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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]-?B) 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-?B, 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.

SUBMITTER: Luput L

PROVIDER: S-EPMC7156830 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Luput Lavinia L Sesarman Alina A Porfire Alina A Achim Marcela M Muntean Dana D Casian Tibor T Patras Laura L Rauca Valentin Florian VF Drotar Denise Minerva DM Stejerean Ioana I Tomuta Ioan I Vlase Laurian L Dragos Nicolae N Toma Vlad Alexandru VA Licarete Emilia E Banciu Manuela M

Cancer science 20200214 4

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 agg ...[more]

PMID: 31960547

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Project description:BackgroundDespite the introduction of several novel therapeutic approaches that improved survival, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease. Herein we report the synergistic antitumor interaction between two well-known drugs used for years in clinical practice, the antiepileptic agent with histone deacetylase inhibitory activity valproic acid and the cholesterol lowering agent simvastatin, in mCRPC models.MethodsSynergistic anti-tumor effect was assessed on PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells, by calculating combination index (CI), caspase 3/7 activation and colony formation assays as well as on tumor spheroids and microtissues scored with luminescence 3D-cell viability assay. Cancer stem cells (CSC) compartment was studied evaluating specific markers by RT-PCR, western blotting and flow cytometry as well as by limiting dilution assay. Cholesterol content was evaluated by 1H-NMR. Overexpression of wild-type YAP and constitutively active YAP5SA were obtained by lipofectamine-based transfection and evaluated by immunofluorescence, western blotting and RT-PCR. 22Rv1 R_39 docetaxel resistant cells were selected by stepwise exposure to increasing drug concentrations. In vivo experiments were performed on xenograft models of DU145R80, 22Rv1 parental and docetaxel resistant cells, in athymic mice.ResultsWe demonstrated the capacity of the combined approach to target CSC compartment by a novel molecular mechanism based on the inhibition of YAP oncogene via concurrent modulation of mevalonate pathway and AMPK. Because both CSCs and YAP activation have been associated with chemo-resistance, we tested if the combined approach can potentiate docetaxel, a standard of care in mCRCP treatment. Indeed, we demonstrated, both in vitro and in vivo models, the ability of valproic acid/simvastatin combination to sensitize mCRPC cells to docetaxel and to revert docetaxel-resistance, by mevalonate pathway/YAP axis modulation.ConclusionOverall, mCRPC progression and therapeutic resistance driven by CSCs via YAP, can be tackled by the combined repurposing of two generic and safe drugs, an approach that warrants further clinical development in this disease.

Dataset Information

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

Publications

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

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