Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice.

Clin Cancer Res. 2005;11(20):7490-98

 

Treatment options available for primary tumour in case of metastatic breast cancer are surgery, radiation, and chemotherapy, which are not so effective. However, breast cancer at during initial stage is highly treatable. Although paclitaxel has been in use as frontline agent in breast cancers, it is not effective in treating advanced breast cancer, due to drug resistance, probably through the activation of NF-ĸB.

Curcumin has been shown to inhibit NF-ĸB activation induced by various inflammatory stimuli. There were some hypotheses on the influence of Curcumin on therapeutic outcome of paclitaxel treatment for breast cancer.

 

Objective:

To determine whether Curcumin inhibits paclitaxel-induced NF-ĸB activation and NF-ĸB–regulated gene products and prevent breast cancer metastasis to the lung.

 

Study Design:

Cell line Study
  • Human breast cancer cell line MDA-MB-435 was used, which is tumorigenic and metastatic in nude mice
  • Electrophoretic mobility gel shift assay was carried out to determine NF-ĸB activation, in paclitaxel-treated cells
  • Effect of Curcumin on paclitaxel-dependent IĸB-α degradation, phosphorylation and kinase assay was done in MDA-MB-435 cells
Nude Mice Study
  • High incidence of spontaneous metastases was induced in female athymic nude mice by injecting MDA-MB-435LVB human breast cancer cells (a variant of MDA-MB-435)
  • Once the mean tumour diameter reached 10 mm (58-60 days after cell injection), mice were anesthetized, the tumors were removed and the incisions were closed
  • All mice were randomly divided and fed either powdered diet or diet mixed with 2% w/w Curcumin, from day 5 after tumour removal until the end of the study
  • On days 10, 17 and 24 after tumour removal, mice were injected with paclitaxel (10 mg/kg, i.p.) or vehicle
  • Mice were euthanized and autopsied to record the incidence and numbers of visible lung metastases 5 weeks after tumour removal

 

Results and Discussion:

  • Paclitaxel-induced NF-ĸB activation in tumour cells was inhibited by Curcumin (maximum at 25 µmol/L concentration)
  • Curcumin also inhibited paclitaxel-mediated degradation and phosphorylation of IĸB-α completely
  • Anti-apoptotic proteins like IAP1/2, XIAP, Bcl-2 and Bcl-xL are regulated by NF-ĸB and Curcumin modulated these proteins induced by paclitaxel, in a dose-dependent manner
  • Both paclitaxel and Curcumin showed cytotoxicity of breast cancer cells in culture, however, combination of these two compounds was more effective than either one alone
  • In xenograft model, the incidence of breast cancer metastasis in lung tissue was significantly inhibited by Curcumin and paclitaxel combination (both the incidence and numbers of visible lung metastases)

 

Conclusion:

Overall, it was concluded that Curcumin showed therapeutic potential alone as well as in combination with paclitaxel in preventing breast cancer metastasis possibly through suppression of NF-ĸB and NF-ĸB-regulated gene products.

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