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You are here: Home / Abstracts / Simvastatin Enhances Radiation Sensitivity of Colorectal Cancer by Targeting Colorectal Cancer Initiating Cells

Simvastatin Enhances Radiation Sensitivity of Colorectal Cancer by Targeting Colorectal Cancer Initiating Cells

Georgios Karagkounis, Jennifer DeVecchio, BA, Sylvain Ferrandon, PhD, Matthew F Kalady, MD. Cleveland Clinic

Introduction: Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with improved response to neoadjuvant CRT in rectal cancer patients. In addition, we have shown that colorectal cancer initiating cells (CR-CIC), known also as cancer stem cells, are important mediators of tumor resistance to cytotoxic therapy. The purpose of this study was to study the effects of simvastatin on patient-derived CR-CICs and explore its potential as a radiation-sensitizer in vitro.

Methods: Three patient-derived CR-CIC lines were used to test the effects of simvastatin alone, radiation alone, and combination therapy. Differentiated cells (non-CICs) derived from the same three cell lines were used as control. Outcome measures included ATP-based cell viability assays, and CR-CIC sphere formation assays, which define the CR-CIC phenotype and correlates directly with tumor formation in mice.

Results: CR-CICs were more resistant than non-CICs to both low-dose (2 Gy) and high-dose radiation (6 Gy) (decrease in viability 10-50% compared to 90-95% for non-CICs, p<0.001). However, all CR-CIC lines were more sensitive to treatment with simvastatin alone at both 1uM and 5uM concentrations compared to non-CICs (decrease in viability 60-98% compared to 0-15%, p<0.001). In addition, the combination of simvastatin and radiation was more effective than either therapy alone in inhibiting CR-CIC viability. Importantly, this also translated into effects on the sphere forming ability of CR-CICs: while radiation alone demonstrated limited inhibition, the addition of simvastatin significantly reduced the percentage of CR-CICs that formed spheres (further decrease 50-75%, p<0.01).

Conclusions: Treatment with simvastatin hinders CR-CIC viability and enhances radiation sensitivity in vitro. These findings suggest that simvastatin could be a potential adjunct therapy for rectal cancer patients. Mechanistic and in vivo studies are in progress, with the ultimate goal of paving the way for a clinical trial.


Presented at the SAGES 2017 Annual Meeting in Houston, TX.

Abstract ID: 79205

Program Number: S042

Presentation Session: Colorectal 1

Presentation Type: Podium

54

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