Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model

Int J Cancer. 2009;125(9):2187-97

 

In 2007, in the United States, 10% of the overall cancer incidence was colorectal cancer (CRC) becoming the third leading cause of cancer death. Due to their resistance to chemotherapy, very few patients experience complete pathologic responses, thus making it necessary to look out for novel approaches to enhance the effects of chemotherapeutic drugs and reduce their resistance.

Several study results have shown that NF-ĸB pathway plays a major role in CRC growth and metastasis and hence, agents that block NF-ĸB activation will reduce chemoresistance.

Curcumin is one such agent that has been shown to be inhibiting NF-ĸB activation and downregulate the expression of NF-ĸB-regulated gene products that play a role at various stages of cancer cycle. Moreover, Curcumin has been reported to be augmenting the effects of chemotherapeutic drugs, such as paclitaxel, docetaxel and gemcitabine in vivo.

 

Objective:

To determine whether Curcumin can modulate the effects of capecitabine against CRC, in an orthotopic nude mouse model.

 

Study Design:

  • Proliferation assay was carried to determine effects of Curcumin on cell proliferation
  • Role of Curcumin in potentiating the apoptotic effects of capecitabine in colon cancer cells was determined by apoptosis assay
  • Male athymic nu/nu mice (4 weeks old) were injected with HCT 116 cells to implant the tumor
  • One week after implantation, mice were randomly assigned to the following treatment groups (n=5-8): (i) corn oil (100 µL daily) as the vehicle; (ii) curcumin alone (1 g/kg once daily, orally), (iii) capecitabine alone (60 mg/kg, twice weekly by gavage) and (iv) curcumin (1 g/kg, once daily, orally) and capecitabine (60 mg/kg, twice weekly by gavage)
  • Tumor volumes were monitored weekly
  • At the end of the study, extracted tumor tissues were evaluated for various immunohistochemical parameters
  • Protein concentration was determined using nuclear extracts from tumor samples
  • NF-ĸB activation was also determined using colon cancer cells

 

Results and Discussion:

  • A dose-dependent inhibition of cell proliferation was seen in all three-cell lines when treated with Curcumin; HCT 116 cells being the most sensitive
  • Depending on the type of cell line, Curcumin enhanced the effect of capecitabine from 5–11% to 47–95%
  • NF-ĸB activation was significantly inhibited by Curcumin in a dose-dependent manner
  • Curcumin also inhibited the expression of cyclin D1, c-Myc, COX- 2, VEGF, MMP-9, ICAM-1, CXCR4 and Bcl-2 in a dose-dependent manner, which are known to be regulated by NF-ĸB
  • Effect of Curcumin was determined by measuring tumor volume in in an orthotopic nude mice model, wherein the curcumin and capecitabine group significantly lowered the tumor volume than that in the capecitabine or control group by Day 27 after treatment (p< 0.001 vs. capecitabine; p < 0.001 vs. control)
  • Curcumin alone (p<0.001 vs. control) significantly decreased CRC growth, which was further decreased when curcumin was used in combination with capecitabine (p<0.031 vs. capecitabine)
  • Curcumin in combination with capecitabine more significantly decreased cell proliferation and angiogenesis markers when compared with Curcumin alone, which also showed a significant inhibition vs. control

 

Conclusion:

Overall, Curcumin was found to be potentiating the antitumor and antimetastatic effects of capecitabine by suppressing NF-ĸB cell signaling pathway, thus could be an effective adjunctive in the management of CRC.

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