 97
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char = e;code = 101
char = d;code = 100
char = ;code = 32
char = J;code = 74
char = N;code = 78
char = K;code = 75
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = r;code = 114
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char = d;code = 100
char = u;code = 117
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = 3;code = 51
char = 8;code = 56
char = ;code = 32
char = M;code = 77
char = A;code = 65
char = P;code = 80
char = K;code = 75
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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 = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = N;code = 78
char = -;code = 45
char = A;code = 65
char = c;code = 99
char = e;code = 101
char = t;code = 116
char = y;code = 121
char = l;code = 108
char = c;code = 99
char = y;code = 121
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = e;code = 101
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = (;code = 40
char = b;code = 98
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char = t;code = 116
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = t;code = 116
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char = o;code = 111
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char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
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char = o;code = 111
char = x;code = 120
char = i;code = 105
char = d;code = 100
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = c;code = 99
char = h;code = 104
char = ;code = 32
char = a;code = 97
char = s;code = 115
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char = d;code = 100
char = i;code = 105
char = p;code = 112
char = h;code = 104
char = e;code = 101
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char = y;code = 121
char = l;code = 108
char = e;code = 101
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char = e;code = 101
char = i;code = 105
char = o;code = 111
char = d;code = 100
char = o;code = 111
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char = u;code = 117
char = m;code = 109
char = ,;code = 44
char = ;code = 32
char = T;code = 84
char = i;code = 105
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = ,;code = 44
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char = c;code = 99
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char = a;code = 97
char = l;code = 108
char = a;code = 97
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char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = c;code = 99
char = o;code = 111
char = r;code = 114
char = b;code = 98
char = i;code = 105
char = c;code = 99
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char = a;code = 97
char = c;code = 99
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char = d;code = 100
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = v;code = 118
char = i;code = 105
char = t;code = 116
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
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char = E;code = 69
char = );code = 41
char = ;code = 32
char = r;code = 114
char = e;code = 101
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 = 69
char = G;code = 71
char = F;code = 70
char = R;code = 82
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = y;code = 121
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char = A;code = 65
char = p;code = 112
char = l;code = 108
char = i;code = 105
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = N;code = 78
char = -;code = 45
char = A;code = 65
char = c;code = 99
char = e;code = 101
char = t;code = 116
char = y;code = 121
char = l;code = 108
char = c;code = 99
char = y;code = 121
char = s;code = 115
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char = e;code = 101
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char = a;code = 97
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char = P;code = 80
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char = s;code = 115
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char = p;code = 112
char = a;code = 97
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char = t;code = 116
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = l;code = 108
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char = h;code = 104
char = i;code = 105
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char = J;code = 74
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char = K;code = 75
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char = a;code = 97
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char = d;code = 100
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char = M;code = 77
char = A;code = 65
char = P;code = 80
char = K;code = 75
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char = a;code = 97
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char = a;code = 97
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char = i;code = 105
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char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
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char = i;code = 105
char = n;code = 110
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char = a;code = 97
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char = l;code = 108
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char = l;code = 108
char = a;code = 97
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char = l;code = 108
char = e;code = 101
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char = e;code = 101
char = l;code = 108
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char = o;code = 111
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char = G;code = 71
char = S;code = 83
char = H;code = 72
char = ;code = 32
char = a;code = 97
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char = f;code = 102
char = e;code = 101
char = c;code = 99
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char = e;code = 101
char = d;code = 100
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char = A;code = 65
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char = i;code = 105
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char = n;code = 110
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char = e;code = 101
char = a;code = 97
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char = m;code = 109
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char = l;code = 108
char = l;code = 108
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char = w;code = 119
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char = t;code = 116
char = h;code = 104
char = ;code = 32
char = G;code = 71
char = S;code = 83
char = H;code = 72
char = ;code = 32
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = N;code = 78
char = -;code = 45
char = a;code = 97
char = c;code = 99
char = e;code = 101
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char = y;code = 121
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char = i;code = 105
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char = i;code = 105
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char = d;code = 100
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char = a;code = 97
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char = G;code = 71
char = S;code = 83
char = H;code = 72
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char = e;code = 101
char = p;code = 112
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char = e;code = 101
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char = i;code = 105
char = o;code = 111
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char = a;code = 97
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char = s;code = 115
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char = d;code = 100
char = ,;code = 44
char = ;code = 32
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char = u;code = 117
char = c;code = 99
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char = i;code = 105
char = o;code = 111
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = E;code = 69
char = G;code = 71
char = F;code = 70
char = R;code = 82
char = ,;code = 44
char = ;code = 32
char = S;code = 83
char = r;code = 114
char = c;code = 99
char = ,;code = 44
char = ;code = 32
char = J;code = 74
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char = K;code = 75
char = ,;code = 44
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char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = 3;code = 51
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char = ;code = 32
char = M;code = 77
char = A;code = 65
char = P;code = 80
char = K;code = 75
char = .;code = 46
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char = R;code = 82
char = e;code = 101
char = m;code = 109
char = a;code = 97
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char = k;code = 107
char = a;code = 97
char = b;code = 98
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char = i;code = 105
char = d;code = 100
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char = o;code = 111
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char = G;code = 71
char = F;code = 70
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char = J;code = 74
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char = K;code = 75
char = ,;code = 44
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char = 3;code = 51
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char = M;code = 77
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char = P;code = 80
char = K;code = 75
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char = w;code = 119
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char = 4;code = 52
char = 9;code = 57
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char = A;code = 65
char = C;code = 67
char = H;code = 72
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char = t;code = 116
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char = a;code = 97
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char = T;code = 84
char = h;code = 104
char = e;code = 101
char = s;code = 115
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char = i;code = 105
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char = t;code = 116
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char = o;code = 111
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char = ;code = 32
char = A;code = 65
char = p;code = 112
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char = i;code = 105
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result sql = We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin induced a specific cellular stress response program, including sustained activation of the epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase Src, and the serine/threonine kinases JNK and p38 MAPK. Aplidin-induced apoptosis was only partially blocked by the general caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone and was also sensitive to AG1478 (an EGFR inhibitor), PP2 (an Src inhibitor), and SB203580 (an inhibitor of JNK and p38 MAPK) in MDA-MB-231 cells. Supporting a role for EGFR in Aplidin action, EGFR-deficient mouse embryo fibroblasts underwent apoptosis upon treatment more slowly than wild-type EGFR fibroblasts and also showed delayed JNK and reduced p38 MAPK activation. N-Acetylcysteine and ebselen (but not other antioxidants such as diphenyleneiodonium, Tiron, catalase, ascorbic acid, and vitamin E) reduced EGFR activation by Aplidin. N-Acetylcysteine and PP2 also partially inhibited JNK and p38 MAPK activation. The intracellular level of GSH affected Aplidin action; pretreatment of cells with GSH or N-acetylcysteine inhibited, whereas GSH depletion caused, hyperinduction of EGFR, Src, JNK, and p38 MAPK. Remarkably, Aplidin also induced apoptosis and activated EGFR, JNK, and p38 MAPK in two cell lines (A-498 and ACHN) derived from human renal cancer, a neoplasia that is highly refractory to chemotherapy. These data provide a molecular basis for the anticancer activity of Aplidin.

Publication: J. Biol. Chem. 2003 Jan 3 ;278(1)::241-50.
Publication Date: 2003 Jan 3
Study Author(s): Cuadrado, Ana;Garcia-Fernandez, Luis F;Gonzalez, Laura;Suarez, Yajaira;Losada, Alejandro;Alcaide, Victoria;Martinez, Teresa;Fernandez-Sousa, Jose Maria;Sanchez-Puelles, Jose Maria;Munoz, Alberto;
Institution: Drug Discovery Department, PharmaMar S. A., Tres Cantos, E-28760 Madrid, Spain.
Shortcut link to this study:
We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin induced a specific cellular stress response program, including sustained activation of the epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase Src, and the serine/threonine kinases JNK and p38 MAPK. Aplidin-induced apoptosis was only partially blocked by the general caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone and was also sensitive to AG1478 (an EGFR inhibitor), PP2 (an Src inhibitor), and SB203580 (an inhibitor of JNK and p38 MAPK) in MDA-MB-231 cells. Supporting a role for EGFR in Aplidin action, EGFR-deficient mouse embryo fibroblasts underwent apoptosis upon treatment more slowly than wild-type EGFR fibroblasts and also showed delayed JNK and reduced p38 MAPK activation. N-Acetylcysteine and ebselen (but not other antioxidants such as diphenyleneiodonium, Tiron, catalase, ascorbic acid, and vitamin E) reduced EGFR activation by Aplidin. N-Acetylcysteine and PP2 also partially inhibited JNK and p38 MAPK activation. The intracellular level of GSH affected Aplidin action; pretreatment of cells with GSH or N-acetylcysteine inhibited, whereas GSH depletion caused, hyperinduction of EGFR, Src, JNK, and p38 MAPK. Remarkably, Aplidin also induced apoptosis and activated EGFR, JNK, and p38 MAPK in two cell lines (A-498 and ACHN) derived from human renal cancer, a neoplasia that is highly refractory to chemotherapy. These data provide a molecular basis for the anticancer activity of Aplidin.
PMID: 12414812

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