Curcumin (diferuloylmethane), which has been shown to inhibit growth of transformed cells, has no discernible toxicity and achieves high levels in colonic mucosa. 5-fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but with limited success. The present investigation was, therefore, undertaken to examine whether curcumin in combination with conventional chemotherapeutic agent(s)/regimen will be a superior therapeutic strategy for colorectal cancer. Indeed, results of our in vitro studies demonstrated that curcumin together with FOLFOX produced a significantly greater inhibition (p < 0.01) of growth and stimulated apoptosis (p < 0.001) of colon cancer HCT-116 and HT-29 cells than that caused by curcumin, 5-FU, curcumin 1 5-FU or FOLFOX. These changes were associated with decreased expression and activation (tyrosine phosphorylation) of EGFR, HER-2, HER-3 (72-100%) and IGF-1R (67%) as well as their downstream effectors such as Akt and cycloxygenase-2 (51-97%). Furthermore, while these agents produced a 2-3-fold increase in the expression of IGF-binding protein-3 (IGFBP-3), curcumin together with FOLFOX caused a 5-fold increase in the same, when compared to controls. This in turn led to increased sequestration of IGF by IGFBP-3 rendering IGF-1 unavailable for binding to and activation of IGF-1R. We conclude that the superior effects of the combination therapy of curcumin and FOLFOX are due to attenuation of EGFRs and IGF-1R signaling pathways. We also suggest that inclusion of curcumin to the conventional chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy for colorectal cancer. ' 2007 Wiley-Liss, Inc.Key words: colorectal cancer; EGFR; IGF-1R; curcumin; chemotherapy; IGFBP3There will be an estimated 148,610 new cases and 55,170 deaths due to colorectal caner (CRC) in 2006 in the USA. 1 CRC is estimated to be the second and third leading cause of cancerrelated deaths in men and women, respectively, in 2006. 1 Surgery and subsequent chemotherapy can cure over 75% colon cancer patients, but more than 30% of these patients develop new neoplastic polyps, and 10% progress to frank second malignancy. [2][3][4] The risk of second malignancy is higher for microsatellite instable tumor (MSI). 5 Metastatic colorectal cancer has poor a prognosis with 5-year survival of less than 10%. 6 As a result of great efforts are being spent on improving chemotherapeutic interventions for metastatic colon cancer, and the median survival has improved to over 20 months of this group of patients. 7 However, this comes at a cost of additional toxicities, some of which are even fatal. 7 The validation of a nontoxic agent that could improve upon the current chemotherapeutic regimen would therefore be highly desirable.Accumulating evidence suggests that the development and progression of many malignancies, including colorectal cancer, are associated with constitutive activation of multiple signaling pathways that promote proliferation, inhibit apoptosis an...
The epidermal growth factor receptor (EGFR) signaling network plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting EGFR would be extremely valuable for pancreatic cancer therapy. EGFR-related protein (ERRP), a recently identified pan-erbB inhibitor, has been shown to inhibit growth and induce apoptosis of pancreatic cancer cells in vitro and tumor growth in a xenograft model. However, the precise molecular mechanism(s) by which ERRP exerts its antitumor activity remains unclear. The current investigation was undertaken to delineate the tumor growth inhibitory mechanism(s) of ERRP in pancreatic cancer cells. Using multiple molecular assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis, gene transfection, real-time reverse transcription-PCR, Western blotting, invasion, and electrophoretic mobility shift assay for measuring DNA-binding activity of nuclear factor-KB (NF-KB), we found that ERRP caused marked inhibition of pancreatic cancer cell growth. This was accompanied by increased apoptosis and concomitant attenuation of Notch-1 and NF-KB and down-regulation of NF-KB downstream genes, such as matrix metalloproteinase-9 and vascular endothelial growth factor, resulting in the inhibition of pancreatic cancer cell invasion through the Matrigel. We also found that downregulation of Notch-1 by small interfering RNA before ERRP treatment resulted in enhanced cell growth inhibition and apoptosis. Our data suggest that the ERRP-mediated inactivation of EGFR, Notch-1, NF-KB, and its downstream target genes contributed to the inhibition of cell growth and invasion. We conclude that ERRP could be an effective agent for inhibiting tumor growth and invasion for the treatment of pancreatic cancer. (Cancer Res 2006; 66(15): 7653-60)
A role of the epidermal growth factor receptor (EGFR) family has been suggested in colon cancer etiology, progression, and/ or severity. Our recently identified pan-erbB inhibitor EGFRrelated protein (ERRP) targets EGFRs by attenuating their activation and subsequent signaling leading to cellular growth inhibition. In the present study, we evaluated the therapeutic effectiveness of ERRP on early and intermediate stages of colon cancer by examining regression of chemically induced aberrant crypt foci (ACF) in the colon of CF1 mice and intestinal adenomas in APC Min+/À (Min) mice. After formation of ACF or adenomas, the mice were injected (i.p.) with ERRP (50 Mg/mouse) for 10 consecutive days. This treatment significantly reduced the number of ACF from 25.0 F 3.0 (controls) to 14.9 F 1.6 (ERRP-treated; P = 0.011) and also reduced their size (P < 0.01). In Min mice, ERRP caused the regression of adenomas throughout the small intestine (P < 0.05) and reduced their size (P < 0.001). This could partly be attributed to inhibition of proliferation and stimulation of apoptosis in the intestinal mucosa and was associated with decreased activation of several EGFR family members, suppression of downstream effector nuclear factor KB and down-regulation of cyclooxygenase-2. ERRP-induced attenuation of EGFR activation could be due to increased sequestration of the ligand(s) by ERRP, rendering them unavailable for binding to and activation of the receptor. In conclusion, our data show that ERRP is effective in regressing both early and intermediate intestinal lesions and could be an effective therapeutic agent for colon cancer. [Cancer Res 2007;67(11):5389-96]
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