Curcumin enhances the effect of chemotherapy against colorectal cancer cells by inhibition of NF-κB and Src protein kinase signaling pathways.

Abstract

OBJECTIVE:

Development of treatment resistance and adverse toxicity associated with classical chemotherapeutic agents highlights the need for safer and effective therapeutic approaches. Herein, we examined the effectiveness of a combination treatment regimen of 5-fluorouracil (5-FU) and curcumin in colorectal cancer (CRC) cells.

METHODS:

Wild type HCT116 cells and HCT116+ch3 cells (complemented with chromosome 3) were treated with curcumin and 5-FU in a time- and dose-dependent manner and evaluated by cell proliferation assays, DAPI staining, transmission electron microscopy, cell cycle analysis and immunoblotting for key signaling proteins.

RESULTS:

The individual IC50 of curcumin and 5-FU were approximately 20 µM and 5 µM in HCT116 cells and 5 µM and 1 µM in HCT116+ch3 cells, respectively (p<0.05). Pretreatment with curcumin significantly reduced survival in both cells; HCT116+ch3 cells were considerably more sensitive to treatment with curcumin and/or 5-FU than wild-type HCT116 cells. The IC50 values for combination treatment were approximately 5 µM and 1 µM in HCT116 and 5 µM and 0.1 µM in HCT116+ch3, respectively (p<0.05). Curcumin induced apoptosis in both cells by inducing mitochondrial degeneration and cytochrome c release. Cell cycle analysis revealed that the anti-proliferative effect of curcumin and/or 5-FU was preceded by accumulation of CRC cells in the S cell cycle phase and induction of apoptosis. Curcumin potentiated 5-FU-induced expression or cleavage of pro-apoptotic proteins (caspase-8, -9, -3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins. Although 5-FU activated NF-κB/PI-3K/Src pathway in CRC cells, this was down-regulated by curcumin treatment through inhibition of IκBα kinase activation and IκBα phosphorylation.

CONCLUSIONS:

Combining curcumin with conventional chemotherapeutic agents such as 5-FU could provide more effective treatment strategies against chemoresistant colon cancer cells. The mechanisms involved may be mediated via NF-κB/PI-3K/Src pathways and NF-κB regulated gene products.

• Authors: Mehdi Shakibaei, Ali Mobasheri, Cora Lueders, Franziska Busch, Paviz Shayan, Ajay Goel
• Journal: PloS one (PLoS One) Vol. 8 Issue 2 Pg. e57218 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23451189 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• NF-kappa B
• src-Family Kinases
• Curcumin
• Fluorouracil

Topics

• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, enzymology, metabolism, pathology)
• Curcumin (pharmacology)
• Drug Synergism
• Fluorouracil (therapeutic use)
• Humans
• Microscopy, Electron, Transmission
• NF-kappa B (antagonists & inhibitors)
• Signal Transduction (drug effects)
• src-Family Kinases (antagonists & inhibitors, metabolism)