Abstract
Hydroxytyrosol (HT), a polyphenol of olive oil, downregulates epidermal growth factor (EGFR) expression and inhibits cell proliferation in colon cancer (CC) cells, with mechanisms similar to that activated by the EGFR inhibitor, cetuximab. Here, we studied whether HT treatment would enhance the cetuximab inhibitory effects on cell growth in CC cells.HT-cetuximab combination showed greater efficacy in reducing cell growth in HT-29 and WiDr cells at concentrations 10 times lower than when used as single agents. This reduction was clearly linked to cell cycle blockade, occurring at G2/M phase. The cell cycle arrest in response to combination treatment is related to cyclins B, D1, and E, and cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 down-regulation, and to the concomitant over-expression of CDK inhibitors p21 and p27. HT and cetuximab stimulated a caspase-independent cell death cascade, promotedtranslocation of apoptosis-inducing factor (AIF) from mitochondria to nucleus and activated the autophagy process.Notably, normal colon cells and keratinocytes were less susceptible to combo-induced cell death and EGFR downregulation.These results suggest a potential role of diet, containing olive oil, during cetuximab chemotherapy of colon tumor. HT may be a competent therapeutic agent in CC enhancing the effects of EGFR inhibitors.
Highlights
Hydroxytyrosol (HT), 2-(3,4-dihydroxyphenyl) ethanol, a polyphenol found in olive oil, noted for its antiinflammatory, antioxidant activity, has been reported to reduce proliferation of human cancer cells, colon carcinoma cells [1,2,3], and to exert pro-apoptotic effects [4,5,6]
Marked differences in sensitivity to cetuximab were observed in colon cancer cells primed with epidermal growth factor (EGF), as HT-29 cell growth was reduced by high cetuximab concentrations (10-100 μg/ml; IC50 50.12 μM), while WiDr cells were unaffected by monoclonal antibodies (mAbs) at any concentration tested
Since reports from our and other laboratories showed that HT reduces epidermal growth factor (EGFR) expression [3] and cetuximab down-regulates EGFR levels in colon cancer cells [14], we investigated whether HT and cetuximab per se and in combination, when used at low concentrations, would affect EGFR expression in HT-29 and WiDr cells (Figure 3)
Summary
Hydroxytyrosol (HT), 2-(3,4-dihydroxyphenyl) ethanol, a polyphenol found in olive oil, noted for its antiinflammatory, antioxidant activity, has been reported to reduce proliferation of human cancer cells, colon carcinoma cells [1,2,3], and to exert pro-apoptotic effects [4,5,6]. We uncovered a possible mechanism, as we found that HT markedly accelerates degradation of EGFR, by promoting phosphorylation of the docking site for Cbl, a component of the ubiquitin system [3] These findings suggest the existence of causal relationship between the HT polyphenol and the EGFR burden, widely recognized as the main driver of colon cancer growth. We compared the effects exerted by exposure to HT and cetuximab as single agents and by the HTcetuximab combination on HT-29 and WiDr colon cancer cells, examining functional parameters of tumor growth and clonogenic potential, as well as biochemical ones Among the latter we analyzed: EGFR expression, cell www.impactjournals.com/oncotarget cycle progression molecules, apoptosis and autophagy markers and genes
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