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Experimental Therapeutics, Molecular Targets, and Chemical Biology

Curcumin Potentiates Antitumor Activity of Gemcitabine in an Orthotopic Model of Pancreatic Cancer through Suppression of Proliferation, Angiogenesis, and Inhibition of Nuclear Factor-κB–Regulated Gene Products

Ajaikumar B. Kunnumakkara, Sushovan Guha, Sunil Krishnan, Parmeswaran Diagaradjane, Juri Gelovani and Bharat B. Aggarwal
Ajaikumar B. Kunnumakkara
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Sushovan Guha
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Sunil Krishnan
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Parmeswaran Diagaradjane
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Juri Gelovani
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Bharat B. Aggarwal
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DOI: 10.1158/0008-5472.CAN-06-4257 Published April 2007
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Abstract

Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that has been shown to suppress the transcription factor nuclear factor-κB (NF-κB), which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-κB activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant reductions in volume (P = 0.008 versus control; P = 0.036 versus gemcitabine alone), Ki-67 proliferation index (P = 0.030 versus control), NF-κB activation, and expression of NF-κB–regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31+ microvessel density (P = 0.018 versus control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing proliferation, angiogenesis, NF-κB, and NF-κB–regulated gene products. [Cancer Res 2007;67(8):3853–61]

  • Curcumin
  • Gemcitabine
  • NF-κB
  • Angiogenesis
  • Pancreatic Cancer

Footnotes

  • Note: A.B. Kunnumakkara and S. Guha contributed equally to this work.

  • Received November 20, 2006.
  • Revision received January 25, 2007.
  • Accepted February 2, 2007.
  • ©2007 American Association for Cancer Research.
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Cancer Research: 67 (8)
April 2007
Volume 67, Issue 8
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Curcumin Potentiates Antitumor Activity of Gemcitabine in an Orthotopic Model of Pancreatic Cancer through Suppression of Proliferation, Angiogenesis, and Inhibition of Nuclear Factor-κB–Regulated Gene Products
Ajaikumar B. Kunnumakkara, Sushovan Guha, Sunil Krishnan, Parmeswaran Diagaradjane, Juri Gelovani and Bharat B. Aggarwal
Cancer Res April 15 2007 (67) (8) 3853-3861; DOI: 10.1158/0008-5472.CAN-06-4257

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Curcumin Potentiates Antitumor Activity of Gemcitabine in an Orthotopic Model of Pancreatic Cancer through Suppression of Proliferation, Angiogenesis, and Inhibition of Nuclear Factor-κB–Regulated Gene Products
Ajaikumar B. Kunnumakkara, Sushovan Guha, Sunil Krishnan, Parmeswaran Diagaradjane, Juri Gelovani and Bharat B. Aggarwal
Cancer Res April 15 2007 (67) (8) 3853-3861; DOI: 10.1158/0008-5472.CAN-06-4257
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