|
|
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result sql = Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells.
Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells.char = T;code = 84
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result sql = Thiazolides are a novel class of broad-spectrum anti-infective drugs with promising in vitro and in vivo activities against intracellular and extracellular protozoan parasites. The nitrothiazole-analogue nitazoxanide (NTZ; 2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide) represents the thiazolide parent compound, and a number of bromo- and carboxy-derivatives with differing activities have been synthesized. Here we report that NTZ and the bromo-thiazolide RM4819, but not the carboxy-thiazolide RM4825, inhibited proliferation of the colon cancer cell line Caco2 and nontransformed human foreskin fibroblasts (HFF) at or below concentrations the compounds normally exhibit anti-parasitic activity. Thiazolides induced typical signs of apoptosis, such as nuclear condensation, DNA fragmentation and phosphatidylserine exposure. Interestingly, the apoptosis-inducing effect of thiazolides appeared to be cell cycle-dependent and induction of cell cycle arrest substantially inhibited the cell death-inducing activity of these compounds. Using affinity chromatography and mass spectrometry glutathione-S-transferase P1 (GSTP1) from the GST class Pi was identified as a major thiazolide-binding protein. GSTP1 expression was more than 10 times higher in the thiazolide-sensitive Caco2 cells than in the less sensitive HFF cells. The enzymatic activity of recombinant GSTP1 was strongly inhibited by thiazolides. Silencing of GSTP1 using siRNA rendered cells insensitive to RM4819, while overexpression of GSTP1 increased sensitivity to RM4819-induced cell death. Thiazolides may thus represent an interesting novel class of future cancer therapeutics.
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char = g;code = 103
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char = o;code = 111
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char = t;code = 116
char = h;code = 104
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = i;code = 105
char = n;code = 110
char = d;code = 100
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char = c;code = 99
char = e;code = 101
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char = g;code = 103
char = l;code = 108
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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
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char = S;code = 83
char = -;code = 45
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = n;code = 110
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char = f;code = 102
char = e;code = 101
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char = a;code = 97
char = s;code = 115
char = e;code = 101
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char = P;code = 80
char = i;code = 105
char = ;code = 32
char = (;code = 40
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char = T;code = 84
char = P;code = 80
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char = d;code = 100
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char = l;code = 108
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char = d;code = 100
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char = a;code = 97
char = t;code = 116
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char = i;code = 105
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char = h;code = 104
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char = c;code = 99
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char = o;code = 111
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char = c;code = 99
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
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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 = 46
result sql = Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells.
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char = z;code = 122
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char = r;code = 114
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char = ;code = 32
char = a;code = 97
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = v;code = 118
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char = l;code = 108
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = a;code = 97
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char = s;code = 115
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char = f;code = 102
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char = b;code = 98
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char = a;code = 97
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char = -;code = 45
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char = p;code = 112
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char = c;code = 99
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char = r;code = 114
char = u;code = 117
char = m;code = 109
char = ;code = 32
char = a;code = 97
char = n;code = 110
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char = i;code = 105
char = -;code = 45
char = i;code = 105
char = n;code = 110
char = f;code = 102
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char = e;code = 101
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char = r;code = 114
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char = g;code = 103
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char = s;code = 115
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char = i;code = 105
char = n;code = 110
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char = ;code = 32
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char = ;code = 32
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char = n;code = 110
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char = i;code = 105
char = v;code = 118
char = o;code = 111
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char = a;code = 97
char = c;code = 99
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char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = e;code = 101
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char = ;code = 32
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char = a;code = 97
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char = l;code = 108
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = e;code = 101
char = x;code = 120
char = t;code = 116
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char = a;code = 97
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = l;code = 108
char = u;code = 117
char = l;code = 108
char = a;code = 97
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char = p;code = 112
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char = z;code = 122
char = o;code = 111
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char = p;code = 112
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char = a;code = 97
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char = i;code = 105
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char = e;code = 101
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char = .;code = 46
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char = T;code = 84
char = h;code = 104
char = e;code = 101
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char = e;code = 101
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char = a;code = 97
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char = o;code = 111
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char = u;code = 117
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char = t;code = 116
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char = d;code = 100
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char = (;code = 40
char = N;code = 78
char = T;code = 84
char = Z;code = 90
char = ;;code = 59
char = ;code = 32
char = 2;code = 50
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char = a;code = 97
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char = y;code = 121
char = l;code = 108
char = o;code = 111
char = x;code = 120
char = y;code = 121
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char = N;code = 78
char = -;code = 45
char = (;code = 40
char = 5;code = 53
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char = s;code = 115
char = ;code = 32
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char = h;code = 104
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char = t;code = 116
char = h;code = 104
char = i;code = 105
char = a;code = 97
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char = o;code = 111
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char = d;code = 100
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char = ;code = 32
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char = d;code = 100
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = n;code = 110
char = u;code = 117
char = m;code = 109
char = b;code = 98
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = b;code = 98
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = o;code = 111
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char = h;code = 104
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char = d;code = 100
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char = f;code = 102
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char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = c;code = 99
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char = b;code = 98
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char = e;code = 101
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char = n;code = 110
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char = e;code = 101
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char = i;code = 105
char = z;code = 122
char = e;code = 101
char = d;code = 100
char = .;code = 46
char = ;code = 32
char = H;code = 72
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = p;code = 112
char = o;code = 111
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char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
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char = N;code = 78
char = T;code = 84
char = Z;code = 90
char = ;code = 32
char = a;code = 97
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char = m;code = 109
char = o;code = 111
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char = l;code = 108
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char = d;code = 100
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char = R;code = 82
char = M;code = 77
char = 4;code = 52
char = 8;code = 56
char = 1;code = 49
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char = ,;code = 44
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char = R;code = 82
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char = 2;code = 50
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char = a;code = 97
char = n;code = 110
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char = T;code = 84
char = P;code = 80
char = 1;code = 49
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = r;code = 114
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char = n;code = 110
char = g;code = 103
char = l;code = 108
char = y;code = 121
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 = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
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char = t;code = 116
char = h;code = 104
char = i;code = 105
char = a;code = 97
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char = o;code = 111
char = l;code = 108
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = S;code = 83
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char = l;code = 108
char = e;code = 101
char = n;code = 110
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = G;code = 71
char = S;code = 83
char = T;code = 84
char = P;code = 80
char = 1;code = 49
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = R;code = 82
char = N;code = 78
char = A;code = 65
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = e;code = 101
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char = l;code = 108
char = s;code = 115
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char = i;code = 105
char = n;code = 110
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 = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = R;code = 82
char = M;code = 77
char = 4;code = 52
char = 8;code = 56
char = 1;code = 49
char = 9;code = 57
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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 = r;code = 114
char = e;code = 101
char = x;code = 120
char = p;code = 112
char = r;code = 114
char = e;code = 101
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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 = G;code = 71
char = S;code = 83
char = T;code = 84
char = P;code = 80
char = 1;code = 49
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = e;code = 101
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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 = y;code = 121
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = R;code = 82
char = M;code = 77
char = 4;code = 52
char = 8;code = 56
char = 1;code = 49
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char = e;code = 101
char = d;code = 100
char = ;code = 32
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char = l;code = 108
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char = d;code = 100
char = e;code = 101
char = a;code = 97
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char = i;code = 105
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char = o;code = 111
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char = i;code = 105
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = n;code = 110
char = o;code = 111
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char = e;code = 101
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = s;code = 115
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = t;code = 116
char = u;code = 117
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char = e;code = 101
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = p;code = 112
char = e;code = 101
char = u;code = 117
char = t;code = 116
char = i;code = 105
char = c;code = 99
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char = <;code = 60
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result sql = Thiazolides are a novel class of broad-spectrum anti-infective drugs with promising in vitro and in vivo activities against intracellular and extracellular protozoan parasites. The nitrothiazole-analogue nitazoxanide (NTZ; 2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide) represents the thiazolide parent compound, and a number of bromo- and carboxy-derivatives with differing activities have been synthesized. Here we report that NTZ and the bromo-thiazolide RM4819, but not the carboxy-thiazolide RM4825, inhibited proliferation of the colon cancer cell line Caco2 and nontransformed human foreskin fibroblasts (HFF) at or below concentrations the compounds normally exhibit anti-parasitic activity. Thiazolides induced typical signs of apoptosis, such as nuclear condensation, DNA fragmentation and phosphatidylserine exposure. Interestingly, the apoptosis-inducing effect of thiazolides appeared to be cell cycle-dependent and induction of cell cycle arrest substantially inhibited the cell death-inducing activity of these compounds. Using affinity chromatography and mass spectrometry glutathione-S-transferase P1 (GSTP1) from the GST class Pi was identified as a major thiazolide-binding protein. GSTP1 expression was more than 10 times higher in the thiazolide-sensitive Caco2 cells than in the less sensitive HFF cells. The enzymatic activity of recombinant GSTP1 was strongly inhibited by thiazolides. Silencing of GSTP1 using siRNA rendered cells insensitive to RM4819, while overexpression of GSTP1 increased sensitivity to RM4819-induced cell death. Thiazolides may thus represent an interesting novel class of future cancer therapeutics.
Publication: Int. J. Cancer 2008 Oct 15 ;123(8)::1797-806. :doi: 10.1002/ijc.23755.
Publication Date: 2008 Oct 15
Study Author(s): Müller, Joachim;Sidler, Daniel;Nachbur, Ueli;Wastling, Jonathan;Brunner, Thomas;Hemphill, Andrew;
Institution: Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Shortcut link to this study:
Publication Date: 2008 Oct 15
Study Author(s): Müller, Joachim;Sidler, Daniel;Nachbur, Ueli;Wastling, Jonathan;Brunner, Thomas;Hemphill, Andrew;
Institution: Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
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Thiazolides are a novel class of broad-spectrum anti-infective drugs with promising in vitro and in vivo activities against intracellular and extracellular protozoan parasites. The nitrothiazole-analogue nitazoxanide (NTZ; 2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide) represents the thiazolide parent compound, and a number of bromo- and carboxy-derivatives with differing activities have been synthesized. Here we report that NTZ and the bromo-thiazolide RM4819, but not the carboxy-thiazolide RM4825, inhibited proliferation of the colon cancer cell line Caco2 and nontransformed human foreskin fibroblasts (HFF) at or below concentrations the compounds normally exhibit anti-parasitic activity. Thiazolides induced typical signs of apoptosis, such as nuclear condensation, DNA fragmentation and phosphatidylserine exposure. Interestingly, the apoptosis-inducing effect of thiazolides appeared to be cell cycle-dependent and induction of cell cycle arrest substantially inhibited the cell death-inducing activity of these compounds. Using affinity chromatography and mass spectrometry glutathione-S-transferase P1 (GSTP1) from the GST class Pi was identified as a major thiazolide-binding protein. GSTP1 expression was more than 10 times higher in the thiazolide-sensitive Caco2 cells than in the less sensitive HFF cells. The enzymatic activity of recombinant GSTP1 was strongly inhibited by thiazolides. Silencing of GSTP1 using siRNA rendered cells insensitive to RM4819, while overexpression of GSTP1 increased sensitivity to RM4819-induced cell death. Thiazolides may thus represent an interesting novel class of future cancer therapeutics.
PMID: 18688861
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