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Sensitization of ovarian cancer cells to cisplatin by genistein: the role of NF-kappaB.

Solomon LA, Ali S, Banerjee S, Munkarah AR, Morris RT, Sarkar FH - J Ovarian Res (2008)

Bottom Line: Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells in vitro and in vivo by reversing chemo-resistance phenotype.The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response.The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-kappaB DNA binding activity were all found to be down-regulated in the combination groups.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Gynecologic Oncology, Karmanos Cancer Center, Wayne State University, Detroit, Michigan, USA.

ABSTRACT

Background: Platinum-resistance (PR) continues to be a major problem in the management of epithelial ovarian cancer (EOC). Response to various chemotherapeutic agents is poor in patients deemed PR. Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells in vitro and in vivo by reversing chemo-resistance phenotype. The goal of this study was to investigate the effects of combination therapy with genistein and cisplatin as well as other cytotoxic conventional chemotherapeutic agents in platinum-sensitive (PS) and resistant EOC cells.

Methods: The PS human ovarian cancer cell line A2780 and its PR clone C200 cells were pretreated with genistein, followed by the combination of genistein and either cisplatin, taxotere or gemcitabine. Cell survival and apoptosis was assessed by MTT and histone-DNA ELISA. Electrophoretic mobility shift assay (EMSA) was used to evaluate NF-kappaB DNA binding activity. Western blot analysis was performed with antibodies to Bcl-2, Bcl-xL, survivin, c-IAP and PARP.

Results: Reduction in cell viability, and corresponding induction of apoptosis was observed with genistein pretreatment followed by combination treatment with each of the drugs in both cell lines. The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response. The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-kappaB DNA binding activity were all found to be down-regulated in the combination groups.

Conclusion: This study convincingly demonstrated that the current strategy can be translated in a pre-clinical animal model, and thus it should stimulate future clinical trial for the treatment of drug-resistant ovarian cancer.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of potential mechanism of genistein induced chemo-sensitization of ovarian cancer cells to conventional chemo-therapeutic agents.
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Figure 5: Schematic diagram of potential mechanism of genistein induced chemo-sensitization of ovarian cancer cells to conventional chemo-therapeutic agents.

Mentions: Studies have shown that the underlying resistance to apoptosis is in part due to constitutive activation of NF-κB in pancreatic cancer [27]. Our results strongly suggest that the resistance of ovarian cancer cells treated with cisplatin could in part be also due to the activation of NF-κB and that the chemo-sensitization could be due to genistein-induced inactivation of NF-κB signaling, resulting in the inhibition of cell proliferation and induction of apoptosis (Figure. 5). Our hypothesis is also supported by the evidence of down-regulation of the important anti-apoptotic proteins such as Bcl-2, Bcl-xL. survivin and c-IAP2, which also happens to be the downstream genes of NF-κB. C-IAP-2 and survivin are members of the anti-apoptotic IAP (Inhibitors of Apoptosis) family of proteins suppressing apoptosis and their expression in tumors has been associated with poor prognosis and increased tumor recurrence in many tumors. Our findings reveal the expression of these anti-apoptotic proteins is decreased by genistein, and is probably driven by NF-κB activation suggesting another possibility for inhibiting tumor and that NK-κB, survivin and IAP'S may make an important contribution to the development of chemo-resistance.


Sensitization of ovarian cancer cells to cisplatin by genistein: the role of NF-kappaB.

Solomon LA, Ali S, Banerjee S, Munkarah AR, Morris RT, Sarkar FH - J Ovarian Res (2008)

Schematic diagram of potential mechanism of genistein induced chemo-sensitization of ovarian cancer cells to conventional chemo-therapeutic agents.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2611983&req=5

Figure 5: Schematic diagram of potential mechanism of genistein induced chemo-sensitization of ovarian cancer cells to conventional chemo-therapeutic agents.
Mentions: Studies have shown that the underlying resistance to apoptosis is in part due to constitutive activation of NF-κB in pancreatic cancer [27]. Our results strongly suggest that the resistance of ovarian cancer cells treated with cisplatin could in part be also due to the activation of NF-κB and that the chemo-sensitization could be due to genistein-induced inactivation of NF-κB signaling, resulting in the inhibition of cell proliferation and induction of apoptosis (Figure. 5). Our hypothesis is also supported by the evidence of down-regulation of the important anti-apoptotic proteins such as Bcl-2, Bcl-xL. survivin and c-IAP2, which also happens to be the downstream genes of NF-κB. C-IAP-2 and survivin are members of the anti-apoptotic IAP (Inhibitors of Apoptosis) family of proteins suppressing apoptosis and their expression in tumors has been associated with poor prognosis and increased tumor recurrence in many tumors. Our findings reveal the expression of these anti-apoptotic proteins is decreased by genistein, and is probably driven by NF-κB activation suggesting another possibility for inhibiting tumor and that NK-κB, survivin and IAP'S may make an important contribution to the development of chemo-resistance.

Bottom Line: Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells in vitro and in vivo by reversing chemo-resistance phenotype.The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response.The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-kappaB DNA binding activity were all found to be down-regulated in the combination groups.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Gynecologic Oncology, Karmanos Cancer Center, Wayne State University, Detroit, Michigan, USA.

ABSTRACT

Background: Platinum-resistance (PR) continues to be a major problem in the management of epithelial ovarian cancer (EOC). Response to various chemotherapeutic agents is poor in patients deemed PR. Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells in vitro and in vivo by reversing chemo-resistance phenotype. The goal of this study was to investigate the effects of combination therapy with genistein and cisplatin as well as other cytotoxic conventional chemotherapeutic agents in platinum-sensitive (PS) and resistant EOC cells.

Methods: The PS human ovarian cancer cell line A2780 and its PR clone C200 cells were pretreated with genistein, followed by the combination of genistein and either cisplatin, taxotere or gemcitabine. Cell survival and apoptosis was assessed by MTT and histone-DNA ELISA. Electrophoretic mobility shift assay (EMSA) was used to evaluate NF-kappaB DNA binding activity. Western blot analysis was performed with antibodies to Bcl-2, Bcl-xL, survivin, c-IAP and PARP.

Results: Reduction in cell viability, and corresponding induction of apoptosis was observed with genistein pretreatment followed by combination treatment with each of the drugs in both cell lines. The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response. The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-kappaB DNA binding activity were all found to be down-regulated in the combination groups.

Conclusion: This study convincingly demonstrated that the current strategy can be translated in a pre-clinical animal model, and thus it should stimulate future clinical trial for the treatment of drug-resistant ovarian cancer.

No MeSH data available.


Related in: MedlinePlus