Inhibition of cell cycle progression by the hydroxytyrosol–cetuximab combination yields enhanced chemotherapeutic efficacy in colon cancer cells
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Erika Terzuoli1, Ginevra Nannelli1, Maria Frosini1, Antonio Giachetti1, Marina Ziche1 and Sandra Donnini1
1Department of Life Sciences, University of Siena, 53100 Siena, Italy
Sandra Donnini, email: [email protected]
Marina Ziche, email: [email protected]
Keywords: hydroxytyrosol, cetuximab, colon cancer, cell cycle, AIF-dependent apoptosis
Received: June 29, 2017 Accepted: July 30, 2017 Published: August 24, 2017
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.
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