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In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer.

Publication ,  Journal Article
Banerjee, S; Zhang, Y; Wang, Z; Che, M; Chiao, PJ; Abbruzzese, JL; Sarkar, FH
Published in: Int J Cancer
February 15, 2007

We recently reported the potential of genistein in augmenting gemcitabine-induced killing of pancreatic cancer (Banerjee, S. et al., Cancer Research 2005;65:9064-72). Since cis-diaminedichloroplatinum (II) (cisplatin) is widely used against solid tumors, we further investigated whether genistein pretreatment could be used as a novel strategy for cisplatin-induced killing of pancreatic cancer cells in vitro and enhanced antitumor activity in vivo. Our in vitro results showed that pretreatment of cells with genistein followed by cisplatin resulted in significant loss of cell viability and potentiated apoptosis irrespective of the metastatic ability of cells. Mechanistically, genistein augmented cisplatin induced killing by down regulating transcription factor-NF-kappaB and anti-apoptotic Akt expression. NF-kappaB was found upregulated when pancreatic cancer cells were exposed to cisplatin, suggesting the potential mechanism of acquired chemo-resistance. In addition, we also showed, for the first time, that genistein in combination with cisplatin is more effective antitumor agent in our orthotopic tumor model. But most importantly, our data also showed that a specific target, such as NF-kappaB, was inactivated in animal tumors treated with genistein and cisplatin. Immunohistochemical data showed reduced staining for phospho-p65, Bcl-xL and MMP-9 in treated tumors compared to control tumors, but the lowest activity was seen in the combination group. These results provide strong molecular in vivo evidence in support of our hypothesis that inactivation of the NF-kappaB signaling pathway by genistein results in the chemo-sensitization of pancreatic tumors to cisplatin, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.

Duke Scholars

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Published In

Int J Cancer

DOI

ISSN

0020-7136

Publication Date

February 15, 2007

Volume

120

Issue

4

Start / End Page

906 / 917

Location

United States

Related Subject Headings

  • bcl-X Protein
  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Transcription Factor RelA
  • Signal Transduction
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-akt
  • Poly(ADP-ribose) Polymerases
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
 

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Banerjee, S., Zhang, Y., Wang, Z., Che, M., Chiao, P. J., Abbruzzese, J. L., & Sarkar, F. H. (2007). In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int J Cancer, 120(4), 906–917. https://doi.org/10.1002/ijc.22332
Banerjee, Sanjeev, Yuxiang Zhang, Zhiwei Wang, Mingxin Che, Paul J. Chiao, James L. Abbruzzese, and Fazlul H. Sarkar. “In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer.Int J Cancer 120, no. 4 (February 15, 2007): 906–17. https://doi.org/10.1002/ijc.22332.
Banerjee S, Zhang Y, Wang Z, Che M, Chiao PJ, Abbruzzese JL, et al. In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int J Cancer. 2007 Feb 15;120(4):906–17.
Banerjee, Sanjeev, et al. “In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer.Int J Cancer, vol. 120, no. 4, Feb. 2007, pp. 906–17. Pubmed, doi:10.1002/ijc.22332.
Banerjee S, Zhang Y, Wang Z, Che M, Chiao PJ, Abbruzzese JL, Sarkar FH. In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int J Cancer. 2007 Feb 15;120(4):906–917.
Journal cover image

Published In

Int J Cancer

DOI

ISSN

0020-7136

Publication Date

February 15, 2007

Volume

120

Issue

4

Start / End Page

906 / 917

Location

United States

Related Subject Headings

  • bcl-X Protein
  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Transcription Factor RelA
  • Signal Transduction
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-akt
  • Poly(ADP-ribose) Polymerases
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis