TY - JOUR
T1 - Curcumin potentiates the antitumor effects of bacillus Calmette-Guerin against bladder cancer through the downregulation of NF-κB and upregulation of TRAIL receptors
AU - Kamat, Ashish M.
AU - Tharakan, Sheeja T.
AU - Sung, Bokyung
AU - Aggarwal, Bharat B.
PY - 2009/12/1
Y1 - 2009/12/1
N2 - Although Bacillus Calmette-Guerin (BCG) intravesical therapy is a standard treatment for bladder cancer, eventual failure of response is a major problem. Treatments that can augment BCG therapy are urgently needed. We investigated whether curcumin, a component of Curcuma longa (also called turmeric), has potential to improve the current therapy using in vitro and in vivo MBT-2 murine tumor models. We found that curcumin potentiated BCG-induced apoptosis of human bladder cancer cells. BCG stimulated the release of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from peripheral mononuclear neutrophils in a dose- and time-dependent manner, whereas curcumin enhanced the upregulation of TRAIL receptors. Electrophoretic mobility shift assay revealed that curcumin also suppressed the BCG-induced activation of the cell survival transcription factor NF-κB. In a syngeneic bladder cancer model, curcumin alone reduced the bladder tumor volume, but a significantly greater reduction was observed when BCG and curcumin were used in combination (P < 0.0001 versus control; P < 0.003 versus BCG alone). This was accompanied by a significant decrease in the proliferation marker Ki-67 (P < 0.01 versus control; P < 0.01 versus BCG alone) and microvessel density (CD31; P < 0.01 versus control; P < 0.01 versus BCG alone), decreased NF-κB in tumor tissue compared with the control, induced apoptosis, and decreased cyclin D1, vascular endothelial growth factor, cyclooxygenase-2, c-myc, and Bcl-2 expression in the tumor tissue. Upregulation of TRAIL receptor by the combination was also observed in tumor tissues. Overall, our results suggest that curcumin potentiates the antitumor effect of BCG through the inhibition of NF-κB and induction of TRAIL receptors in bladder cancer cells.
AB - Although Bacillus Calmette-Guerin (BCG) intravesical therapy is a standard treatment for bladder cancer, eventual failure of response is a major problem. Treatments that can augment BCG therapy are urgently needed. We investigated whether curcumin, a component of Curcuma longa (also called turmeric), has potential to improve the current therapy using in vitro and in vivo MBT-2 murine tumor models. We found that curcumin potentiated BCG-induced apoptosis of human bladder cancer cells. BCG stimulated the release of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from peripheral mononuclear neutrophils in a dose- and time-dependent manner, whereas curcumin enhanced the upregulation of TRAIL receptors. Electrophoretic mobility shift assay revealed that curcumin also suppressed the BCG-induced activation of the cell survival transcription factor NF-κB. In a syngeneic bladder cancer model, curcumin alone reduced the bladder tumor volume, but a significantly greater reduction was observed when BCG and curcumin were used in combination (P < 0.0001 versus control; P < 0.003 versus BCG alone). This was accompanied by a significant decrease in the proliferation marker Ki-67 (P < 0.01 versus control; P < 0.01 versus BCG alone) and microvessel density (CD31; P < 0.01 versus control; P < 0.01 versus BCG alone), decreased NF-κB in tumor tissue compared with the control, induced apoptosis, and decreased cyclin D1, vascular endothelial growth factor, cyclooxygenase-2, c-myc, and Bcl-2 expression in the tumor tissue. Upregulation of TRAIL receptor by the combination was also observed in tumor tissues. Overall, our results suggest that curcumin potentiates the antitumor effect of BCG through the inhibition of NF-κB and induction of TRAIL receptors in bladder cancer cells.
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U2 - 10.1158/0008-5472.CAN-09-2045
DO - 10.1158/0008-5472.CAN-09-2045
M3 - Article
C2 - 19903839
AN - SCOPUS:71549171910
SN - 0008-5472
VL - 69
SP - 8958
EP - 8966
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -