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char = l;code = 108
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char = .;code = 46
result sql = A coumarin derivative (RKS262) inhibits cell-cycle progression, causes pro-apoptotic signaling and cytotoxicity in ovarian cancer cells.

A coumarin derivative (RKS262) inhibits cell-cycle progression, causes pro-apoptotic signaling and cytotoxicity in ovarian cancer cells.

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char = -;code = 45
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = O;code = 79
char = V;code = 86
char = C;code = 67
char = A;code = 65
char = R;code = 82
char = -;code = 45
char = 3;code = 51
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = .;code = 46
char = ;code = 32
char = R;code = 82
char = K;code = 75
char = S;code = 83
char = 2;code = 50
char = 6;code = 54
char = 2;code = 50
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
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = a;code = 97
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 = m;code = 109
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = c;code = 99
char = h;code = 104
char = o;code = 111
char = n;code = 110
char = d;code = 100
char = r;code = 114
char = i;code = 105
char = a;code = 97
char = -;code = 45
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = s;code = 115
char = m;code = 109
char = e;code = 101
char = m;code = 109
char = b;code = 98
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = e;code = 101
char = -;code = 45
char = d;code = 100
char = e;code = 101
char = p;code = 112
char = o;code = 111
char = l;code = 108
char = a;code = 97
char = r;code = 114
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 = p;code = 112
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = .;code = 46
char = ;code = 32
char = R;code = 82
char = K;code = 75
char = S;code = 83
char = 2;code = 50
char = 6;code = 54
char = 2;code = 50
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
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char = i;code = 105
char = n;code = 110
char = c;code = 99
char = l;code = 108
char = u;code = 117
char = d;code = 100
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = u;code = 117
char = p;code = 112
char = -;code = 45
char = r;code = 114
char = e;code = 101
char = g;code = 103
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
char = ;code = 32
char = o;code = 111
char = f;code = 102
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 = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = r;code = 114
char = k;code = 107
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = l;code = 108
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 = 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 = p;code = 112
char = r;code = 114
char = o;code = 111
char = -;code = 45
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 = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = M;code = 77
char = A;code = 65
char = P;code = 80
char = -;code = 45
char = K;code = 75
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 = (;code = 40
char = p;code = 112
char = 3;code = 51
char = 8;code = 56
char = ,;code = 44
char = ;code = 32
char = S;code = 83
char = A;code = 65
char = P;code = 80
char = /;code = 47
char = J;code = 74
char = N;code = 78
char = K;code = 75
char = );code = 41
char = .;code = 46
char = ;code = 32
char = R;code = 82
char = K;code = 75
char = S;code = 83
char = 2;code = 50
char = 6;code = 54
char = 2;code = 50
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = e;code = 101
char = r;code = 114
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = y;code = 121
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
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char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = w;code = 119
char = n;code = 110
char = -;code = 45
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = D;code = 68
char = N;code = 78
char = A;code = 65
char = -;code = 45
char = p;code = 112
char = k;code = 107
char = ;code = 32
char = K;code = 75
char = U;code = 85
char = -;code = 45
char = 8;code = 56
char = 0;code = 48
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = u;code = 117
char = n;code = 110
char = i;code = 105
char = t;code = 116
char = ;code = 32
char = e;code = 101
char = x;code = 120
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 = a;code = 97
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char = d;code = 100
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = u;code = 117
char = s;code = 115
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
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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 = 46
char = ;code = 32
char = A;code = 65
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char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = e;code = 101
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = R;code = 82
char = K;code = 75
char = S;code = 83
char = 2;code = 50
char = 6;code = 54
char = 2;code = 50
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = r;code = 114
char = e;code = 101
char = g;code = 103
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
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
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char = m;code = 109
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = c;code = 99
char = h;code = 104
char = o;code = 111
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char = d;code = 100
char = r;code = 114
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = B;code = 66
char = c;code = 99
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char = 2;code = 50
char = -;code = 45
char = f;code = 102
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = w;code = 119
char = a;code = 97
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = P;code = 80
char = r;code = 114
char = o;code = 111
char = -;code = 45
char = a;code = 97
char = p;code = 112
char = o;code = 111
char = p;code = 112
char = t;code = 116
char = o;code = 111
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char = i;code = 105
char = c;code = 99
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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 = s;code = 115
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char = B;code = 66
char = i;code = 105
char = d;code = 100
char = ,;code = 44
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char = B;code = 66
char = a;code = 97
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char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = B;code = 66
char = o;code = 111
char = k;code = 107
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
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char = u;code = 117
char = p;code = 112
char = -;code = 45
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = i;code = 105
char = l;code = 108
char = e;code = 101
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char = e;code = 101
char = x;code = 120
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 = p;code = 112
char = r;code = 114
char = o;code = 111
char = -;code = 45
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = a;code = 97
char = l;code = 108
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 = s;code = 115
char = ;code = 32
char = B;code = 66
char = c;code = 99
char = l;code = 108
char = -;code = 45
char = x;code = 120
char = l;code = 108
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = M;code = 77
char = c;code = 99
char = l;code = 108
char = -;code = 45
char = 1;code = 49
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
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char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = .;code = 46
char = ;code = 32
char = M;code = 77
char = o;code = 111
char = r;code = 114
char = e;code = 101
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = -;code = 45
char = c;code = 99
char = y;code = 121
char = t;code = 116
char = o;code = 111
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char = o;code = 111
char = x;code = 120
char = i;code = 105
char = c;code = 99
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char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = R;code = 82
char = K;code = 75
char = S;code = 83
char = 2;code = 50
char = 6;code = 54
char = 2;code = 50
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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 = O;code = 79
char = V;code = 86
char = C;code = 67
char = A;code = 65
char = R;code = 82
char = -;code = 45
char = 3;code = 51
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char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
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char = y;code = 121
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char = l;code = 108
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char = g;code = 103
char = h;code = 104
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char = G;code = 71
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char = p;code = 112
char = h;code = 104
char = a;code = 97
char = s;code = 115
char = e;code = 101
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char = a;code = 97
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char = d;code = 100
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char = u;code = 117
char = p;code = 112
char = -;code = 45
char = r;code = 114
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char = g;code = 103
char = u;code = 117
char = l;code = 108
char = a;code = 97
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char = e;code = 101
char = d;code = 100
char = ;code = 32
char = p;code = 112
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char = w;code = 119
char = h;code = 104
char = i;code = 105
char = l;code = 108
char = e;code = 101
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char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
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char = D;code = 68
char = 1;code = 49
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = C;code = 67
char = d;code = 100
char = k;code = 107
char = -;code = 45
char = 6;code = 54
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char = w;code = 119
char = e;code = 101
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char = e;code = 101
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = w;code = 119
char = n;code = 110
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char = r;code = 114
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char = g;code = 103
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
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char = ,;code = 44
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char = i;code = 105
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char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
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char = ;code = 32
char = R;code = 82
char = K;code = 75
char = S;code = 83
char = 2;code = 50
char = 6;code = 54
char = 2;code = 50
char = ;code = 32
char = i;code = 105
char = s;code = 115
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char = a;code = 97
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char = s;code = 115
char = p;code = 112
char = e;code = 101
char = c;code = 99
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
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char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
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char = n;code = 110
char = /;code = 47
char = C;code = 67
char = D;code = 68
char = K;code = 75
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = m;code = 109
char = m;code = 109
char = a;code = 97
char = r;code = 114
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = R;code = 82
char = K;code = 75
char = S;code = 83
char = 2;code = 50
char = 6;code = 54
char = 2;code = 50
char = ;code = 32
char = h;code = 104
char = a;code = 97
char = s;code = 115
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char = b;code = 98
char = e;code = 101
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char = i;code = 105
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
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char = m;code = 109
char = o;code = 111
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = l;code = 108
char = o;code = 111
char = n;code = 110
char = g;code = 103
char = i;code = 105
char = n;code = 110
char = g;code = 103
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char = t;code = 116
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = w;code = 119
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
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char = r;code = 114
char = a;code = 97
char = p;code = 112
char = e;code = 101
char = u;code = 117
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char = ;code = 32
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char = ;code = 32
char = s;code = 115
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char = ;code = 32
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char = f;code = 102
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result sql = Coumarin derivative RKS262 belongs to a new class of potential anti-tumor agents. RKS262 was identified by structural optimization of Nifurtimox which is currently undergoing phase II clinical trials to treat high-risk neuroblastoma. In a NCI(60) cell-line assay RKS262 exhibited significant cytotoxicity in ovarian cancer cells and a variety of other cell lines exceeding effects of commercial drugs such as cisplatin, 5-FU, cyclophosphamide or sapacitabine. Various leukemia cell-lines were most sensitive (GI(50): ~ 10 nM) while several non-small cell lung cancer cell lines and few cell lines from other tissues were relatively resistant (GI(50) > 1 µM) to RKS262 treatment. The mechanism of cytotoxicity was examined using ovarian cancer cell-line OVCAR-3 as a model. RKS262 treatment resulted in a reduced mitochondria-transmembrane-depolarization potential. RKS262 effects included up-regulation of apoptotic markers and were not correlated with activation of pro-apoptotic MAP-Kinases (p38, SAP/JNK). RKS262 exerted strong inhibitory effects on oncogene ras, down-regulated DNA-pk KU-80 subunit expression and caused activation of Akt. A signature effect of RKS262 is the regulation of the mitochondrial Bcl2-family pathway. Pro-apoptotic factors Bid, Bad and Bok were up-regulated while expression of pro-survival factors Bcl-xl and Mcl-1 was inhibited. Moreover, at sub-cytotoxic doses RKS262 delayed OVCAR-3 cell-cycle progression through G2 phase and up-regulated p27 while cyclin-D1 and Cdk-6 were down-regulated, indicating that RKS262 is a specific cyclin/CDK inhibitor. In summary, RKS262 has been identified as a molecule belonging to a new class of potential chemotherapeutic agents affecting the viability of multiple cancer cell-lines and causing selective adverse effects on the viability of ovarian cancer cells.

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