In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer.
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.
Banerjee
Sanjeev
S
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Zhang
Yuxiang
Y
Wang
Zhiwei
Z
Che
Mingxin
M
Chiao
Paul J
PJ
Abbruzzese
James L
JL
Sarkar
Fazlul H
FH
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004273:DNA, Neoplasm / Q000378:metabolism; D004357:Drug Synergism; D019833:Genistein / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
D004273:DNA, Neoplasm; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D051020:bcl-X Protein; D019833:Genistein; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; D002945:Cisplatin