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. 2012 Jan 14;18(2):126-35.
doi: 10.3748/wjg.v18.i2.126.

Suppression of Esophageal Cancer Cell Growth Using Curcumin, (-)-epigallocatechin-3-gallate and Lovastatin

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Free PMC article

Suppression of Esophageal Cancer Cell Growth Using Curcumin, (-)-epigallocatechin-3-gallate and Lovastatin

Fei Ye et al. World J Gastroenterol. .
Free PMC article

Abstract

Aim: To determine the effects of curcumin, (-)-epigallocatechin-3-gallate (EGCG), lovastatin, and their combinations on inhibition of esophageal cancer.

Methods: Esophageal cancer TE-8 and SKGT-4 cell lines were subjected to cell viability methyl thiazolyl tetrazolium and tumor cell invasion assays in vitro and tumor formation and growth in nude mouse xenografts with or without curcumin, EGCG and lovastatin treatment. Gene expression was detected using immunohistochemistry and Western blotting in tumor cell lines, tumor xenografts and human esophageal cancer tissues, respectively.

Results: These drugs individually or in combinations significantly reduced the viability and invasion capacity of esophageal cancer cells in vitro. Molecularly, these three agents reduced the expression of phosphorylated extracellular-signal-regulated kinases (Erk1/2), c-Jun and cyclooxygenase-2 (COX-2), but activated caspase 3 in esophageal cancer cells. The nude mouse xenograft assay showed that EGCG and the combinations of curcumin, EGCG and lovastatin suppressed esophageal cancer cell growth and reduced the expression of Ki67, phosphorylated Erk1/2 and COX-2. The expression of phosphorylated Erk1/2 and COX-2 in esophageal cancer tissue specimens was also analyzed using immunohistochemistry. The data demonstrated that 77 of 156 (49.4%) tumors expressed phosphorylated Erk1/2 and that 121 of 156 (77.6%) esophageal cancers expressed COX-2 protein. In particular, phosphorylated Erk1/2 was expressed in 23 of 50 (46%) cases of esophageal squamous cell carcinoma (SCC) and in 54 of 106 (50.9%) cases of adenocarcinoma, while COX-2 was expressed in 39 of 50 (78%) esophageal SCC and in 82 of 106 (77.4%) esophageal adenocarcinoma.

Conclusion: The combinations of curcumin, EGCG and lovastatin were able to suppress esophageal cancer cell growth in vitro and in nude mouse xenografts, these drugs also inhibited phosphorylated Erk1/2, c-Jun and COX-2 expression.

Keywords: (-)-epigallocatechin-3-gallate; Chemoprevention; Curcumin; Cyclooxygenase-2; Esophageal cancer; Statin.

Figures

Figure 1
Figure 1
Suppression of esophageal cancer cell growth by curcumin, (-)-epigallocatechin-3-gallate, lovastatin and their combinations. Esophageal cancer SKGT-4 and TE-8 cells were grown in monolayer overnight and then treated with or without curcumin (Cur) (40 μmol/L), (-)-epigallocatechin-3-gallate (EGCG) (40 μmol/L), lovastatin (L) (4 μmol/L) and their combinations for up to 5 d. Methyl thiazolyl tetrazolium assays were then carried out to detect changes in cell viability (see Methods section). The experiments were repeated three times and the results are summarized as a % of the control (Con) (mean ± SD) and analyzed statistically using the Student’s t test. aP < 0.05, bP < 0.01.
Figure 2
Figure 2
Suppression of tumor cell invasion by curcumin, (-)-epigallocatechin-3-gallate, lovastatin and their combinations. Esophageal cancer SKGT-4 and TE-8 cells were grown and treated with or without curcumin (Cur) (40 μmol/L), (-)-epigallocatechin-3-gallate (EGCG) (40 μmol/L), lovastatin (L) (4 μmol/L) and their combinations in monolayer for 3 d and then subjected to cell invasion assays in Boyden chambers containing Matrigel for 48 h. The invasive cells were stained with 1% crystal violet solution, counted and the results are summarized as a % of the control (Con) (mean ± SD). The data were then analyzed statistically using the Student’s t test. aP < 0.05, bP < 0.01.
Figure 3
Figure 3
Modulation of gene expression by curcumin, (-)-epigallocatechin-3-gallate, lovastatin and their combinations. Esophageal cancer SKGT-4 and TE-8 cells were grown in monolayer overnight and treated with or without curcumin (Cur) (40 μmol/L), (-)-epigallocatechin-3-gallate (EGCG) (40 μmol/L), lovastatin (Lov) (4 μmol/L) and their combinations for 2 d and total cellular protein was extracted from the cells and subjected to Western blotting analysis of gene expression. Erk1/2: Extracellular-signal-regulated kinases; COX-2: Cyclooxygenase-2.
Figure 4
Figure 4
Inhibition of esophageal cancer cell growth by curcumin, (-)-epigallocatechin-3-gallate, lovastatin and their combinations in nude mouse xenografts. Esophageal adenocarcinoma SKGT-4 cells were inoculated subcutaneously into nude mice (5 per group). Two days before tumor cell injection, the mice started treatment with or without curcumin (Cur) (50 μg/kg per day), (-)-epigallocatechin-3-gallate (EGCG) (50 μg/kg per day), lovastatin (Lov) (50 μg/kg per day) and their combinations (the same doses as given individually) for 30 d (5 d/wk by oral gavage). At the end of the experiments, the xenograft tumor mass was isolated and weighed and summarized.
Figure 5
Figure 5
Reduced expression of Ki67, phosphorylated extracellular-signal-regulated kinases and cyclooxygenase-2 in xenografts following treatment of mice with or without curcumin, (-)-epigallocatechin-3-gallate, lovastatin and their combinations. Tumor cell xenografts obtained from the nude mouse experiments were processed and subjected to immunohistochemical analyses of Ki67, phosphorylated extracellular-signal-regulated kinases (Erk1/2) and cyclooxygenase-2 (COX-2) expression. Representative images were obtained in each treatment group. EGCG: (-)-epigallocatechin-3-gallate; L: Lovastatin; Cur: Curcumin.
Figure 6
Figure 6
Expression of phosphorylated extracellular-signal-regulated kinases and cyclooxygenase-2 in esophageal cancer specimens. Paraffin sections of esophageal cancer tissues were immunostained with anti-phosphorylated extracellular-signal-regulated kinases (Erk1/2) or cyclooxygenase-2 (COX-2) antibody. Representative images were obtained from these tissue sections. SCC: Squamous cell carcinoma.

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