New CXCR4 Antagonist Peptide R (Pep R) Improves Standard Therapy in Colorectal Cancer

he chemokine receptor CXCR4 is overexpressed and functional in colorectal cancer. To investigate the role of CXCR4 antagonism in potentiating colon cancer standard therapy, the new peptide CXCR4 antagonist Peptide R (Pep R) was employed. Human colon cancer HCT116 xenograft-bearing mice were treated with chemotherapeutic agents (CT) 5-Fluorouracil (5FU) and oxaliplatin (OX) or 5FU and radio chemotherapy (RT-CT) in the presence of Pep R. After two weeks, CT plus Pep R reduced by 4-fold the relative tumor volume (RTV) as compared to 2- and 1.6-fold reductions induced, respectively, by CT and Pep R. In vitro Pep R addition to CT/RT-CT impaired HCT116 cell growth and further reduced HCT116 and HT29 clonal capability. Thus, the hypothesis that Pep R could target the epithelial mesenchyme transition (EMT) process was evaluated. While CT decreased ECAD and increased ZEB-1 and CD90 expression, the addition of Pep R restored the pretreatment expression. In HCT116 and HT29 cells, CT/RT-CT induced a population of CD133+CXCR4+ cells, supposedly a stem-resistant cancer cell population, while Pep R reduced it. Taken together, the results showed that targeting CXCR4 ameliorates the effect of treatment in colon cancer through inhibition of cell growth and reversal of EMT treatment-induced markers, supporting further clinical studies

Engineering of thermoresponsive gels as a fake metastatic niche

Chemoattraction through the CXCR4-CXCL12 axis has been shown to be an important mechanism to direct circulating tumor cells toward distant sites. The objective of this work was to prepare a fake metastatic niche made up of a gel loaded with CXCL12. The gel is designed to create a steep concentration gradient of the chemokine in the proximity of the site of administration/injection, aimed to divert and capture circulating CXCR4+ tumor cells. To this aim, different thermoresponsive gels based on methylcellulose (MC) or poloxamers, loaded with CXCL12, with or without hyaluronic acid (HA) were designed and their mechanical properties correlated with the ability to attract and capture in vitro CXCR4+ cells. Results of in vitro cell studies showed that all prepared gels induced CEM tumor cell migration whereas only gels based on MC embedded with CXCL12 are able to capture them