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

Abstract

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-jB and anti-apoptotic Akt expression. NF-jB 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-jB, 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-jB 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. ' 2006 Wiley-Liss, Inc.

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

“…We also found that piperlongumine downregulated the constitutive activation of NF-kB in pancreatic cancer cell lines. These results on downregulation of NF-kB activation by piperlongumine are consistent with previous reports that piperlongumine inhibited activation of NF-kB in other cancer cell lines (30,39) and with reports that resveratrol (45), genistein (46), dihydroartemisinin (44), zyflamend (47), g-tocotrienol (48), curcumin (49), shikonin (9), and 3,3 0 -Diindolylmethane (50), all present within piperlongumine, are associated with NF-kB inactivation.…”

Genistein selectively potentiates arsenic trioxide‐induced apoptosis in human leukemia cells via reactive oxygen species generation and activation of reactive oxygen species‐inducible protein kinases (p38‐MAPK, AMPK)

“…This later result might be surprising, since genistein was earlier reported to enhance the toxicity of cisplatin in other tumor cell types. 22,47 Nonetheless, the inability of genistein to increase apoptosis induction by drugs other than ATO in U937 cells seems to be consistent with its failure to inhibit Akt phosphorylation and NF-jB activation, since Akt and NF-jB are protective factors against multiple stressing treatments. Of note, our results only indicate that Akt and NF-jB do not play a main regulatory role under the present experimental conditions, but do not prejudge the capacity of genistein to modulate Akt/NF-jB in leukemia cells in other conditions, nor necessarily contradicts earlier observations in other cell types.…”

Evodiamine induces apoptosis in pancreatic carcinoma PANC-1 cells via NF κB inhibition

“…The constitutive activation of NF-κB is believed to promote inhibition of apoptosis and resistance to chemotherapy (Arlt and Schafer, 2002;Holocomb et al, 2008;Liptay et al, 2003). This notion is further supported by the fact that inactivation of NF-κB sensitizes cancer cells to conventional chemotherapies (Banerjee et al, 2005;Banerjee et al, 2007). Therefore, treating pancreatic cancer with NF-κB inhibitors can improve the outcomes of chemotherapy.…”

“…Previous reports have demonstrated that inhibition of spontaneous NF-κB activation can potentiate the anticancer effect of various chemotherapeutic agents (Banerjee et al, 2007). Thus, we treated the cell with evodiamine in the presence of SN50, a specific NFκBp65 inhibitor and cell death was measured by live/ dead assay and apoptosis assay.…”