Liposomal simvastatin sensitizes C26 murine colon carcinoma to the antitumor effects of liposomal 5‐fluorouracil in vivo

Abstract

5-Fluorouracil-based therapy remains the main approach in colorectal cancer, even though there are still some drawbacks, such as chemoresistance. In this study we combined 5-fluorouracil encapsulated in long-circulating liposomes with simvastatin, also encapsulated in long-circulating liposomes, that was previously proved to exert antitumor actions on the same tumor model. The production of angiogenic/inflammatory proteins was assessed by protein array and the production of markers for tumor aggressiveness (Bcl-2, Bax, and nuclear factor [NF]-κB) were determined by western blot analysis. Intratumor oxidative stress was evaluated through measurement of malondialdehyde level by HPLC, and through spectrophotometric analysis of catalytic activity of catalase and of total antioxidant capacity. Immunohistochemical analysis of tumors for CD31 expression was assessed. Intratumor activity of MMP-2 by gelatin zymography was also carried out. Our results revealed that combined therapies based on liposomal formulations exerted enhanced antitumor activities compared with combined treatment with free drugs. Sequential treatment with liposomal simvastatin and liposomal 5-fluorouracil showed the strongest antitumor activity in C26 colon carcinoma in vivo, mainly through inhibition of tumor angiogenesis. Important markers for cancer progression (Bcl-2, Bax, NF-κB, and intratumor antioxidants) showed that liposomal simvastatin might sensitize C26 cells to liposomal 5-fluorouracil treatment in both regimens tested. The outcome of simultaneous treatment with liposomal formulations was superior to sequential treatment with both liposomal types as the invasive capacity of C26 tumors was strongly increased after the latest treatment. The antitumor efficacy of combined therapy in C26 colon carcinoma might be linked to the restorative effects on proteins balance involved in tumor angiogenesis. K E Y W O R D S 5-fluorouracil, combined therapy, liposomes, resistance, simvastatin | 1345 LUPUT eT aL. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Luput L, Sesarman A, Porfire A, et al. Liposomal simvastatin sensitizes C26 murine colon carcinoma to the antitumor effects of liposomal 5-fluorouracil in vivo.

Statins: a repurposed drug to fight cancer

“…Similarly, as the main therapeutic strategy for colorectal cancer, 5-FU-based treatment options have some shortcomings, including the risk of chemotherapy resistance. Recent evidence suggests that simvastatin may enhance the sensitivity of C26 mouse colon cancer cells to 5-FU treatment [ 301 ]. Pereira et al found that statins temporarily modulated the epidermal growth factor receptor (EGFR) and prostate specific membrane antigen (PSMA) on the surface of tumor cells, which enhanced the tumor-binding avidity of the monoclonal antibodies panitumumab, cetuximab and huJ591, thereby synergizing with the antitumor effects of these agents [ 302 ].…”

Active Tumor-Targeting Nano-formulations Containing Simvastatin and Doxorubicin Inhibit Melanoma Growth and Angiogenesis

“…Moreover, the co-culture between melanoma cells and IL-13-LCL-SIM-treated M2 macrophages rendered B16.F10 melanoma cells more susceptible to the antiproliferative effects of PEG-EV-DOX ( Figure 2B ), which was also confirmed by the 2-fold decrease in the IC 50 of PEG-EV-DOX-treated B16.F10 proliferation in the presence of IL-13-LCL-SIM treated TAMs ( Table 3 ). Based on these results and on previous studies in which we demonstrated that liposomal SIM can sensitize cancer cells to cytotoxic agents ( Luput et al, 2020 ) or that intrinsic DOX resistance in melanoma can be overcome by simultaneous administration of inhibitors of TAM pro-tumor functions ( Licarete et al, 2020 ), we administered the novel combination therapy in vivo , sequentially as detailed in Supplementary Figure S1 . Our data clearly showed that among the monotherapies, IL-13-conjugated LCL-SIM and PEG-EV-DOX elicited the strongest reduction in tumor volume ( Figures 3A,B ).…”

Temozolomide, Simvastatin and Acetylshikonin Combination Induces Mitochondrial Dependent Apoptosis in GBM Cells which is Regulated by Autophagy

“…Co-treatment of Simva and flavons decreases chemo-resistance to doxorubicine via degradation of multi drug resistance (MDR) proteins in human colon cancer cells [80]. In another investigation, it has been showed that liposomal Simva sensitizes C26 colon carcinoma cells to liposomal 5-FU via inhibition of tumor angiogenesis in vivo [81]. Simvastatin also sensitizes A549 non-small cell lung cancer to Sulindac, or Pemetrexed (multi-target antifolate medication) induced caspase-dependent apoptosis via damaging mitochondria and increasing ROS [82,83].…”