Synergistic Effects of Simvastatin and Irinotecan against Colon Cancer Cells with or without Irinotecan Resistance

Abstract

Aims . We here investigated whether the combination of simvastatin and irinotecan could induce the synergistic effect on colon cancer cells with or without resistance to irinotecan. Methods . We investigated cell proliferation assay and assessed cell death detection ELISA and caspase-3 activity assay of various concentrations of simvastatin and irinotecan to evaluate the efficacy of drug combination on colon cancer cells with or without irinotecan resistance. Results . The IC 50 values of simvastatin alone and irinotecan alone were<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mn fontstyle="italic">115.4</mml:mn><mml:mo>±</mml:mo><mml:mn fontstyle="italic">0.14</mml:mn></mml:math> μ M (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>r</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle="italic">0.98</mml:mn></mml:math>) and<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mn fontstyle="italic">62.5</mml:mn><mml:mo>±</mml:mo><mml:mn fontstyle="italic">0.18</mml:mn></mml:math> μ M (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>r</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle="italic">0.98</mml:mn></mml:math>) in HT-29 cells without resistance to irinotecan. The IC 50 values of these two drugs were<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mn fontstyle="italic">221.9</mml:mn><mml:mo>±</mml:mo><mml:mn fontstyle="italic">0.22</mml:mn></mml:math> μ M (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mi>r</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle="italic">0.98</mml:mn></mml:math>) and<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"><mml:mn fontstyle="italic">195.9</mml:mn><mml:mo>±</mml:mo><mml:mn fontstyle="italic">0.16</mml:mn></mml:math> μ M (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"><mml:mi>r</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle="italic">0.99</mml:mn></mml:math>), respectively, in HT-29 cell with resistance to irinotecan. The results of combinations of the various concentrations of two drugs showed that combined treatment with irinotecan and simvastatin more efficiently suppressed cell proliferation of HT-29 cells even with resistance to irinotecan as well as without resistance. Furthermore, the combination of simvastatin and irinotecan at<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"><mml:mn fontstyle="italic">2</mml:mn><mml:mo>:</mml:mo><mml:mn fontstyle="italic">1</mml:mn></mml:math>molar ratio showed the best synergistic interaction. Conclusion . Simvastatin could act synergistically with irinotecan to overcome irinotecan resistance of colon cancer.