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Purpose: Besides cholesterol lowering effects, simvastatin (SIM) at very high doses possesses antitumor actions. Moreover our previous studies demonstrated that tumor-targeted delivery of SIM by using long-circulating liposomes (LCL) improved the therapeutic index of this drug in murine melanoma-bearing mice. To evaluate whether this finding can be exploited for future therapy of colorectal cancer the antitumor activity and the underlying mechanisms of long-circulating liposomal simvastatin (LCL-SIM) efficacy for inhibition of C26 murine colon carcinoma growth in vivo were investigated. Materials and Methods: To find LCL-SIM dose with the highest therapeutic index, dose-response relationship and side effects of different LCL-SIM doses were assessed in C26 colon carcinoma-bearing mice. The underlying mechanisms of LCL-SIM versus free SIM treatments were investigated with regard to their actions on C26 cell proliferation and apoptosis (via tumor tissues immunostaining for PCNA and Bax markers), tumor inflammation (via western blot analysis of NF-κΒ production), angiogenesis (using an angiogenic protein array), and oxidative stress (by HPLC assessment of malondialdehyde). Results: Our findings suggest that LCL-SIM antitumor activity on C26 colon carcinoma is a result of the tumor-targeting property of the liposome formulation, as free SIM treatment was ineffective. Moreover, LCL-SIM exerted significant antiproliferative and pro-apoptotic actions on C26 cells, notable suppressive effects on two main supportive processes for tumor development, inflammation and angiogenesis, and only slight anti-oxidant actions. Conclusion: Our data proved that LCL-SIM antitumor activity in C26 colon carcinoma was based on cytotoxic effects on these cancer cells and suppressive actions on tumor angiogenesis and inflammation.

In Vivo Double Targeting of C26 Colon Carcinoma Cells and Microenvironmental Protumor Processes Using Liposomal Simvastatin